Osteoporosis is a metabolic bone disorder that affects both sexes and is the most common cause of fractures. Osteoporosis therapies primarily inhibit osteoclast activity, and are seldom designed to trigger new bone growth thereby frequently causing severe systemic adverse effects. Physiologically, the intracellular redox state depends on the ratio of pro-oxidants, oxidizing agents (reactive oxygen species, ROS) and antioxidants. ROS is the key contributor to oxidative stress in osteoporosis as changes in redox state are responsible for dynamic bone remodeling and bone regeneration. Imbalances in ROS generation vs. antioxidant systems play a pivotal role in pathogenesis of osteoporosis, stimulating osteoblasts and osteocytes towards osteoclastogenesis. ROS prevents mineralization and osteogenesis, causing increased turnover of bone loss. Alternatively, antioxidants either directly or indirectly, contribute to activation of osteoblasts leading to differentiation and mineralization, thereby reducing osteoclastogenesis. Owing to the unpredictability of immune responsiveness and reported adverse effects, despite promising outcomes from drugs against oxidative stress, treatment in clinics targeting osteoclast has been limited. Nanotechnology-mediated interventions have gained remarkable superiority over other treatment modalities in regenerative medicine. Nanotherapeutic approaches exploit the antioxidant properties of nanoparticles for targeted drug delivery to trigger bone repair, by enhancing their osteogenic and anti-osteoclastogenic potentials to influence the biocompatibility, mechanical properties and osteoinductivity. Therefore, exploiting nanotherapeutics for maintaining the differentiation and proliferation of osteoblasts and osteoclasts is quintessential.

C1q nephropathy is a rare glomerular disease. Clinical presentation is diverse and ranges from asymptomatic hematuria or proteinuria to symptoms and signs of nephrotic/nephritic syndrome. On light microscopy, it can be classified into two subtypes: minimal change disease (MCD)/focal segmental glomerulosclerosis (FSGS) group and immune complex mediated proliferative glomerulonephritis group. A case of a 19-year-old male patient presenting nausea and decreased appetite will be reported. The labs showed severe nephrotic syndrome and a progressive kidney injury over a few months that were never diagnosed. The immune workup came back negative. The patient mentioned that he was taking protein shakes a few months earlier for bettering his physical fitness. A renal biopsy was done and showed a major reduction in renal mass and C1q nephropathy. He received steroids without any improvement. He was started on hemodialysis afterward then got transplanted 8 months later. In front of this rapid deterioration, FSGS might be the underlying etiology rather than MCD. Further studies are warranted to establish a connection between protein supplements, and progression of kidney disease.

The brain and gut are connected both physically and biochemically. The gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems, the enteric nervous system and vagus nerve, and the gut microbiome. It can influence brain function and even behavior, suggesting that dietary interventions may help enhance and protect mental health and cognitive performance. This review focuses on the role of the microbiome and its metabolites in sleep regulation, neurodegenerative disorders, mechanisms of stress, and mood. It also provides examples of nutritional interventions which can restore healthy gut microbiota and aid with risk reduction and management of many disorders related to mental and cognitive health. Evidence suggests a shift in the gut microbiota towards a balanced composition could be a target to maintain brain health, reduce stress and improve quality of life.

Chronic kidney disease (CKD) is a major health problem but there are many modalities to prevent and manage CKD progression. Diet is one of these factors, which needs to be evaluated more. Adenine is a water-soluble nucleoprotein that exists in both vegetables and animal foods, which triggers and aggravates fibrosis process besides other metabolic derangements such as diabetes mellitus affection that accelerates glomerular filtration rate decline rapidly.

Retroelements are mobile genomic components requiring an RNA intermediate which is reverse-transcribed into complementary DNA for transposition. Human genome contains a vast amount of retroelements including retrotransposons and endogenous retroviruses. These elements are categorized according to presence or absence of long terminal repeats, LTRs or non-LTRs, as well as autonomous and non-autonomous according to involvement of reverse transcriptase. The retroelements have been accumulated in mammalian genomes over all evolutionary times through vertical transmission, and many of them were inactivated through accumulation of mutations. However, the retroelements entered into genome within the last 200,000 years are mostly functional. Some of the active retroelements are associated with varying autoimmune diseases because anti-retroelement antibodies might cross-react with other proteins in the human body. For instance, autoimmunity and inflammation could be stimulated by increased expression of long interspersed element 1 (LINE-1 or L1) or decreased L1 degradation. Different regulation of L1 expression might be related to the genetic and sex-related variations or environmental factors. Activation of retroelements is also controlled by epigenetic silencing mechanisms such as histone modification. Elevated levels of L1 retroelements could trigger the production of type I interferon, a crucial innate defense mechanism in mammals against viruses, and systemic autoimmune response is induced. Loss-of-function in some deoxyribonucleases (DNases) such as three prime repair exonuclease 1 that degrades reverse-transcribed DNA is also related to autoimmune diseases. Additionally, human endogenous retroviruses also play a role in autoimmune diseases. Involvement of retroelements in autoimmune disorders is exemplified with three diseases, i.e. systemic lupus erythematosus, Aicardi–Goutières syndrome, and multiple sclerosis.

Chronic kidney disease (CKD) is a worldwide public health issue and has ultimately progressed to an end-stage renal disease that requires life-long dialysis or renal transplantation. However, the underlying molecular mechanism of these pathological development and progression remains to be fully understood. The human gut microbiota is made up of approximately 100 trillion microbial cells including anaerobic and aerobic species. In recent years, more and more evidence has indicated a clear association between dysbiosis of gut microbiota and CKD including immunoglobulin A (IgA) nephropathy, diabetic kidney disease, membranous nephropathy, chronic renal failure and end-stage renal disease. The current review describes gut microbial dysbiosis and metabolites in patients with CKD thus helping to understand human disease. Treatment with prebiotics, probiotics and natural products can attenuate CKD through improving dysbiosis of gut microbiota, indicating a novel intervention strategy in patients with CKD. This review also discusses therapeutic options, such as prebiotics, probiotics and natural products, for targeting dysbiosis of gut microbiota in patients to provide more specific concept-driven therapy strategy for CKD treatment.

Around the world, more than 6.2 million individuals have died as a result of coronavirus disease 2019 (COVID-19). According to a recent survey conducted among immunologists, epidemiologists, and virologists, this disease is expected to become endemic. This implies that the disease could have a continuous presence and/or normal frequency in the population. Pharmacological interventions to prevent infection, as well as to treat the patients at an early phase of illness to avoid hospitalization are essential additions to the vaccines. Taurine is known to inhibit the generation of all inflammatory mediators linked to the cytokine storm. It can also protect against lung injury by suppressing increased oxidants production and promoting the resolution of the inflammatory process. Neutrophil lactoferrin degranulation stimulated by taurine may have antiviral effects against SARS-CoV-2, limiting viral replication. It is hypothesized that if taurine is administered early in the onset of COVID-19 disease, it may stop the cytokine storm from progressing, lowering morbidity and mortality.

The human body contains trillions of microbes which generally live in symbiosis with the host. The interaction of the gut microbiome with elements of the host immune system has far-reaching effects in the development of normal gut and systemic immune responses. Disturbances to this intricate relationship may be responsible for a multitude of gastrointestinal and systemic immune mediated diseases. This review describes the development of the gut microbiome and its interaction with host immune cells in both health and disease states.

Cardiovascular diseases are among the leading causes of death worldwide, imposing major health threats. Reactive oxygen species (ROS) are one of the most important products from the process of redox reactions. In the onset and progression of cardiovascular diseases, ROS are believed to heavily influence homeostasis of lipids, proteins, DNA, mitochondria, and energy metabolism. As ROS production increases, the heart is damaged, leading to further production of ROS. The vicious cycle continues on as additional ROS are generated. For example, recent evidence indicated that connexin 43 (Cx43) deficiency and pyruvate kinase M2 (PKM2) activation led to a loss of protection in cardiomyocytes. In this context, a better understanding of the mechanisms behind ROS production is vital in determining effective treatment and management strategies for cardiovascular diseases.

A case of combined acute and chronic liver injury related to consumption of multi-ingredient nutritional oral supplements containing Aloe Vera gel and vitamin A among other vitamins, minerals and dietary elements such as fish and calamari oil in a 59-year-old female with unexplained hypertransaminasemia is reported. A unique complex liver injury was diagnosed on liver biopsy combining histological features of protracted acute hepatitis, mild manifestation of hypervitaminosis A and lipogranulomatous reaction attributed to Aloe Vera, vitamin A and lipids, respectively. Normalization of liver tests was achieved after discontinuation of all nutritional supplements. Updated Roussel Uclaf Causality Assessment Method (RUCAM) score (+8, probable) further supported herb-induced liver injury. The present case highlights the increasing incidence of complex histological liver injury linked to the constantly growing consumption of multi-ingredient dietary supplements and alternative medications.

Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) molecule approved for the treatment of both type 2 diabetes (T2D) and obesity. Semaglutide has a greater impact on glycated haemoglobin (HbA1c) reduction, compared to other GLP-1 RAs, and is the first molecule of this class available in oral formulation for T2D therapy, representing a useful option for subjects and physicians less prone to start an injective drug. Interestingly, due to its remarkable effects on weight reduction, higher than other GLP-1 RAs and very close to bariatric surgery, semaglutide is designated to change the approach to obesity therapy also in the subject not affected by diabetes. In addition to these favorable features, semaglutide, similarly to other GLP-1 RAs, offers beneficial effects on cardio-vascular (CV), renal, and liver protection, making this molecule an advantageous choice in the therapeutic management of “diabesity” (coexistence of both diabetes and obesity) and its co-morbidity.

Melatonin is the primary hormone of the pineal gland that is secreted at night. It regulates many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. The precise functions of melatonin are mediated by guanosine triphosphate (GTP)-binding protein (G-protein) coupled melatonin receptor 1 (MT1) and MT2 receptors. However, nuclear receptors are also associated with melatonin activity. Circadian rhythm disruption, shift work, and light exposure at night hamper melatonin production. Impaired melatonin level promotes various pathophysiological changes, including cancer. In our modern society, breast cancer is a serious problem throughout the world. Several studies have been indicated the link between low levels of melatonin and breast cancer development. Melatonin has oncostatic properties in breast cancer cells. This indolamine advances apoptosis, which arrests the cell cycle and regulates metabolic activity. Moreover, melatonin increases the treatment efficacy of cancer and can be used as an adjuvant with chemotherapeutic agents.

T cells play a central role in anti-tumor immunity, and reactive oxygen species (ROS) lie at the crossroad on the anti-tumor T cell responses. To activate efficient T cell immunity, a moderate level of ROS is needed, however, excessive ROS would cause toxicity to the T cells, because the improper level leads to the formation and maintenance of an immunosuppressive tumor microenvironment. Up to date, strategies that modulate ROS, either increasing or decreasing, have been widely investigated. Some of them are utilized in anti-tumor therapies, showing inevitable impacts on the anti-tumor T cell immunity with both obverse and reverse sides. Herein, the impacts of ROS-increasing and ROS-decreasing treatments on the T cell responses in the tumor microenvironment are reviewed and discussed. At the same time, outcomes of combination immunotherapies are introduced to put forward inspirations to unleash the potential of immunotherapies.

Since obesity is one of the main factors in the development of insulin resistance (IR) and is also associated with increased oxidative stress (OxS) rate, this study aims to review the published literature to collate and provide a comprehensive summary of the studies related to the status of the OxS in the pathogenesis of obesity and related IR. OxS represents an imbalance between the production of reactive oxygen and nitrogen species (RONS) and the capacity of the antioxidant defense system (AOS) to neutralize RONS. A steady-state of RONS level is maintained through endogenous enzymatic and non-enzymatic AOS components. Three crucial enzymes, which suppress the formation of free radicals, are superoxide dismutases, catalases, and glutathione peroxidases. The second line of AOS includes non-enzymatic components such as vitamins C and E, coenzyme Q, and glutathione which neutralizes free radicals by donating electrons to RONS. Emerging evidence suggests that high RONS levels contribute to the progression of OxS in obesity by activating inflammatory pathways and thus leading to the development of pathological states, including IR. In addition, decreased level of AOS components in obesity increases the susceptibility to oxidative tissue damage and further progression of its comorbidities. Increased OxS in accumulated adipose tissue should be an imperative target for developing new therapies in obesity-related IR.

The redox status in pathogenesis is critically regulated by careful balance between the generation of reactive oxygen species (ROS) and their elimination. Increased ROS level above the cellular tolerability threshold results in apoptotic or necrotic cell death. ROS belongs to a group of highly reactive compounds that have evolved to play key roles in cellular signaling pathways. It’s widely assumed that a reasonable amount of ROS is essential for a variety of biological processes. Elevated levels of ROS are known to cause various pathologic conditions like neurological disorders, cardiovascular conditions, inflammation, autoimmunity, and cancer. ROS is well known to initiate and assist in progression of tumor by promoting proliferation and survival of cancer cells and thus facilitates pro-tumorigenic signaling in tumor microenvironment. As cancer cells become more resilient to the effects of ROS manipulating drugs, increased antioxidant capacity attenuates their susceptibility to cancer treatment. Excessive environmental stress, on the other hand, can cause cancer cells to die. This review summarizes various molecular mechanisms including the role of checkpoint inhibitors that can be harnessed to develop effective therapeutic strategies for targeting ROS related signaling in cancer.

Cancer is the leading cause of mortality worldwide, which necessitates our consideration related to novel treatment approach. Tumor cells at the tumor microenvironment (TME), regulate a plethora of key mechanistic signaling pathways that obstruct antitumor immune responses by immune suppression, immune resistance or acquired immune tolerance. The present therapeutic regimes are provided independently or in combination, or as immunotherapies for cancer immune targeting. Immunotherapy has altered the arena of oncology and patient care. By using the host immune system, the immunostimulatory molecules can exert a robust, personalized response against the patient’s own tumors. Alternatively, tumors may exploit these strategies to escape immune recognition, and accordingly, such mechanisms represent chances for immunotherapy intervention. Nonetheless, despite promising outcomes from immunotherapies in recurrent and metastatic cancers, immune-therapeutics in clinics have been limited owing to unpredictability in the produced immune response and reported instances of immune-related adverse effects. The unrealized potential of immunotherapies in cancer management maybe due to the obstacles such as heterogeneous nature, multiple targets, patients’ immune response, specificity for cancer or variability in response generation in toxicity levels, delivery and cost related to therapeutics etc. Further revolutionary trends related to immunotherapies are noticeable with slower progress for cancer management. Recent advances in nanomedicine strategize to ameliorate the lacuna of immunotherapy as it relies on the inherent biophysical characteristics of nanocarriers: size, shape, surface charge and multifunctionality and exploiting them as first line therapy for delivery of biomolecules, single checkpoint inhibitors and for imaging of TME. Therefore, nano-assisted immunotherapies can boost the immunotherapeutic approach, overcoming factors that are with imminent potential risks related to it, thereby significantly improving the survival rate associated with it in cancer patients. Nanotechnology is anticipated to overcome the confines of existing cancer immunotherapy and to successfully combine various cancer treatment modes.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a fundamental role in regulating endothelial function and vascular tone in the physiological conditions of a vascular system. However, oxidative stress has detrimental effects on human health, and numerous studies confirmed that high ROS/RNS production contributes to the initiation and progression of cardiovascular diseases. The antioxidant defense has an essential role in the homeostatic functioning of the vascular endothelial system. Endogenous antioxidative defense includes various molecules and enzymes such as superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. Together all these antioxidative enzymes are essential for defense against harmful ROS features. ROS are mainly generated from redox-active compounds involved in the mitochondrial respiratory chain. Thus, targeting antioxidative enzymes and mitochondria oxidative balance may be a promising approach for vascular diseases occurrence and treatment. This review summarized the most recent research on the regulation of antioxidative enzymes in vascular diseases.

Pseudoexfoliation (PXF) syndrome is an important public health concern requiring individual population level analysis. Disease prevalence differs by geographic location and ethnicity, and has environmental, demographic, genetic, and molecular risk factors have been demonstrated. Epidemiological factors that have been associated with PXF include age, sex, environmental factors, and diet. Genetic and molecular components have also been identified that are associated with PXF. Underserved populations are often understudied within scientific research, including research about eye disease such as PXF, contributing to the persistence of health disparities within these populations. In each population, PXF needs may be different, and by having research that identifies individual population needs about PXF, the resources in that population can be more efficiently utilized. Otherwise, PXF intervention and care management based only on the broadest level of understanding may continue to exacerbate health disparities in populations disproportionally burdened by PXF.

The processes of cancer and embryonic development have a partially overlapping effect. Several transcription factor families, which are highly conserved in the evolutionary history of biology, play a key role in the development of cancer and are often responsible for the pivotal developmental processes such as cell survival, expansion, senescence, and differentiation. As an evolutionary conserved and ubiquitously expression protein, CCCTC-binding factor (CTCF) has diverse regulatory functions, including gene regulation, imprinting, insulation, X chromosome inactivation, and the establishment of three-dimensional (3D) chromatin structure during human embryogenesis. In various cancers, CTCF is considered as a tumor suppressor gene and plays homeostatic roles in maintaining genome function and integrity. However, the mechanisms of CTCF in tumor development have not been fully elucidated. Here, this review will focus on the key roles of CTCF in cancer evolution and development (Cancer Evo-Dev) and embryogenesis.

Tissue-resident macrophages play critically important roles in host homeostasis and pathogenesis of diseases, with the functions of phagocytosis, metabolism, and immune modulation. Recently, two research studies accomplished by a collaborated group of researchers showed that there are two populations of liver resident Kupffer cells (KCs), including a major cluster of differentiation 206 low expression (CD206^low)endothelial cell-selective adhesion molecule negative (ESAM⁻) population (KC1) and a minor CD206^highESAM⁺ population (KC2). Both KC1 and KC2 express KC markers, such as C-type lectin domain family 4 member F (CLEC4F) and T-cell membrane protein 4 (Tim4). In fatty liver, the frequency of KC2 was increased, and those KC2 expressed some markers like liver sinusoidal endothelial cells (LSECs), such as CD31 and ESAM. In addition, KC2 population had a relatively higher expression of CD36, as fatty acid transporter, which was implicated in the production of reactive oxygen species (ROS) and lipid peroxidation. Furthermore, this collaborated group also showed that KC2 can cross-present hepatocellular antigens to prime antiviral function of CD8⁺ T cells by sensing interleukin-2 (IL-2) in hepatitis B virus (HBV) replication-competent transgenic mice. Increasing evidence shows that targeting hepatic macrophages can prevent and reverse non-alcoholic fatty liver disease (NAFLD), with a new suggested name metabolic dysfunction-associated fatty liver disease (MAFLD) to include metabolic dysfunction-associated fatty liver diseases, such as viruses and alcohol. In summary, differentiating specific populations of hepatic macrophages is critically important for the treatment of MAFLD or NAFLD, and their overlaps. Markers specifically expressed on sub-types of hepatic macrophages may be applied for liver disease diagnosis.

Non-alcoholic fatty liver disease (NAFLD) as the most common chronic liver disease poses a significant impact on public healthcare and economic risk worldwide. As a multifactorial disease, NAFLD is usually associated with many comorbidities such as obesity, insulin resistance, hypertension, hyperlipidemia, diabetes, and cardiovascular disease. Without effectively preventive intervention, the advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). However, there is no approved therapeutic treatment. Excessive fat accumulation in the liver is the hallmark of NAFLD, which can lead to mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Dysfunction of two organelles also induces the upregulation of reactive oxygen species (ROS), activation of the unfolded protein response (UPR), and disruption of calcium transport, which promote NAFLD progression. Herein, this review summarized the current understanding of the roles of mitochondrial dysfunction and ER stress in the pathogenesis of NAFLD. Specifically, this review focused on the key molecules associated with the ER-mitochondria communication and different treatment options by targeting ER stress and mitochondrial dysfunction to treat NAFLD or NASH. Clinical trials to evaluate the therapeutic efficacy of representative agents, such as natural products, metabolites, and modulators of stress, have been reviewed and analyzed. Overall, recent findings suggest that targeting ER stress and mitochondrial dysfunction holds a promise for NAFLD treatment.

Antenatal screening for hepatitis B surface antigen seropositivity is widely adopted to identify pregnant women with chronic hepatitis B virus (HBV) infection in order to target their newborn infants for combined passive-active neonatal immunization to prevent the maternal-to-child transmission of HBV. It is less certain whether the presence of chronic HBV infection in these largely asymptomatic women could impact their pregnancy outcome. There is now gathering information in the literature, though sometimes conflicting, on the obstetric implications of chronic HBV infection. The conflicting data is most probably related to confounding factors such as the immunological phase of chronic HBV infection, viral genotype and activity, presence of hepatic inflammation and other co-existing liver disorders such as non-alcoholic fatty liver disease, and coinfection with other virus such as hepatitis C virus and micro-organisms, which are usually not examined, but which could have made significant influence on the occurrence of many of the pregnancy complications and adverse fetal and neonatal outcome. For pregnancy complications, the evidence suggests association with increased gestational diabetes mellitus, preterm birth, intrahepatic cholestasis of pregnancy, caesarean delivery, and postpartum haemorrhage, probably increased placental abruption and prelabour rupture of the membranes, and no effect or a reduction in the hypertensive disorders of pregnancy, especially preeclampsia. For perinatal outcome, there may be increased miscarriage and fetal malformations, and increase in both low birthweight and large-for-gestational age/macrosomic infants, as well as increased intrauterine fetal demise/stillbirth and fetal distress. However, most studies have not elaborated on the mechanisms or explanations of many of the adverse outcomes. Taken together, maternal chronic HBV infection increases the risk of adverse obstetric outcome overall, but further prospective studies are warranted to elucidate the reasons and mechanisms of, and with a view to mitigating, these adverse obstetric outcomes.

According to the Global Cancer Observatory (GLOBOCAN) 2020, colorectal carcinoma (CRC) was the second leading cause of cancer death globally. Current literature utilizes reported databases such as Surveillance, Epidemiology, and End Results (SEER) to better understand the epidemiology of CRC. The global cancer observatory’s “Cancer Tomorrow” data visualization tools were used to predict the future incidence and mortality of colorectal cancers until 2030 as a guided tool to look over ways to reduce incidence by controlling risk factors of CRC. The total number of CRC is expected to rise by 2030, with a percent change of 17.3%. The expected percent change in colon cancer is more than rectal cancer (19.8% vs. 11.6%). The estimated number of deaths secondary to CRC is expected to increase in 2030, an estimated percent change of 22.2%. The incidence and mortality rate was higher in men vs. women; however, the gap seems to be closing on trend analysis. Major risk factors for CRC include familial syndromes, family history, race, gender, obesity, diet, alcohol, and smoking. Risk can be reduced by exercise and dietary changes, fiber intake, vitamin D, calcium, and minerals. Individualized screening based on age, gender, and additional risk factors could be an option that needs further comparative data to propose a definitive benefit over established screening guidelines.

Excessive reactive oxygen species (ROS) may cause oxidative stress which is involved in aging and in the pathogenesis of various human diseases. Whereas unregulated levels of the ROS may be harmful, regulated basal level of ROS is even necessary to support cellular functions as a second messenger for homeostasis under physiological conditions. Therefore, redox medicine could develop as a new therapeutic concept for human health-benefits. Here, we introduce the involvement of ROS on the crossroads of stemness, senescence, and carcinogenesis in a stem cell and cancer cell biology. Amazingly, the anti-proliferative (APRO) family anti-proliferative proteins characterized by immediate early growth responsive genes may also be involved in the crossroads machinery. The biological functions of APRO proteins (APROs) seem to be quite intricate, however, which might be a key modulator of microRNAs (miRNAs). Given the crucial roles of ROS and APROs for pathophysiological functions, upcoming novel therapeutics should include vigilant modulation of the redox state. Next generation of medicine including regenerative medicine and/or cancer therapy will likely comprise strategies for altering the redox environment with the APROs via the modulation of miRNAs as well as with the regulation of ROS of cells in a sustainable manner.

Recently, Arrese and Colleagues have published a review article entitled, “Insights into Nonalcoholic Fatty-Liver Disease (NAFLD) Heterogeneity” (Semin Liver Dis. 2021;41:421–34. doi: 10.1055/s-0041-1730927). This milestone publication clearly and exhaustively explains the multitude of pathogenic pathways involved in the development and progression of disease eventually conducive to heterogeneous clinical phenotypes and different disease outcomes. The present commentary first briefly discusses the biological grounds of NAFLD heterogeneity and then illustrates the work by Arrese et al. In conclusion, the presently adopted nomenclatures appear inadequate in rendering the complexity of disease in the individual patient. In order to adopt the principles of personalized care, what remains to be done is to propose and validate a simple and accurate classification system. This should give full consideration to the principal disease modifiers and should shape a scheme to be adopted in both clinical practice and in the research arena. Care should be taken to not neglect the systemic nature of disease.

Pregnancy increases the risk of common vascular events and also the rarer events like aortic dissection (AD)/aortic rupture and this is even more pronounced in patients with predisposing aortopathies. AD was found to occur in 0.0004% of all pregnancies, and it is more pronounced in patients with underlying connective tissue disorders. The normal hemodynamic changes on a weak aorta will lead to AD and/or rupture, more so with increase in the period of gestation. Hence the haemodynamic and hormonal changes during pregnancy make pregnancy itself a risk factor for AD. It is advised that women with Marfan syndrome who are planning pregnancy should go through prophylactic aortic repair if the diameter of the ascending aorta exceeds 4 cm. Pre-pregnancy counselling is very important in these patients and must include complete history taking, including family history, physical examination and advanced aortic imaging. There is a general consensus among various authors advising against surgery during pregnancy in stable patients due to increased maternal and fetal morbidity but it is justified if the condition is refractory to medical management or in life threatening stage like acute AD. Though the incidence of aortopathy in pregnancy is rare, there is a high maternal and fetal mortality associated with this condition.

With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.

The development of heart failure under various pathological conditions such as myocardial infarction (MI), hypertension and diabetes are accompanied by adverse cardiac remodeling and cardiac dysfunction. Since heart function is mainly determined by coordinated activities of different subcellular organelles including sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils for regulating the intracellular concentration of Ca²⁺, it has been suggested that the occurrence of heart failure is a consequence of subcellular remodeling, metabolic alterations and Ca²⁺-handling abnormalities in cardiomyocytes. Because of the elevated plasma levels of angiotensin II (ANG II) due to activation of the renin-angiotensin system (RAS) in heart failure, we have evaluated the effectiveness of treatments with angiotensin converting enzyme (ACE) inhibitors and ANG II type 1 receptor (AT1R) antagonists in different experimental models of heart failure. Attenuation of marked alterations in subcellular activities, protein content and gene expression were associated with improvement in cardiac function in MI-induced heart failure by treatment with enalapril (an ACE inhibitor) or losartan (an AT1R antagonist). Similar beneficial effects of ANG II blockade on subcellular remodeling and cardiac performance were also observed in failing hearts due to pressure overload, volume overload or chronic diabetes. Treatments with enalapril and losartan were seen to reduce the degree of RAS activation as well as the level of oxidative stress in failing hearts. These observations provide evidence which further substantiate to support the view that activation of RAS and high level of plasma ANG II play a critical role in inducing subcellular defects and cardiac dysfunction during the progression of heart failure.

Acute aortic syndromes, including aortic dissection (AD), are rare. The AD detection risk score (ADDRS) and associated investigation pathway were developed to reduce missed diagnosis of AD. The methodology for its development was sub-optimal and it has not been robustly validated in the emergency department chest pain population. Recent research suggests that it will drive over-investigation and that the risks of missed diagnosis may not be in balance with the risks of the testing strategy. There are serious doubts about whether the score and investigation pathway are fit for purpose.

Submucosal esophageal hematoma is an uncommon clinical complication of anticoagulation. Current literature is scarce regarding presentation and management in acute submucosal hematomas in critically ill patients. Patients often present with retrosternal chest pain, making the diagnosis challenging due to overlap with common presentations of cardiopulmonary disorders. A high degree of suspicion is necessary in sedated patients. Several factors contribute to its etiology, and diagnosis often requires invasive techniques like endoscopy. However, management is usually supportive and aimed at its underlying cause. This is a case of a 68-year-old female who developed submucosal esophageal hematomas following anticoagulation for subarachnoid hemorrhage-related delayed neurological deficits in the intensive care unit.

The term non-alcoholic fatty liver disease (NAFLD) appears unfitting both in adults and in children. As obesity and metabolic syndrome play a relevant pathogenic role, an international group of adults’ liver disease experts has proposed to rename this condition metabolic (dysfunction)-associated fatty liver disease (MAFLD). While this new more appropriate and useful definition has mostly been met with good reactions in adults, it may present a tangled path in pediatrics. Here we further stress the recommendations of the North American and the European Societies for Pediatric Gastroenterology, Hepatology and Nutrition that a hyperechogenic liver in a child affected by obesity or overweight with chronically elevated liver enzymes should not be assumed to have NAFLD only. Especially in those patients who are not in the classic age range or who have particularly severe laboratory anomalies, other genetic, metabolic (inborn errors of metabolism, IEM), endocrine, intestinal and hepatic pediatric-onset conditions, should in fact be excluded, particularly when response to a weight loss trial is not available. The term pediatric fatty liver disease (PeFLD) with three subtypes [1. contextual diagnosis of an IEM; 2. metabolic (dysfunction)-associated fatty liver; 3. unknown cause of fatty liver] has recently been proposed aiming to separate true MAFLD from IEM and/or the other above mentioned conditions, which may be rare when considered individually but represent a large group when considered collectively. Although the cost-effectiveness ratio of this attitude is still indeterminate, it is likely that the advantage of the early identification of a specifically treatable pediatric-onset liver disease associated to/mimicking MAFLD would be rewarding.

Central pontine myelinolysis (CPM) is a rare manifestation of osmotic demyelination syndrome (ODS) which involves the pons and causes significant morbidity and mortality. CPM usually occurs in the setting of rapid correction of severe chronic hyponatremia. A rare case of CPM due to hyperglycemia in a 27-year-old man with type 1 diabetes is reported. During the patient’s hospitalization, his plasma glucose level showed a wide variability ranging from 38 mg/dL to 530 mg/dL; while plasma sodium level was constantly normal. At computed tomography (CT) scans, areas of hypodensity with a hyperdense ring were identified in the anterior part of the pons. At magnetic resonance imaging (MRI) scan, pontine abnormalities compatible with CPM were observed. According to laboratory tests, we concluded that CPM resulted from rapid and wide shifts in osmolar gradient owing to variability in plasma glucose levels. While universally recognized in several clinical settings, CPM is rarely observed in diabetic patients. Our report supports the notion that hyperosmolarity per se plays a key role in the pathogenesis of CPM, which may occur independently of sodium abnormalities.

Obesity and metabolic syndrome are conditions at high risk for the development of complications such as type 2 diabetes mellitus, atherosclerotic cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). The growing prevalence of NAFLD has recently raised attention in the clinical practice, due to the worsening prognosis observed in the affected patients. Sex hormones abnormalities, commonly found in subjects suffering from obesity and metabolic syndrome, have been recently hypothesized to be directly involved in the physiopathology of obesity-related comorbidites; however, their role in the pathogenesis of NAFLD remains unclear. In this review of the available literature, a summary of the knowledge about the role of sex steroids abnormalities in the risk of developing NAFLD was performed, mentioning the possible clinical implications for therapy.

The adrenal cortex plays a key role in the regulation of metabolism, salt and water homeostasis and sex differentiation by synthesizing glucocorticoid, mineralocorticoid and androgen hormones. Evidence exists that angiotensin II regulates adrenocortical function and it has been contended that angiotensin peptides of the non-canonical branch of the renin angiotensin system (RAS) might also modulate steroidogenesis in adrenals. Thus, the aim of this review is to examine the role of the RAS, and particularly of the angiotensin peptides and their receptors, in the regulation of adrenocortical hormones with particular focus on aldosterone production.

The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher brain functions, including cognition, memory, depression and anxiety. For many years, angiotensin II (Ang II) has been considered the major bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects to those exerted by Ang II. Today, it is considered that the RAS is primarily constituted by two opposite arms. The pressor arm is composed by Ang II and the Ang II type 1 (AT1) receptor (AT1R), which mediates the vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory effects of the RAS. The depressor arm is mainly composed by Ang-(1-7), its Mas receptor (MasR) which mediates the depressor, vasodilatory, antiproliferative, antioxidant and anti-inflammatory effects of Ang-(1-7) and the AT2 receptor (AT2R), which opposes to the effects mediated by AT1R activation. Central Ang-(1-7) is implicated in the control of the cardiovascular function, thus participating in the regulation of blood pressure. Ang-(1-7) also exerts neuroprotective actions through MasR activation by opposing to the harmful effects of the Ang II/AT1R axis. This review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain, its main neuroprotective effects and the evidence regarding its involvement in the pathophysiology of several diseases at cardiovascular and neurological level.

Immunotherapy is a unique approach to treat cancer that targets tumours besides triggering the immune cells. It attempts to harness the supremacy and specificity of immune cells for the regression of malignancy. The key strategy of immunotherapy is that it boosts the natural defence and manipulates the immune system at both cellular and molecular levels. Long-lasting anti-tumour response, reduced metastasis, and recurrence can be achieved with immunotherapy than conventional treatments. For example, targeting cytotoxic T-lymphocyte antigen-4 (CTLA4) by monoclonal antibody is reported as an effective strategy against cancer progression in vivo and chimeric antigen receptor (CAR) modified T-cells are known to express a stronger anti-tumour activity. CTLA4 and CAR are, therefore, beneficial in cancer immunotherapy; however, in clinical settings, both are expensive and cause adverse side effects. Nanomaterials have augmented advantages in cancer immunotherapy, besides their utility in effective delivery and diagnostics. In particular, materials based on lipids, polymers, and metals have been sought-after for delivery technologies. Moreover, the surface of nanomaterials can be engineered using ligands, antigens, and antibodies to target immune cells. In this sense, checkpoint inhibitors, cytokines, agonistic antibodies, surface receptors, and engineered T-cells are promising to regulate the immune system against tumours. Therefore, emerging nanomaterials that can be used for the treatment of cancer is the prime focus of this review. The correlation of mode of administration and biodistribution of various nanomaterials is reviewed here. Besides, the acute and chronic side effects and outcome of clinical trials in the context of cancer immunotherapy are discussed.

Some have said that it is inappropriate and perhaps impossible to consider wave and Windkessel phenomena simultaneously. For 50 years, arterial hemodynamics has been dominated by the frequency-domain “impedance analysis” in which it was assumed that all variations in aortic pressure and flow were caused only by forward- and backward-going waves. This paper is a review of the results of incorporating the effects of Frank’s Windkessel. We have taken the view that measured aortic pressure is the sum of a Windkessel component and forward-going and backward-going wave components. When the Windkessel component is initially subtracted out, the pattern of propagation and reflection of wave components becomes clear. Furthermore, this analysis obviates the implications of impedance analysis that have not been explained satisfactorily.

Vascular aging, aortic stiffness and hypertension are mechanistically interrelated. The perspective presented here will focus mainly on the molecular mechanisms of age-associated increases in the stiffness of the vascular smooth muscle cell (VSMC). This review will highlight the mechanisms by which the VSMC contributes to disorders of vascular aging. Distinct functional sub-components of the vascular cell and the molecular mechanisms of the protein-protein interactions, signaling mechanisms and intracellular trafficking processes in the setting of the aging aorta will be detailed.

The limitations of current cancer treatments have stimulated the application of nanotechnology to develop more effective and safer cancer therapies. Remarkable progress has been made in the development of nanomedicine to overcome issues associated with conventional cancer treatment, including low drug solubility, insufficient targeting, and drug resistance. The modulation of nanoparticles allows the improvement of drug pharmacokinetics, leading to improved targeting and reduced side effects. In addition, nanoparticles can be conjugated to ligands that specifically target cancer cells. Furthermore, strategies that exploit tumor characteristics to locally trigger drug release have shown to increase targeted drug delivery. However, although some clinical successes have been achieved, most nanomedicines fail to reach the clinic. Factors that hinder clinical translation vary from the complexity of design, incomplete understanding of biological mechanisms, and high demands during the manufacturing process. Clinical translation might be improved by combining knowledge from different disciplines such as cell biology, chemistry, and tumor pathophysiology. An increased understanding on how nanoparticle modifications affect biological systems is pivotal to improve design, eventually aiding development of more effective nanomedicines. This review summarizes the key successes that have been made in nanomedicine, including improved drug delivery and release by polymeric nanoparticles as well as the introduction of strategies that overcome drug resistance. In addition, the application of nanomedicine in immunotherapy is discussed, and several remaining challenges addressed.

Nucleolin (NCL) is a multifunctional nucleolar phosphoprotein harboring critical roles in cells such as cell proliferation, survival, and growth. The dysregulation and overexpression of NCL are related to various pathologic and oncological indications. These characteristics of NCL make it an ideal target for the treatment of various cancers. AS1411 is a synthetic quadruplex-forming nuclease-resistant DNA oligonucleotide aptamer which shows a considerably high affinity for NCL, therefore, being capable of inducing growth inhibition in a variety of tumor cells. The high affinity and specificity of AS1411 towards NCL make it a suitable targeting tool, which can be used for the functionalization of therapeutic payload-delivery nanosystems to selectively target tumor cells. This review explores the advances in NCL-targeting cancer therapy through AS1411-functionalized delivery nanosystems for the selective delivery of a broad spectrum of therapeutic agents.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening drug reaction, which can affect multiple organs. Patients with DRESS syndrome and hepatic manifestations may present alterations ranging from mild hepatitis to acute liver failure. The diagnosis might be difficult, and the management of these patients is challenging. This report analyzes a series of five cases reporting the clinical presentation, which ranged from acute hepatitis to liver failure, and discussed their treatment.

In recent years, cancer immunotherapy has received unprecedented attention due to the clinical achievements. The applications of biomedical engineering and materials science to cancer immunotherapy have solved the challenges caused by immunotherapy to a certain extent. Among them, cell-derived vesicles are natural biomaterials chosen as carriers or immune-engineering in view of their many unique advantages. This review will briefly introduce the recent applications of cell-derived vesicles for cancer immunotherapy.

Patients submitted to liver transplantation (LT) are exposed to high risk of cardiovascular (CV) complications which are the main determinants of both short-term and long-term morbidity and mortality in LT. Non-alcoholic fatty liver disease (NAFLD) is a very frequent condition in general population and is associated with a high risk of cardiovascular disease (CVD) which represents the first cause of death of these patients. NAFLD is predicted to become the first indication to LT and nowadays is also frequently detected in patients submitted to LT for other indications. Thus, the risk of CVD in patients submitted to LT is forecasted to increase in the next years. In this review the extent of CV involvement in patients submitted to LT and the role of NAFLD, either recurring after transplantation or as de novo presentation, in increasing CV risk is analysed. The risk of developing metabolic alterations, including diabetes, hypertension, dyslipidemia and weight gain, all manifestations of metabolic syndrome, occurring in the first months after LT, is depicted. The different presentations of cardiac involvement, represented by early atherosclerosis, coronary artery disease, heart failure and arrhythmias in patients with NAFLD submitted to LT is described. In addition, the tools to detect cardiac alterations either before or after LT is reported providing the possibility for an early diagnosis of CVD and an early therapy able to reduce morbidity and mortality for these diseases. The need for long-term concerted multidisciplinary activity with dietary counseling and exercise combined with drug treatment of all manifestations of metabolic syndrome is emphasized.

Silent coronary artery disease (CAD) is one of the manifestations of heart disease that particularly affects subjects with type 2 diabetes mellitus (T2DM). From a clinical point of view, silent CAD represents a constant challenge for the diabetologist, who has to decide whether a patient could or could not be screened for this disease. In the present narrative review, several aspects of silent CAD are considered: the epidemiology of the disease, the associated risk factors, and main studies conducted, in the last 20 years, especially aimed to demonstrate the usefulness of the screening of silent CAD, to improve cardiovascular outcomes in type 2 diabetes.

Glycemic homeostasis is an essential mechanism for the proper working of an organism. However, balance in blood lipid and protein levels also plays an important role. The discovery of the hormone insulin and the description of its function for glycemic control made fundamental scientific progress in this field. However, since then our view of the problem has been deeply influenced only in terms of glucose and insulin (in an insulin-centric and glucose-centric way). Based on recent scientific discoveries, a fine and sophisticated network of hormonal and metabolic interactions, involving almost every apparatus and tissue of the human body, has been theorized. Efficient metabolic homeostasis is founded on these intricate interactions. Although it is still not fully defined, this complex network can undergo alterations that lead to metabolic disorders such as diabetes mellitus (DM). The endocrine pancreas plays a crucial role in the metabolic balance of an organism, but insulin is just one of the elements involved and each single pancreatic islet hormone is worthy of our concern. Moreover, pancreatic hormones need to be considered in a general view, concerning both their systemic function as direct mediators and as hormones, which, in turn, are regulated by other hormones or other substances. This more complex scenario should be taken into account for a better understanding of the pathophysiology and the therapeutic algorithms of DM. As a consequence, improvements in modern medicine could help to contemplate this new perspective. This review is focused on some aspects of gut-pancreas interaction, aiming to integrate this synergy into a wider context involving other organs and tissues.

This commentary is the product of a concerted effort to understand the needs, barriers, and gaps in the field of speech and language biomarkers for Alzheimer’s disease (AD). It distills interviews, surveys, and extensive correspondence with global leaders in the areas of dementia research, clinical trials, linguistics, and data analytics into an idealized clinical-study design for the harmonized collection of voice recordings. The ultimate goal of the effort is to democratize the ongoing speech and language analytics efforts by making such rich datasets available to the wider research ecosystem.

Technology in diabetes is rapidly evolving, with the aim of helping affected people to safely optimize their blood glucose control. New technologies are now considered as an essential tool for managing glycemia predominantly in people with type 1 diabetes, and clinical trials have demonstrated that in these subjects the use of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems are associated with improved glycemic control along with a better quality of life. Literature regarding technologies and type 2 diabetes is relatively lacking, but innovations may have an important role also in the management of these patients. Some studies in adults with type 2 diabetes have shown benefits with the use of CGM in terms of glycemic variability and improved therapeutic adjustments. Clinical trials about CSII and CGM use in type 2 diabetes may have some pitfalls and future studies are needed to assess how these advanced systems could improve clinical outcomes and also ensure cost-effectiveness in this population. In this narrative review, we aim to highlight the most relevant studies on this topic and to focus on the potential role of new technological devices in type 2 diabetes management.

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver alteration worldwide. It encompasses a spectrum of disorders that range from simple steatosis to a progressive form, defined non-alcoholic steatohepatitis (NASH), that can lead to advanced fibrosis and eventually cirrhosis and hepatocellular carcinoma. On liver histology, NASH is characterized by the concomitant presence of significant fat accumulation and inflammatory reaction with hepatocellular injury. Until now, liver biopsy is still required to differentiate simple steatosis from NASH and evaluate the degree of liver fibrosis. Unfortunately, this technique has well-known limitations, including invasiveness and expensiveness. Moreover, it may be biased by sampling error and intra- or inter-observed variability. Furthermore, due to the increasing prevalence of NAFLD worldwide, to program a systematic screening with liver biopsy is not imaginable. In recent years, different techniques were developed and validated with the aim of non-invasively identifying NASH and assess liver fibrosis degrees. The non-invasive tests range from simple blood-tests analyses to composite scores and complex imaging techniques. Nevertheless, even if they could represent cost-effective strategies for diagnosing NASH, advanced fibrosis and cirrhosis, their accuracy and consequent usefulness are to be discussed. With this aim, in this review the authors summarize the current state of non-invasive assessment of NAFLD. In particular, in addition to the well-established tests, the authors describe the future perspectives in this field, reporting the latest tests based on OMICS, gut-miocrobioma and micro-RNAs. Finally, the authors provide an accurate assessment of how these non-invasive tools perform in clinical practice depending on the clinical context, with the aim of giving the clinicians a useful tool to try to resolve the diagnostic conundrum of NAFLD.

The pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. The purpose of this paper was to review the current knowledge of these mechanisms in a unified manner. Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. This occurs due to an increase in the influx of FFAs from peripheral adipose tissue by the activation of hormone-sensitive lipase. In addition, there is de novo increased lipogenesis, a transcription factor, the sterols regulatory element-binding transcription factor 1c (SREBP-1c), which activates the expression of several genes strongly promotes lipogenesis by the liver and facilitate storage of triglycerides. Lipids accumulation in the liver induces a chronic stress in the endoplasmic reticulum of the hepatocytes. Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. In particular, the alteration of patatin-like phospholipase domain-containing protein 3 contributes to the susceptibility to NAFLD. Furthermore, the lipotoxicity of ceramides and diacylglycerol, well known in T2DM, triggers a chronic inflammatory process favoring the progression from hepatic steatosis to steatohepatitis. Reactive oxygen species produced by mitochondrial dysfunction trigger both liver inflammation and beta-cells damage, promoting the progression of both NAFLD and T2DM. The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. Future studies on the mechanisms will have to deepen the knowledge of the interaction between the two pathologies and should allow the identification of new therapeutic targets for the treatment of NAFLD, currently substantially absent.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver chronic disease worldwide. The pathogenesis of NAFLD is complex and involves many metabolic enzymes and multiple pathways. Posttranslational modifications of proteins (PMPs) added another layer of complexity to the pathogenesis of NAFLD. PMPs change protein properties and regulate many biological functions, including cellular localization, stability, intracellular signaling, and protein function. Lysine acetylation is a common reversible PMP that consists of the transfer of an acetyl group from acetyl-coenzyme A (CoA) to a lysine residue on targeted proteins. The deacetylation reaction is catalyzed by deacetylases called sirtuins. This review summarizes the role of acetylation in NAFLD with a focus on sirtuins 1 and 3.

Nonalcoholic fatty liver disease (NAFLD) is a serious condition that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is associated with metabolic syndrome (MetS) and all of its components. According to data, around 25–30% of population has NAFLD. Giving the growing incidence of MetS, obesity and diabetes mellitus type 2, NAFLD related terminal-stage liver disease is becoming prevailing indication for liver transplantation. In order to prevent terminal stage of this disease, it is crucial to determine those that are in risk group, to modify their risk factors and monitor their potential progression. In the absence of other causes of chronic liver disease, the prime diagnosis of NAFLD in daily clinical practice includes anamnesis, laboratory results (increased levels of aminotransferases and gammaglutamil transferases) and imaging methods. The biggest challenge with NAFLD patients is to differentiate simple steatosis from nonalcoholic steatohepatitis, and detection of fibrosis, that is the main driver in NAFLD progression. The gold standard for NAFLD diagnosis still remains the liver biopsy (LB). However, in recent years many noninvasive methods were invented, such as transient elastography (TE). TE (FibroScan®, Echosens, Paris, France) is used for diagnosis of pathological differences of liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). Investigations in the last years have confirmed that elastographic parameters of steatsis (CAP) and fibrosis (LSM) are reliable biomarkers to non-invasively assess liver steatosis and fibrosis respectively in NAFLD patients. A quick, straightforward and non-invasive method for NAFLD screening in patients with MetS components is TE-CAP. Once diagnosed, the next step is to determine the presence of fibrosis by LSM which should point out high risk patients. Those patients should be referred to hepatologists. LB may be avoided in a substantial number of patients if TE with CAP is used for screening.

The prevalence of nonalcoholic or more recently re-defined metabolic associated fatty liver disease (MAFLD) is rapidly growing worldwide. It is characterized by hepatic fat accumulation exceeding 5% of liver weight not attributable to alcohol consumption. MAFLD refers to an umbrella of conditions ranging from simple steatosis to nonalcoholic steatohepatitis which may finally progress to cirrhosis and hepatocellular carcinoma. MAFLD is closely related to components of the metabolic syndrome and to environmental factors. In addition to the latter, genetic predisposition plays a key role in MAFLD pathogenesis and strictly contributes to its progressive forms. The candidate genes which have been related to MAFLD hereditability are mainly involved in lipids remodeling, lipid droplets assembly, lipoprotein packaging and secretion, de novo lipogenesis, and mitochondrial redox status. In the recent years, it has emerged the opportunity to translate the genetics into clinics by aggregating the genetic variants mostly associated with MAFLD in polygenic risk scores. These scores might be used in combination with metabolic factors to identify those patients at higher risk to develop more severe liver disease and to schedule an individual therapeutic approach.

Diabetes and cancer are widespread worldwide and the number of subjects presenting both diseases increased over the years. The management of cancer patients having diabetes represents a challenge not only because of the complexity and heterogeneity of these pathologies but also for the lack of standardised clinical guidelines. The diagnosis of cancer is traumatizing and monopolizes the attention of both patients and caregivers. Thus, pre-existent or new-onset diabetes can be overshadowed thus increasing the risk for short- and long-term adverse events. Moreover, drugs used for each disease can interfere with the clinical course of the concomitant disease, making challenging the management of these patients. Over the years, this issue has become more relevant because of the increased patients’ life expectancy due to the improved efficacy of diabetes and cancer therapies.

The purpose of this review is to highlight what is known and what should be taken into consideration to optimise the clinical management of patients with diabetes and cancer. Due to the complexity of these diseases, a multidisciplinary, shared approach, including all the protagonists involved, is necessary to improve patients’ quality of life and lifespan.

The currently ongoing coronavirus disease 19 (COVID-19) pandemic has affected globally human health and economy. Research in progress has shown facts associated with this disease and raised questions relevant for disease control and prevention. In this perspective, the collaboration between science and art in visual communication using the artwork “Enseñanza” (“Teaching”) contributes to the representation of the lessons learned from COVID-19 and the way forward. To advance preparedness for current and future pandemics, the authors propose to address international collaborations, support to science, access to food supplies and health services, sustainable development and a “One Health” approach searching a balanced interaction of humanity with nature and a more holistic approach to disease prevention and control.

Pooled prevalence of nonalcoholic fatty liver disease (NAFLD) globally is about 25%. Nonalcoholic steatohepatitis (NASH) with advanced fibrosis has been linked with substantial morbidity and mortality, without having to-date any licensed treatment. C-C chemokine receptor (CCR) antagonists have been investigated as candidates for the treatment of NASH. Inhibition of CCR2 is expected to mitigate hepatic inflammation, through reducing the activation of Kupffer cells, as well as the infiltration of monocytes and macrophages into the liver. Inhibition of CCR5 is expected to mitigate hepatic fibrogenesis, through impairing the activation of hepatic stellate cells, as well as to mitigate hepatic inflammation, through impairing the activation of Kupffer cells and macrophages. Cenicriviroc (CVC) is the first in class, dual inhibitor of CCR2 and CCR5. After exhibiting favorable results in animal models, CVC was shown to be beneficial in NASH patients with more severe fibrosis at a phase 2b trial (CENTAUR) and is currently at a phase 3 clinical trial (AURORA). Apart from CVC, other CCR5 mono-antagonists, such as maraviroc, are under evaluation in clinical trials with human immunodeficiency virus patients with NAFLD. The aim of this review was to summarize existing evidence on CVC and other CCR antagonists in NASH patients, primarily focusing on their clinical efficacy and safety.

Nonalcoholic fatty liver disease (NAFLD) is a substantial and growing problem worldwide and has become the second most common indication for liver transplantation as it may progress to cirrhosis and develop complications from portal hypertension primarily caused by advanced fibrosis and erratic tissue remodeling. However, elevated portal venous pressure has also been detected in experimental models of fatty liver and in human NAFLD when fibrosis is far less advanced and cirrhosis is absent. Early increases in intrahepatic vascular resistance may contribute to the progression of liver disease. Specific pathophenotypes linked to the development of portal hypertension in NAFLD include hepatocellular lipid accumulation and ballooning injury, capillarization of liver sinusoidal endothelial cells, enhanced contractility of hepatic stellate cells, activation of Kupffer cells and pro-inflammatory pathways, adhesion and entrapment of recruited leukocytes, microthrombosis, angiogenesis and perisinusoidal fibrosis. These pathological events are amplified in NAFLD by concomitant visceral obesity, insulin resistance, type 2 diabetes and dysbiosis, promoting aberrant interactions with adipose tissue, skeletal muscle and gut microbiota. Measurement of the hepatic venous pressure gradient by retrograde insertion of a balloon-tipped central vein catheter is the current reference method for predicting outcomes of cirrhosis associated with clinically significant portal hypertension and guiding interventions. This invasive technique is rarely considered in the absence of cirrhosis where currently available clinical, imaging and laboratory correlates of portal hypertension may not reflect early changes in liver hemodynamics. Availability of less invasive but sufficiently sensitive methods for the assessment of portal venous pressure in NAFLD remains therefore an unmet need. Recent efforts to develop new biomarkers and endoscopy-based approaches such as endoscopic ultrasound-guided measurement of portal pressure gradient may help achieve this goal. In addition, cellular and molecular targets are being identified to guide emerging therapies in the prevention and management of portal hypertension.

Rational government of patient fluxes from primary care to hepatology clinic is a priority of nonalcoholic fatty liver disease (NAFLD) research. Estimating pre-test probability of disease, risk of fibrosis progression, and exclusion of competing causes of liver disease must be addressed. Here we propose a novel taxonomic classification of NAFLD based on hepatic, pathogenic and systemic features of disease in the individual patient. The variable course of disease in any given patient remains a clinical enigma. Therefore, future studies will have to better characterize the role of genetic polymorphisms, family and personal history, diet, alcohol, physical activity and drugs as modifiers of the course of disease and clues to the early diagnosis of hepatocellular carcinoma. A better understanding of these, together with a taxonomic diagnosis, may prompt a more accurate personalization of care. For example, understanding the putative role of psycho-depression in NAFLD promises to revolutionize disease management in a proportion of cases. Similarly, sex differences in outcome and response to treatment are insufficiently characterized. More studies are awaited regarding those forms of NAFLD which occur secondary to endocrine derangements. The intersections between NAFLD and the lung must better be defined. These include the bi-directional associations of NAFLD and chronic obstructive pulmonary disease and sleep apnoea syndrome, as well as the totally unexplored chapter of NAFLD and coronavirus disease 2019 (COVID-19). Finally, the therapeutic roles of intermittent fasting and anticoagulation must be assessed. In conclusion, over the last 20 years, NAFLD has taught us a lot regarding the pathogenic importance of insulin resistance, the limitations of correcting this in the treatment of NAFLD, the root causes of diabetes and the metabolic syndrome, sex differences in disease and the role of nuclear receptors. However, the overwhelming COVID-19 pandemic is now expected to reset the priorities of public health.

Left ventricular ejection fraction is the critical parameter used for heart failure classification, decision making and assessing prognosis. It is defined as a volumetric ratio and is essentially a composite of arterial and ventricular elastances, but not intrinsic contractility. The clinician should be aware of its numerous limitations when measuring and reporting it. And make a step toward more insightful understanding of hemodynamics.

Non-alcoholic fatty liver disease (NAFLD) remains a major cause of chronic liver disease worldwide. Despite extensive studies, the heterogeneity of the risk factors as well as different disease mechanisms complicate the goals toward effective diagnosis and management. Recently, it has been shown that sex differences play a role in the prevalence and progression of NAFLD. In vitro, in vivo, and clinical studies revealed that the lower prevalence of NAFLD in premenopausal as compared to postmenopausal women and men is mainly due to the protective effects of estrogen and body fat distribution. It has been also described that males and females present differential pathogenic features in terms of biochemical profiles and histological characteristics. However, the exact molecular mechanisms for the gender differences that exist in the pathogenesis of NAFLD are still elusive. Lipogenesis, oxidative stress, and inflammation play a key role in the progression of NAFLD. For NAFLD, only a few studies characterized these mechanisms at the molecular level. Therefore, we aim to review the reported differential molecular mechanisms that trigger such different pathogenesis in both sexes. Differences in lipid metabolism, glucose homeostasis, oxidative stress, inflammation, and fibrosis were discussed based on the evidence reported in recent publications. In conclusion, with this review, we hope to provide a new perspective for the development of future practice guidelines as well as a new avenue for the management of the disease.

Chronic kidney disease (CKD) is a disease regularly seen in clinical practice. At present, CKD is described as a change of kidney structure and/or function and it is classified in relation to cause, values of glomerular filtration rate and albuminuria category. Seeing that CKD is closely linked to the development of end-stage renal disease and other comorbidities, the determination of additional independent predictors for CKD is clinically necessary. At present, there is evidence associating non-alcoholic fatty liver disease (NAFLD) with CKD, thereby suggesting that NAFLD patients may require intensive surveillance to reduce their risk of CKD. In 2008, genome-wide association studies documented an association between the variant rs738409 (C > G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene (mainly implicated in the lipid regulation) and the entire spectrum of NAFLD (i.e., liver steatosis, non-alcoholic steatohepatitis, fibrosis, and hepatocellular carcinoma). In the last years, accumulating epidemiological evidence suggests the existence of a relationship between PNPLA3 rs738409 and risk of CKD, indicating that rs738409 may also contribute to the kidney injury. This is of particular scientific interest, as such association may explain, at least in part, the epidemiological association between liver and kidney disease. In this narrative review, we will discuss the accumulating evidence regarding the association between PNPLA3 rs738409 and risk of CKD, the putative biological mechanisms underpinning such relationship, and the possible future perspective.

Retinopathy of prematurity (ROP) is a blinding morbidity of preterm infants, which represents a significant clinical problem, accounting for up to 40% of all childhood blindness. ROP displays a range of severity, though even mild disease may result in life-long visual impairment. This is complicated by the fact that our current treatments have significant ocular and potentially systemic effects. Therefore, disease prevention is desperately needed to mitigate the life-long deleterious effects of ROP for preterm infants. Although ROP demonstrates a delayed onset of retinal disease following preterm birth, representing a potential window for prevention, we have been unable to sufficiently alter the natural disease course and meaningfully prevent ROP. Prevention therapeutics requires knowledge of early ROP molecular changes and risk, occurring prior to clinical retinal disease. While we still have an incomplete understanding of these disease mechanisms, emerging data integrating contributions of maternal/placental pathobiology with ROP are poised to inform novel approaches to prevention. Herein, we review the molecular basis for current prevention strategies and the clinical outcomes of these interventions. We also discuss how insights into early ROP pathophysiology may be gained by a better understanding of maternal and placental factors playing a role in preterm birth.