The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is increasing rapidly worldwide due to the obesity epidemic. Advanced stages of the MAFLD, such as non-alcoholic steatohepatitis (NASH) with advanced fibrosis or cirrhosis are affecting global health. Extracellular vesicles (EVs) are released by all cell types and are important in cell-to-cell communication and maintaining homeostasis, but they also play a role in the pathogenesis of various diseases. EVs contain biological information such as lipids, proteins, messenger RNAs (mRNAs), small RNAs, and DNA, and they act on (distant) target cells. The cargo of EVs is dependent on the type and the state of the releasing cell. EVs have been proposed as biomarkers, prognostic, and even therapeutic agents, also in the context of liver diseases. This review aims to give an overview of the current knowledge on EVs in MAFLD, including the role and interaction of EVs with different cell types in the liver. Several aspects of EVs, including their origin, characteristics, cargo, and functions are reviewed. Moreover, the potential of EVs as targets for the treatment of MAFLD is discussed.

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Stroke is one of the most common causes of disability and exerts a high burden of direct and indirect costs. Stroke may cause spasticity, which limits patients’ abilities and affects their activities of daily living, decreasing their quality of life. Conventional treatments are based on physical therapy, anti-spasticity medication, and botulinum toxin type A (BTX-A). However, recently, non-pharmacological approaches have been used, such as dry needling (DN) of myofascial trigger points. BTX-A and DN are two treatments that aim to decrease spasticity in patients with stroke, but their mode of action, application, and costs differ. Thus, there is a need to determine the comparative economics of post-stroke spasticity treatments. For this purpose, a search for all types of cost-effectiveness studies (randomized controlled trials, matched controls, and cohorts) and models of epidemiological data was performed. Studies were selected if they included economic outcomes in stroke patients treated with BTX-A or DN. As a result, 7 studies of BTX-A and 2 of DN were selected. Similarities were found in the outcomes used to assess the effectiveness of both treatments in most studies, with modifications of the Ashworth Scale [Modified Ashworth Scale (MAS)/Modified Modified Ashworth Scale (MMAS)] and quality-adjusted life year (QALY) being the main indicators of effectiveness. However, both the duration of the studies and the evaluation of costs were highly heterogeneous, making comparison difficult. In conclusion, both BTX-A and DN are cost-effective to treat spasticity in patients with stroke, but there is a need for comparative studies to make direct comparisons of cost-effectiveness with the most frequently used outcomes such as the MMAS and QALYs.

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Neuroendocrine tumor (NET) is a rare tumor that has been observed in different sites such as lungs and throughout the gastrointestinal tract. Clinical features are usually non-specific and vary considerably depending upon the location of the tumor. Symptoms are similar to those of common conditions such as peptic ulcer disease, gastritis, irritable bowel syndrome, asthma, etc. Thus, an initial diagnosis of a NET usually occurs at an advanced stage. This report describes a case of pancreatic NET (PNET, grade 2) with liver metastasis in a 37-year-old male which was found to be inoperable due to extensive direct involvement of the proximal jejunal branches and superior mesenteric vein. Peptide receptor radionuclide therapy (PRRT) with lutetium-177 dotatate (¹⁷⁷Lu-DOTATATE) was administered due to the inoperability of primary PNET. Complete resolution of symptoms occurred with three cycles of PRRT.

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Immunity is usually classified into two categories: innate immunity and adaptive immunity, distinguished by the process and characteristics of the immunological impact. It was widely assumed that only adaptive immunity possessed memory features; however, current research has revealed that innate immunity, like adaptive immunity, possesses memory properties as well. “Trained immunity”, also known as “innate immune memory”, is a phenomenon that occurs when the immune system’s innate cells are stimulated and then undergo epigenetic reprogramming and metabolic alterations. When it comes to innate immunity, macrophages are essential since they have immunological memory capabilities and play a significant role in the body’s immunity. The concept of innate immune memory expands the definition of immunological memory and offers a broader view of immune response research. This article reviews the properties, mechanism, and significance of macrophage innate immune memory in disease.

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“There is many a slip twist the cup and the lip” is a proverb that dates back to the 3rd century. This proverb comes to mind while writing a review on pregnancy loss; so many complications can occur between fertilization and development of the embryo through the long period of gestation until successful delivery of the baby. These include failure of implantation of the embryo, spontaneous miscarriage in the first trimester, pre-eclampsia in the second trimester, premature rupture of fetal membranes, pre-term labour, and pre-term delivery. The maternal immune system which does a phenomenal job of protecting the host from a daunting variety of infections, sometimes also mounts adverse reactions that complicate pregnancy and endanger the fetus. Maternal immune reactions that can adversely affect pregnancy have been shown to be mediated by lymphocytes, macrophages and natural killer cells, and by cytokines secreted by these cellular effectors. This review summarizes the deleterious effects of cytokines leading to recurrent spontaneous miscarriage, pre-eclampsia and pre-term delivery, which are the major complications of pregnancy. It then goes on to discuss the potential use of progesterone and dydrogesterone, an orally-administered progestogen, as immunomodulatory molecules that can be considered for the prevention and/or treatment of these complications.

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Polycystic ovary syndrome (PCOS) is one of the most frequently observed endocrinopathies among women of reproductive age that redound to subfertility. The specific etiology of this heterogenic syndrome remains ambiguous. Metabolic complications, hormonal imbalance, deregulation in the immune system and their interrelationship make PCOS more complex. Hyperandrogenism and chronic low-grade inflammation modulate each other and enhance the self-perpetuation of PCOS. Even though there are many literature studies on PCOS and immune deregulation, this review focuses on the endocrine-immune nexus and how the altered endocrine system is embroiled in the immunopathology of PCOS.

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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.

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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.

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Biliary tract cancer (BTC) is an aggressive tumor characterized by a poor prognosis. In the latest years, targetable genetic alterations have been discovered in BTC patients, leading to the approval of new targeted therapies. Liquid biopsy, which is a non-invasive method for detecting tumor biomarkers from fluid samples, is a useful tool for diagnosis and molecular characterization, but also for prognosis assessment and monitoring of treatment response. In this review, recent works on liquid biopsy in BTC patients were analyzed, focusing on some relevant aspects for clinical use and trying to depict the future role of this technique. Moreover, differences between plasma and bile samples were pointed out, in light of the peculiar biology of BTC and the possibility of using bile as an alternative source of cell-free DNA (cfDNA) for genomic analysis. In the era of precision oncology, the increasing adoption of liquid biopsy in BTC patients will certainly improve the management of this disease.

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The glymphatic system, or glial-lymphatic system, is a waste clearance system composed of perivascular channels formed by astrocytes that mediate the clearance of proteins and metabolites from the brain. These channels facilitate the movement of cerebrospinal fluid throughout brain parenchyma and are critical for homeostasis. Disruption of the glymphatic system leads to an accumulation of these waste products as well as increased interstitial fluid in the brain. These phenomena are also seen during and after subarachnoid hemorrhages (SAH), contributing to the brain damage seen after rupture of a major blood vessel. Herein this review provides an overview of the glymphatic system, its disruption during SAH, and its function in recovery following SAH. The review also outlines drugs which target the glymphatic system and may have therapeutic applications following SAH.

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The glymphatic system, first described in 2012, is a brain-wide perivascular network that plays an important role in promoting interstitial metabolic waste removal from the brain. Glymphatic pathway function has been reported to be dramatically diminished in the aging brain. Furthermore, glymphatic system dysfunction has been linked to a spectrum of neurodegenerative diseases including Alzheimer’s disease (AD). This waste clearance pathway of the brain is most active during sleep and is largely disengaged during wakefulness. While norepinephrine (NE) is responsible for suppressing the glymphatic function, electroencephalographic slow-wave (delta) activity has a facilitating effect. An intriguing question is whether these regulators of glymphatic activity can be modulated by meditation-based approaches and whether such approaches have the ability to increase glymphatic function in the awake brain. The present article hypothesizes that meditation-based approaches, such as immersive sound meditation, may have the potential to enhance glymphatic pathway transport and solute clearance by reducing NE and increasing slow-wave activity. If confirmed, meditation could be an attractive approach to promoting healthy brain aging and to preventing neurodegenerative conditions like AD.

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The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER⁺), progesterone receptor-positive (PR⁺), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.

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