The glucocorticoid receptor (GR) signaling pathway is essential for supporting the integrity of the intestinal barrier, regulating the gut microbiome, and preserving systemic homeostasis in critically ill patients. GR signaling limits bacterial translocation and systemic inflammation by suppressing pro-inflammatory cytokines, reinforcing tight junction proteins, and promoting epithelial renewal. Additionally, physiological levels of glucocorticoids (GCs) stimulate glutamine and proline metabolism, supporting intestinal maturation, with potential clinical relevance. GR signaling modulates inter-organ communication via the gut-lung and gut-brain axes, improving outcomes. Probiotics enhance GC therapy by restoring microbial balance, increasing short-chain fatty acid (SCFA) production, and modulating immune responses. Vitamins A, C, D, and E contribute to gut resilience by stabilizing tight junctions, mitigating oxidative stress, and strengthening mucosal immunity. Specifically, vitamin D balances T-cell subsets and promotes antimicrobial peptides; vitamin C supports collagen synthesis, antioxidant defenses, and immune function; vitamin A promotes immune tolerance and epithelial regeneration; and vitamin E mitigates oxidative damage and excessive cytokine release. GCs, probiotics, and vitamins counteract key drivers of critical illness, including hyperinflammation and dysbiosis, while maintaining strong safety profiles. This integrative approach leverages these interventions’ distinct yet complementary roles to provide a multi-layered defense against gut dysfunction. GCs reduce excessive inflammation and restore immune balance; probiotics enhance microbial diversity and strengthen gut-associated immunity; and vitamins support epithelial integrity and antioxidant defenses. Targeting multiple pathways simultaneously protects the gut barrier and modulates systemic immunity, potentially reducing complications such as sepsis, multiple organ dysfunction syndrome (MODS), and prolonged intensive care unit (ICU) stays. Incorporating these elements into critical care practice offers a novel strategy to mitigate gut dysfunction, reduce systemic inflammation, and enhance immune resilience. This approach may lower infection rates, decrease the incidence of sepsis and MODS, and accelerate recovery by targeting GR signaling, restoring microbial homeostasis, and reinforcing epithelial integrity.

Iatrogenic hypoparathyroidism is a serious complication that can arise from neck surgery, predominantly during thyroidectomy, parathyroidectomy, and laryngectomy; it can be transient or permanent, requiring lifelong treatment. Early detection and treatment are crucial to prevent severe hypocalcemia, which is potentially fatal. This case report describes a 59-year-old male with a history of well-differentiated squamous cell carcinoma of the vocal cords who developed severe postoperative hypoparathyroidism following total laryngectomy with right hemithyroidectomy. Despite initial treatment with cholecalciferol by nasogastric tube, the patient experienced recurrent severe hypocalcemia, requiring intravenous administration of calcitriol due to his inability to swallow. This case highlights the risk factors for triggering postoperative hypoparathyroidism, such as previous surgery or radiotherapy in the cervical region, underlines the importance of careful monitoring of postoperative hypoparathyroidism and proposes the use of intravenous calcitriol as an effective strategy in acute treatment when oral administration is not feasible.

Hormone replacement therapy (HRT) is essential for alleviating menopausal symptoms and mitigating complications linked to type 2 diabetes mellitus (T2DM) in postmenopausal women. Studies indicate that HRT may contribute to better glycemic control, improved lipid metabolism, and enhanced kidney function, which could help lower the risk of diabetes-related complications. Early initiation of HRT near menopause has shown cognitive and metabolic benefits, while transdermal estrogen is preferred for women with cardiovascular risk due to its safer profile. However, HRT is associated with risks, including thromboembolic events and increased risks of breast and endometrial cancers, necessitating individualized evaluations. Despite its potential, significant gaps remain regarding HRT’s long-term safety and efficacy, its interaction with modern diabetes therapies, and its impact on diverse populations. The optimization of estrogen replacement therapy (ERT) strategies requires further exploration, particularly regarding patient screening, individualized treatment regimens, and personalization of care based on risk factors such as metabolic status, cardiovascular health, and diabetes severity. Current evidence supports the cautious use of HRT in strictly screened postmenopausal women with T2DM, adhering to key principles including early intervention (within 10 years of menopause), low-dose and short-duration therapy (usually < 5 years), and integration of lifestyle interventions (e.g., diet, exercise). Future research should focus on defining clear screening criteria, optimizing treatment regimens, and personalizing ERT to maximize benefits while mitigating risks. This review examines the benefits, risks, and optimization strategies of HRT in postmenopausal women with T2DM. It focuses on its metabolic, cardiovascular, cognitive, and renal effects and emphasizes personalized treatment approaches.

Pediatric adrenocortical tumors (pACTs) are rare endocrine neoplasms with variable prognosis, commonly associated with germline pathogenic variants (PVs) in the tumor suppressor gene TP53. Here, we report the case of a 3.1-year-old female presenting with virilization and Cushing syndrome due to a left-sided adrenal mass. The tumor was completely resected and confirmed as stage II adrenocortical carcinoma (ACC) based on the Wieneke index. Comprehensive molecular profiling revealed heterozygous germline PVs in BRCA2 [c.9382C>T p.(Arg3128*)] and CHEK2 [c.1232G>A p.(Trp411*)]. These findings suggest a potential role of impaired DNA damage repair in ACC pathogenesis, as both PVs are associated with hereditary breast and ovarian cancer (HBOC) syndromes and genomic instability. This case expands the genetic spectrum of pACT and underscores the importance of advanced molecular analyses in identifying rare germline alterations that may inform personalized treatment strategies and cancer prevention programs. Although no additional treatment was required in this case, BRCA2 status highlights the potential for tailored therapeutic approaches, including poly(ADP-ribose) polymerase (PARP) inhibitors, in selected patients. Further research is warranted to explore the specific contributions of BRCA2 and CHEK2 PVs to ACC tumorigenesis and their implic ations for targeted therapies.

Diabetes mellitus is a major risk factor for both cardiovascular and chronic kidney disease (CKD) while CKD is also associated with cardiovascular morbidity. In fact, cardiovascular disease is the leading cause of death in patients with diabetes mainly from heart failure or myocardial infarction. The newer therapeutic agents in diabetes have positive impact on both cardiovascular and renal outcomes. Thus, the American Diabetes Association (ADA)’s annual update on the Standards of Medical Care in Diabetes is an important resource for all caregivers involved in diabetes management as it incorporates the latest scientific research, clinical evidence, and emerging technologies in diabetes management. The 2025 guidelines present significant updates that reflect a deeper understanding of diabetes management, emphasizing expanded usage of technologies such as continuous glucose monitoring, personalized pharmacological approaches, and lifestyle interventions. This commentary provides an analysis of the key updates in the 2025 ADA guidelines exploring implications for clinical practice, laboratory assessments, and public health policy. Where relevant, comparisons to the 2024 version will be made.

Obesity is a multifactorial disease linked to many comorbidities and has an impact on brain health. It is also known that obesity disrupts the endocannabinoid (eCB) system in the central nervous system and in the periphery, which complicates the underlying mechanisms behind obesity. However, weight loss through lifestyle interventions or bariatric surgery may alleviate obesity-related comorbidities, as well as restore eCB tone. Several studies have reported a decrease in circulating eCBs following weight loss, likely due to the positive association of these mediators with fat mass. However, further research is needed to clarify whether this reduction is a consequence of weight loss or plays a role in facilitating it. This review explores changes in circulating eCBs following weight loss and their potential roles in cerebral homeostasis and the reward system. It examines how lifestyle modifications and bariatric surgery may influence central eCB signalling and contribute to long-term weight loss success. Understanding the mechanisms behind improved brain function after weight loss could provide insights into optimizing obesity treatments.

The glucocorticoid receptor alpha (GRα), a vital component of the ancient glucocorticoid (GC) signaling system, is essential for vertebrate survival. It regulates fertility, fetal development, organ function, vascular and neural integrity, metabolism, immune responses, and stress adaptation. While GRα’s anti-inflammatory properties have been acknowledged since the mid-20th century, its crucial role as the master regulator of homeostatic corrections in both health and critical illness has only recently come to light. In critical illness, GRα facilitates a seamless transition through three essential phases of homeostatic correction. Initially, in the Priming Phase, it activates immune responses and mobilizes energy reserves to defend against stressors like infection and injury, enhancing glucose metabolism, supporting mitochondrial function, and strategically deploying immune cells to areas of damage. Next, during the Modulatory Phase, GRα fine-tunes inflammatory responses, manages oxidative stress, regulates vascular tone, and maintains cellular integrity. Finally, in the Restorative Phase, GRα plays a crucial role in resolving inflammation, initiating tissue repair, supporting cellular regeneration, facilitating debris clearance, and reestablishing anatomical and physiological balance for long-term recovery. GRα coordinates complex molecular interactions, including co-regulation with pro-inflammatory transcription factors, ensures mitochondrial stability, and metabolic balance under stress. However, depleted bioenergetic and micronutrient reserves in critically ill patients can impair GRα’s capacity, increasing morbidity and mortality risks. This review highlights the need to reassess current GC treatment strategies and integrate micronutrient support to optimize GRα function. Such an approach could strengthen immediate immune defenses, enhance long-term recovery, reduce GC dose and duration, and minimize adverse effects.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as a global health crisis, affecting over 30% of the population and demanding urgent attention. This redefined condition, previously known as non-alcoholic fatty liver disease (NAFLD), reflects a deeper understanding of the intricate interplay between metabolic dysfunction and liver health. At the heart of MASLD lies the troubling accumulation of triglycerides (TGs) in hepatocytes, which precipitates insulin resistance and oxidative stress, ultimately leading to more severe forms like metabolic dysfunction-associated steatohepatitis (MASH). Excitingly, recent research has spotlighted the farnesoid X receptor (FXR) as a groundbreaking therapeutic target. FXR not only regulates lipid metabolism but also combats inflammation and insulin resistance, making it a potential game-changer in the fight against MASLD. With only one FDA-approved drug, resmetirom, currently available, the exploration of FXR agonists opens new avenues for innovative treatments that could revolutionize patient care. By harnessing the power of FXR to restore metabolic balance and integrating advanced strategies like lipidomics and fatty acid profiling, we stand on the brink of transforming how we approach MASLD and its associated complications, paving the way for a healthier future. This review delves into the promising role of FXR in combating MASLD and its implications for related metabolic disorders, emphasizing the urgency for advanced strategies to detect and manage this burgeoning epidemic.

The accumulation of adipose tissue is associated with metabolic disorders, including insulin resistance, type 2 diabetes (T2D), dyslipidemia, metabolic syndrome, and cardiovascular diseases (CVD). Menopause might predispose women to increase body weight and adipose tissue, and decrease lean muscle mass. Furthermore, postmenopausal women display fat mass redistribution with greater accumulation in the visceral area mainly due to hormonal shifts that result in a higher testosterone/estradiol ratio. These effects are associated with a less favorable adipokine profile, dyslipidemia, insulin resistance, and cardiac dysfunction after menopause. Fat mass is determined by the balance between the storage of triacylglycerol (TAG) (lipogenesis) and the removal of stored TAG (lipolysis) in combination with the differentiation of new adipocytes (adipogenesis). Disturbances in adipose tissue dynamics lead to an increase in lipogenesis (hypertrophy) and/or in adipogenesis (hyperplasia) to accommodate excess energy intake. While large adipocytes are dysfunctional and have greater secretion of inflammatory adipocytokines, small adipocytes are healthier and associated with metabolic improvements. Different strategies can be used to prevent or reduce body weight gain and fat mass, as well as to maintain healthy adipose tissue; however, due to robust evidence, lifestyle interventions should be pillars in this process. This review provides a comprehensive summary of findings on the role of a balanced diet and physical exercise in improving body composition and promoting healthy adipose tissue in postmenopausal women.

Metabolic disorders are due to a deficiency of enzymes, which can severely impact health or cause serious complications without treatment. This study aimed to identify the molecular causes of an infant death who had been hospitalized with complicated health problems and metabolism syndrome. Whole-exome sequencing (WES) was used to screen pathogenic variants in the patient’s genome, followed by examination of variants segregation in her parents. The WES analysis identified two homozygous variants, c.[614C>G; 649A>G] in the HMGCL gene of the patient. These two variants co-locate within the exon 7 of the HMGCL gene, resulting in 2 amino acid substitutions, p.[T205S; M217V], in the conservative region of enzyme protein. Sanger sequencing showed that the patient’s unaffected mother and father carried one mutant allele of the HMGCL gene containing two c.[614C>G; 649A>G] variants. The HMGCL gene encodes the 3-hydroxy-3-methylglutaryl-CoA lyase enzyme, which is critical in the ketogenic pathway. The deficiency of this enzyme was reported to be a life-threatening illness in the neonatal period, and two variants detected in this study were also found in a Japanese patient with sudden, unexpected death in infancy. The frequency of these two variants in the Vietnamese in-hour database and their further functional analysis were also reported in this study. The results of this study have explored the molecular etiology that causes the severe, deadly condition of the patient and provide an understanding of the risk of disease in her family.

Type 2 diabetes mellitus (DM) and hypertension (HT) are common major cardiovascular disease (CVD) risk factors. They share common pathophysiological mechanisms and are commonly co-existent. Prevalence of HT is increased among diabetic patients but also DM is more common in hypertensive patients. CVD risk increases multiplicatively in coexistence of HT and DM. Lowering blood pressure (BP) has been shown to be associated with improved morbidity related to both macro- and micro-vascular complications. Although there is debate about target BP levels, in many randomized controlled trials and guidelines a goal of < 130/80 mmHg is advocated in patients with DM, if well tolerated. However, an individualized approach should be cared for depending on risk factors, co-morbidities, and frailty of patients. Lifestyle modifications including weight loss, regular exercise, avoiding smoking and excessive alcohol consumption, and a healthy diet including limitation of salt and fat and total energy intake, are important both as a part of preventive therapy and treatment modality for both DM and HT. Among antihypertensive drugs angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are warranted due to their potential advantages for slowing albuminuria and progression to kidney failure which is more common in DM. Usually, their combination with calcium-channel blockers (CCBs) or thiazide/thiazide-like diuretics, in a step-wise manner, is recommended. Resistant HT is more common in DM and requires the addition of mineralocorticoid receptor antagonists (MRAs). New antidiabetic drugs like glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to lower BP. Apart from their antihypertensive effects they also improve CVD and renal outcomes. There’re ongoing new trials for new agents. Development of more potent and longer-term effective BP lowering drugs, single pill multiple drug combinations of antiHT agents and combination of antiHT agents with glucose-lowering and antilipidemic agents will probably improve compliance to treatment and achievement of goals in diabetic patients.