Unraveling the role of the FHL family in cardiac diseases: Mechanisms, implications, and future directions.

Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.

The role of a novel mineralocorticoid receptor antagonist, finerenone, in chronic kidney disease: mechanisms and clinical advances.

BACKGROUND: Chronic kidney disease (CKD) poses a significant health risk in contemporary society. Current CKD treatments primarily involve renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, albeit associated with hyperkalemia risks. A novel selective mineralocorticoid receptor antagonist, finerenone, offers a promising, safer alternative for CKD therapy. This review comprehensively assesses the role and efficacy of finerenone in CKD treatment by analyzing clinical and animal studies. Emerging evidence consistently supports finerenone's ability to effectively slow the progression of CKD. By targeting the mineralocorticoid receptor, finerenone not only mitigates renal damage but also exhibits a favorable safety profile, minimizing hyperkalemia concerns. CONCLUSION: Finerenone emerges as a valuable addition to CKD therapy, demonstrating potential benefits in delaying CKD progression while minimizing side effects. Nevertheless, further clinical trials are necessary to provide a comprehensive understanding of its safety and efficacy.

Metagenomic and metabolomic analysis showing the adverse risk-benefit trade-off of the ketogenic diet.

BACKGROUND: Ketogenic diets are increasingly popular for addressing obesity, but their impacts on the gut microbiota and metabolome remain unclear. This paper aimed to investigate how a ketogenic diet affects intestinal microorganisms and metabolites in obesity. METHODS: Male mice were provided with one of the following dietary regimens: normal chow, high-fat diet, ketogenic diet, or high-fat diet converted to ketogenic diet. Body weight and fat mass were measured weekly using high-precision electronic balances and minispec body composition analyzers. Metagenomics and non-targeted metabolomics data were used to analyze differences in intestinal contents. RESULTS: Obese mice on the ketogenic diet exhibited notable improvements in weight and body fat. However, these were accompanied by a significant decrease in intestinal microbial diversity, as well as an increase in Firmicutes abundance and a 247% increase in the Firmicutes/Bacteroidetes ratio. The ketogenic diet also altered multiple metabolic pathways in the gut, including glucose, lipid, energy, carbohydrate, amino acid, ketone body, butanoate, and methane pathways, as well as bacterial secretion and colonization pathways. These changes were associated with increased intestinal inflammation and dysbiosis in obese mice. Furthermore, the ketogenic diet enhanced the secretion of bile and the synthesis of aminoglycoside antibiotics in obese mice, which may impair the gut microbiota and be associated with intestinal inflammation and immunity. CONCLUSIONS: The study suggest that the ketogenic diet had an unfavorable risk-benefit trade-off and may compromise metabolic homeostasis in obese mice.

Secreted frizzled-related protein 5: A promising therapeutic target for metabolic diseases via regulation of Wnt signaling.

Metabolic diseases pose a significant global health challenge, characterized by an imbalance in metabolism and resulting in various complications. Secreted frizzled-related protein 5 (SFRP5), an adipokine known for its anti-inflammatory properties, has gained attention as a promising therapeutic target for metabolic diseases. SFRP5 acts as a key regulator in the Wnt signaling pathway, exerting its influence on critical cellular functions including proliferation, differentiation, and migration. Its significance extends to the realm of adipose tissue biology, where it plays a central role in regulating inflammation, insulin resistance, adipogenesis, lipid metabolism, glucose homeostasis, and energy balance. By inhibiting Wnt signaling, SFRP5 facilitates adipocyte growth, promotes lipid accumulation, and contributes to a decrease in oxidative metabolism. Lifestyle interventions and pharmacological treatments have shown promise in increasing SFRP5 levels and protecting against metabolic abnormalities. SFRP5 is a pivotal player in metabolic diseases and presents itself as a promising therapeutic target. An overview of SFRP5 and its involvement in metabolic disorders and metabolism is provided in this comprehensive review. By elucidating these aspects, valuable insights can be gained to foster the development of effective strategies in combating metabolic diseases.

Astrocytes in Post-Stroke Depression: Roles in Inflammation, Neurotransmission, and Neurotrophin Signaling.

Post-stroke depression (PSD) is a frequent and disabling complication of stroke that affects up to one-third of stroke survivors. The pathophysiology of PSD involves multiple mechanisms, including neurochemical, neuroinflammatory, neurotrophic, and neuroplastic changes. Astrocytes are a type of glial cell that is plentiful and adaptable in the central nervous system. They play key roles in various mechanisms by modulating neurotransmission, inflammation, neurogenesis, and synaptic plasticity. This review summarizes the latest evidence of astrocyte involvement in PSD from human and animal studies, focusing on the alterations of astrocyte markers and functions in relation to monoamine neurotransmitters, inflammatory cytokines, brain-derived neurotrophic factor, and glutamate excitotoxicity. We also discuss the potential therapeutic implications of targeting astrocytes for PSD prevention and treatment. Astrocytes could be new candidates for antidepressant medications and other interventions that aim to restore astrocyte homeostasis and function in PSD. Astrocytes could be new candidates for antidepressant medications and other interventions that aim to restore astrocyte homeostasis and function in PSD.

Irisin protects against obesity-related chronic kidney disease by regulating perirenal adipose tissue function in obese mice.

BACKGROUND: Compared with typical visceral fat deposits in obesity and metabolic syndrome, perirenal adipose tissue (PRAT) dysfunction is more closely linked to obesity-related chronic kidney disease (OB-CKD). The myokine irisin reportedly promotes positive outcomes in metabolic disease. This study investigated whether irisin could reduce urinary albumin excretion and demonstrate renoprotective effects through the regulation of PRAT function in obese mice. METHODS: C57BL/6 J mice received a high-fat diet (HFD) with or without concurrent administration of irisin. Glucose tolerance, plasma levels of free fatty acids, and urinary albumin excretion were assessed, along with renal morphology. The vascular endothelial growth factor and nitric oxide in glomeruli were also analyzed, in addition to PRAT function-associated proteins. RESULTS: Irisin administration significantly reduced the final body weight, fat mass, and free fatty acids, without reducing PRAT mass, in HFD mice. Furthermore, irisin decreased urinary albumin excretion and attenuated both renal fibrosis and lipid accumulation. Irisin administration led to increases in PRAT function-associated proteins, including sirtuin1, uncoupling protein-1, and heme-oxygenase-1. Ex vivo treatment of PRAT and glomeruli with irisin also restored PRAT function. Finally, irisin treatment restored the vascular endothelial growth factor-nitric oxide axis. CONCLUSIONS: Irisin attenuated metabolic disorders and protected against OB-CKD by normalizing the PRAT-kidney axis. These results suggest that agents targeting PRAT activation might be useful for treatment of OB-CKD.

Balancing act: The dilemma of rapid hyperglycemia correction in diabetes management.

The global diabetes surge poses a critical public health challenge, emphasizing the need for effective glycemic control. However, rapid correction of chronic hyperglycemia can unexpectedly trigger microvascular complications, necessitating a reevaluation of the speed and intensity of glycemic correction. Theories suggest swift blood sugar reductions may cause inflammation, oxidative stress, and neurovascular changes, resulting in complications. Healthcare providers should cautiously approach aggressive glycemic control, especially in long-standing, poorly controlled diabetes. Preventing and managing these complications requires a personalized, comprehensive approach with education, monitoring, and interdisciplinary care. Diabetes management must balance short and long-term goals, prioritizing overall well-being. This editorial underscores the need for a personalized, nuanced approach, focusing on equilibrium between glycemic control and avoiding overcorrection.

Emerging therapeutic landscape: Incretin agonists in chronic kidney disease management.

The increasing incidence of chronic kidney disease (CKD) poses a significant public health concern, prompting heightened attention to its treatment. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are intestinal peptides released after nutrient intake, known for their hypoglycemic effects in diabetes management. Recent advancements highlight the promising outcomes of GLP-1 receptor agonists in reducing CKD risk factors and improving renal outcomes. The multifaceted functions of GLP-1, such as its anti-obesity, anti-hypertensive, anti-hyperglycemic, anti-lipid, anti-inflammatory, and endothelial function protective properties, contribute to its potential as a therapeutic agent for CKD. Although experiments suggest the potential benefits of incretin in CKD, a comprehensive understanding of its specific mechanisms is still lacking. This review aims to provide a detailed examination of current evidence and potential future directions, emphasizing the promising yet evolving landscape of incretin agonists in the context of CKD.

Elucidating the cardioprotective mechanisms of sodium-glucose cotransporter-2 inhibitors beyond glycemic control.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a pivotal intervention in diabetes management, offering significant cardiovascular benefits. Empagliflozin, in particular, has demonstrated cardioprotective effects beyond its glucose-lowering action, reducing heart failure hospitalizations and improving cardiac function. Of note, the cardioprotective mechanisms appear to be inde-pendent of glucose lowering, possibly mediated through several mechanisms involving shifts in cardiac metabolism and anti-fibrotic, anti-inflammatory, and anti-oxidative pathways. This editorial summarizes the multifaceted cardiovascular advantages of SGLT2 inhibitors, highlighting the need for further research to elucidate their full therapeutic potential in cardiac care.

Mechanisms and efficacy of traditional Chinese herb monomers in diabetic kidney disease.

Diabetic kidney disease (DKD) is a serious complication of diabetes and is the primary cause of end-stage renal disease. Current treatment strategies primarily focus on the inhibition of the renin-angiotensin-aldosterone system and the attainment of blood glucose control. Although current medical therapies for DKD have been shown to delay disease progression and improve long-term outcomes, their efficacy is limited and they may be restricted in certain cases, particularly when hyperkalemia is present. Traditional Chinese medicine (TCM) treatment has emerged as a significant complementary approach for DKD. TCM monomers, derived from various Chinese herbs, have been found to modulate multiple therapeutic targets and exhibit a broad range of therapeutic effects in patients with DKD. This review aims to summarize the mechanisms of action of TCM monomers in the treatment of DKD, based on findings from clinical trials, as well as cell and animal studies. The results of these investigations demonstrate the potential effective use of TCM monomers in treating or preventing DKD, offering a promising new direction for future research in the field. By providing a comprehensive overview of the mechanisms and efficacy of TCM monomers in DKD, this review highlights the potential of these natural compounds as alternative therapeutic options for improving outcomes in patients with DKD.

Environmental toxicology of bisphenol A: Mechanistic insights and clinical implications on the neuroendocrine system.

Bisphenol A (BPA) is a widely used environmental estrogen found in a variety of products, including food packaging, canned goods, baby bottle soothers, reusable cups, medical devices, tableware, dental sealants, and other consumer goods. This substance has been found to have detrimental effects on both the environment and human health, particularly on the reproductive, immune, embryonic development, nervous, endocrine, and respiratory systems. This paper aims to provide a comprehensive review of the effects of BPA on the neuroendocrine system, with a primary focus on its impact on the brain, neurons, oligodendrocytes, neural stem cell proliferation, DNA damage, and behavioral development. Additionally, the review explores the clinical implications of BPA, specifically examining its role in the onset and progression of various diseases associated with the neuroendocrine metabolic system. By delving into the mechanistic analysis and clinical implications, this review aims to serve as a valuable resource for studying the impacts of BPA exposure on organisms.

The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy.

The growing global burden of cancer, especially among people aged 60 years and over, has become a key public health issue. This trend suggests the need for a deeper understanding of the various cancer types in order to develop universally effective treatments. A prospective area of research involves elucidating the interplay between the senescent microenvironment and tumor genesis. Currently, most oncology research focuses on adulthood and tends to ignore the potential role of senescent individuals on tumor progression. Senescent cells produce a senescence-associated secretory phenotype (SASP) that has a dual role in the tumor microenvironment (TME). While SASP components can remodel the TME and thus hinder tumor cell proliferation, they can also promote tumorigenesis and progression via pro-inflammatory and pro-proliferative mechanisms. To address this gap, our review seeks to investigate the influence of senescent microenvironment changes on tumor development and their potential implications for cancer therapies.

Exploring the multi-targeting phytoestrogen potential of Calycosin for cancer treatment: A review.

Cancer remains a significant challenge in the field of oncology, with the search for novel and effective treatments ongoing. Calycosin (CA), a phytoestrogen derived from traditional Chinese medicine, has garnered attention as a promising candidate. With its high targeting and low toxicity profile, CA has demonstrated medicinal potential across various diseases, including cancers, inflammation, and cardiovascular disease. Studies have revealed that CA possesses inhibitory effects against a diverse array of cancers. The underlying mechanism of action involves a reduction in tumor cell proliferation, induction of tumor cell apoptosis, and suppression of tumor cell migration and invasion. Furthermore, CA has been shown to enhance the efficacy of certain chemotherapeutic drugs, making it a potential component in treating malignant tumors. Given its high efficacy, low toxicity, and multi-targeting characteristics, CA holds considerable promise as a therapeutic agent for cancer treatment. The objective of this review is to present a synthesis of the current understanding of the antitumor mechanism of CA and its research progress.

Epidemiology of 369 diseases and injuries attributable to 84 risk factors: 1990-2019 with 2040 projection.

The global burden of diseases and injuries poses complex and pressing challenges. This study analyzed 369 diseases and injuries attributed to 84 risk factors globally from 1990 to 2019, projecting trends to 2040. In 2019, global risks caused 35 million deaths. Non-communicable diseases were responsible for 8.2 million deaths, primarily from air pollution (5.5 million). Cardiovascular disease from air pollution had a high age-standardized disability-adjusted life year rate (1,073.40). Communicable, maternal, neonatal, and nutritional diseases caused 1.4 million deaths, mainly due to unsafe water and sanitation. Occupational risks resulted in 184,269 transport-related deaths. Behavioral risks caused 21.6 million deaths, with dietary factors causing 6.9 million cardiovascular deaths. Diabetes linked to sugar-sweetened beverages showed significant growth (1990-2019). Metabolic risks led to 18.6 million deaths. Projections to 2040 indicated persistent challenges, emphasizing the urgent need for targeted interventions and policies to alleviate the global burden of diseases and injuries.

The protective effects of SGLT-2 inhibitors, GLP-1 receptor agonists, and RAAS blockers against renal injury in patients with type 2 diabetes.

Diabetic kidney disease is one of the most severe complications of type 2 diabetes mellitus. Patients with diabetic kidney disease have a worse prognosis in terms of mortality and morbidity, compared with patients who have diabetes alone. Strict control of blood pressure and blood glucose is the primary method for prevention of initial kidney damage and delaying further progression of existing damage. Other management approaches include the use of exogenous drugs that can effectively protect the kidneys from diabetes, such as sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers. These drugs may protect against kidney injury through various molecular mechanisms. This review focuses on renal impairment in patients with type 2 diabetes; it discusses the direct and indirect effects of sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers on diabetic kidney disease. Finally, it discusses the effects of combination treatment with two or three types of drugs in patients with chronic kidney disease.

Metabolic diseases and healthy aging: identifying environmental and behavioral risk factors and promoting public health.

Aging is a progressive and irreversible pathophysiological process that manifests as the decline in tissue and cellular functions, along with a significant increase in the risk of various aging-related diseases, including metabolic diseases. While advances in modern medicine have significantly promoted human health and extended human lifespan, metabolic diseases such as obesity and type 2 diabetes among the older adults pose a major challenge to global public health as societies age. Therefore, understanding the complex interaction between risk factors and metabolic diseases is crucial for promoting well-being and healthy aging. This review article explores the environmental and behavioral risk factors associated with metabolic diseases and their impact on healthy aging. The environment, including an obesogenic environment and exposure to environmental toxins, is strongly correlated with the rising prevalence of obesity and its comorbidities. Behavioral factors, such as diet, physical activity, smoking, alcohol consumption, and sleep patterns, significantly influence the risk of metabolic diseases throughout aging. Public health interventions targeting modifiable risk factors can effectively promote healthier lifestyles and prevent metabolic diseases. Collaboration between government agencies, healthcare providers and community organizations is essential for implementing these interventions and creating supportive environments that foster healthy aging.

Secreted frizzled-related proteins: A promising therapeutic target for cancer therapy through Wnt signaling inhibition.

The Wnt signaling system is a critical pathway that regulates embryonic development and adult homeostasis. Secreted frizzled-related proteins (SFRPs) are extracellular inhibitors of Wnt signaling that act by binding directly to Wnt ligands or Frizzled receptors. SFRPs can act as anti-Wnt agents and suppress cancer growth by blocking the action of Wnt ligands. However, SFRPs are often silenced by promoter methylation in cancer cells, resulting in hyperactivation of the Wnt pathway. Epigenetic modifiers can reverse this silencing and restore SFRPs expression. Despite the potential of SFRPs as a therapeutic target, the effects of SFRPs on tumor development remain unclear. Therefore, a review of the expression of various members of the SFRPs family in different cancers and their potential as therapeutic targets is warranted. This review aims to summarize the current knowledge of SFRPs in cancer, focusing on their expression patterns and their potential as novel therapeutic targets.

Global, Regional, and National Epidemiology of Diabetes in Children From 1990 to 2019.

Importance: Diabetes in children is a global epidemic that causes various medical conditions associated with an increased incidence of premature death. Objective: To investigate the trends in diabetes incidence, mortality, and disability-adjusted life-years (DALYs) in children, with risk factors for diabetes-associated death, from 1990 to 2019. Design, Setting, and Participants: This was a cross-sectional study that used data from the Global Burden of Diseases (GBD) 2019 in 204 countries and territories. Children with diabetes who were aged 0 to 14 years were included in the analysis. Data were analyzed from December 28, 2022, to January 10, 2023. Exposure: Childhood diabetes from 1990 to 2019. Main Outcome Measures: Incidence, all-cause and cause-specific deaths, DALYs, and corresponding estimated annual percentage changes (EAPCs). These trends were stratified according to region, country, age, sex, and Sociodemographic Index (SDI). Results: A total of 1 449 897 children (738 923 male [50.96%]) were included in the analysis. In 2019, there were 227 580 incident cases of childhood diabetes worldwide. Cases of childhood diabetes increased by 39.37% (95% uncertainty interval [UI], 30.99%-45.45%) from 1990 to 2019. Over 3 decades, diabetes-associated deaths decreased from 6719 (95% UI, 4823-8074) to 5390 (95% UI, 4450-6507). The global incidence rate increased from 9.31 (95% UI, 6.56-12.57) to 11.61 (95% UI, 7.98-15.98) per 100 000 population; however, the diabetes-associated death rate decreased from 0.38 (95% UI, 0.27-0.46) to 0.28 (95% UI, 0.23-0.33) per 100 000 population. Among the 5 SDI regions, the low SDI region had the highest childhood diabetes-associated mortality rate in 2019. Regionally, North Africa and the Middle East had the largest increase in incidence (EAPC, 2.06; 95% CI, 1.94-2.17). Among 204 countries, Finland had the highest national incidence of childhood diabetes in 2019 (31.60 per 100 000 population; 95% UI, 22.65-40.36), Bangladesh had the highest diabetes-associated mortality rate (1.16 per 100 000 population; 95% UI, 0.51-1.70), and the United Republic of Tanzania had the highest DALYs rate (100.16 per 100 000 population; 95% UI, 63.01-155.88). Globally, environmental/occupational risk, nonoptimal temperature, high temperature, and low temperature were key risk factors for childhood diabetes-associated mortality in 2019. Conclusions and Relevance: Childhood diabetes is an increasing global health challenge with rising incidence. Results of this cross-sectional study suggest that despite the global decline in deaths and DALYs, the number of deaths and DALYs remains high among children with diabetes, especially in low SDI regions. Improved understanding of the epidemiology of diabetes in children may facilitate prevention and control.

Integrated multi-omics analyses reveal effects of empagliflozin on intestinal homeostasis in high-fat-diet mice.

Obesity has become a global epidemic, associated with several chronic complications. The intestinal microbiome is a critical regulator of metabolic homeostasis and obesity. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has putative anti-obesity effects. In this study, we used multi-omics analysis to determine whether empagliflozin regulates metabolism in an obese host through the intestinal microbiota. Compared with obese mice, the empagliflozin-treated mice had a higher species diversity of gut microbiota, characterized by a reduction in the Firmicutes/Bacteroides ratio. Metabolomic analysis unambiguously identified 1,065 small molecules with empagliflozin affecting metabolites mainly enriched in amino acid metabolism, such as tryptophan metabolism. RNA sequencing results showed that immunoglobulin A and peroxisome proliferator-activated receptor signaling pathways in the intestinal immune network were activated after empagliflozin treatment. This integrative analysis highlighted that empagliflozin maintains intestinal homeostasis by modulating gut microbiota diversity and tryptophan metabolism. This will inform the development of therapies for obesity based on host-microbe interactions.

Global burden of non-alcoholic fatty liver disease in 204 countries and territories from 1990 to 2019.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic linked to metabolic disease and is the most prevalent cause of chronic liver disease. We, therefore, designed the study to analyze the global and regional burden of NAFLD from 1990 to 2019. METHODS: We collected data on NAFLD from the Global Burden of Disease study 2019, aiming to conduct a systematic assessment of the changes and trends in NAFLD in 204 countries. Secondary analysis of NAFLD was conducted using age-standardized rates (ASRs) and estimated annual percentage changes (EAPCs) to show the changing trends and development characteristics. Data statistics and visualization were executed with the R program. RESULTS: Globally, incidence, deaths and disability-adjusted life years (DALYs) of NAFLD all showed an upward trend. Between 1990 and 2019, the incidence of NAFLD increased by 95.4%, from 88,177 to 172,330 cases. Meanwhile, the ASIR of the middle SDI region had the highest increase, followed by the low-middle SDI region. Of all countries, the most incident cases were in China, which accounted for approximately 23.6% of NAFLD. China was also the country with the largest cases of deaths and DALYs. And behavioral risk, metabolic factors, smoking and high fasting plasma glucose were the critical risk factors associated with the mortality and DALYs of NAFLD. CONCLUSION: NAFLD has become a considerable health burden in many countries. Therefore, we should control the risk factors of NAFLD and take corresponding measures to achieve its early prevention and treatment.