Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Online First
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Improving Renal Protection in Chronic Kidney Disease Associated with Type 2 Diabetes: The Role of Finerenone
Available online: 08 January 2025More LessChronic kidney disease (CKD) is a major complication of type 2 diabetes mellitus (T2D), which often leads to diabetic kidney disease (DKD). Traditional therapies, including renin–angiotensin–aldosterone system inhibitors and sodium–glucose cotransporter-2 inhibitors, are effective in slowing CKD progression. However, these approaches are insufficient to comprehensively inhibit mineralocorticoid receptor (MR) overactivation in the kidneys, which remains a significant driver of inflammation, fibrosis, and oxidative stress. These pathological processes accelerate kidney damage and cardiovascular complications. Finerenone—a nonsteroidal mineralocorticoid receptor antagonist—represents a new frontier in renal protection. Unlike steroidal mineralocorticoid antagonists (MRAs), finerenone offers a more selective MR blockade, reducing kidney inflammation and fibrosis without significantly raising serum potassium levels. Landmark trials have demonstrated the ability of finerenone to significantly reduce kidney and cardiovascular events in patients with T2D and CKD. Clinical evidence has highlighted finerenone as an effective option for slowing DKD progression while maintaining a favorable safety profile. Based on these findings, recent guidelines have incorporated finerenone as a recommended therapy for patients with T2D and CKD, emphasizing its role in reducing both renal and cardiovascular risks. This review provides a comprehensive overview of the available data to offer a deeper understanding of the potential of finerenone to transform CKD management for T2D patients.
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Identification of Biomarkers Related to Liquid-Liquid Phase Separation for Ulcerative Colitis Based on Single-Cell and Bulk RNA Transcriptome Sequencing Data
Authors: Jicheng Lu, Xu Lu and Bin ChenAvailable online: 08 January 2025More LessBackgroundLiquid-Liquid Phase Separation (LLPS) is a process involved in the formation of established organelles and various condensates that lack membranes; however, the relationship between LLPS and Ulcerative Colitis (UC) remains unclear.
AimsThis study aimed to comprehensively clarify the correlation between ulcerative colitis (UC) and liquid-liquid phase separation (LLPS).
ObjectivesIn this study, bioinformatics analyses and public databases were applied to screen and validate key genes associated with LLPS in UC. Furthermore, the roles of these key genes in UC were comprehensively analyzed.
MethodsBased on the single-cell transcriptomic data of UC obtained from the Gene Expression Omnibus (GEO) database, differences between patients with UC and their controls were compared using the limma package. The single-cell data were then filtered and normalized by the ‘Seurat’ package and subjected to dimension reduction by the Uniform Manifold Approximation and Projection (UMAP) algorithm. The LLPS-related genes (LLPSRGs) were searched on the DrLLPS website to obtain cross-correlated genes, which were scored using the ssGSEA algorithm. Next, functional enrichment, interaction network, immune landscape, and diagnostic and drug prediction of the LLPSRGs were comprehensively explored. Finally, the results were validated using external datasets and quantitative real-time PCR (qRT-PCR).
ResultsA total of eight cell types in UC were classified, namely, fibroblasts, macrophages, endothelial cells, neutrophils, NK cells, B cells, epithelial cells, and T cells. The intersection between differently expressed genes (DEGs) among the eight cell types identified 44 key genes, which were predominantly enriched in immune- and infection-related pathways. According to receiver operating characteristic (ROC) curves, PLA2G2A, GZMK, CD69, HSP90B1, and S100A11 reached an AUC value of 0.94, 0.95, 0.86, 0.89, and 0.93, respectively. Drug prediction revealed that decitabine, tetrachlorodibenzodioxin, tetradecanoylphorbol acetate, thapsigargin, and cisplatin were the potential small molecular compounds for PLA2G2A, GZMK, CD69, HSP90B1, and S100A11. Immune cell infiltration analysis demonstrated that the infiltration of CD4 memory T cell activation, macrophage M1, T macrophage M0, neutrophils, and mast cell activation was higher in the UC group than in the normal group.
ConclusionThe LLPSRGs play crucial roles in UC and can be used as prognostic and diagnostic markers for UC. The current findings contribute to the management of UC.
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Do SGLT2 Inhibitors Protect the Kidneys? An Alternative Explanation
By Jacob IlanyAvailable online: 08 January 2025More LessSGLT2 inhibitors are a family of drugs that were developed to treat diabetes mellitus. In randomized controlled trials, SGLT2 inhibitors seem to prevent kidney deterioration in patients with nephropathies, both diabetic and non-diabetic. However, in contrast to biochemical/physiological results (proteinuria and serum creatinine levels) that improve in all studies, the clinical results (all-cause mortality, cardiovascular death, need for dialysis, or renal transplant) do not consistently improve. In this article, the author would like to suggest that SGLT2 inhibitors do not, in fact, prevent the progression of renal diseases but rather alter laboratory results. This study will present a theory that gives an alternative explanation for the findings in the studies that would explain the above discrepancy between biochemical/physiological and clinical results. In general, the author claims that SGLT2 inhibitors change the kinetics of renal creatinine and microalbumin excretion but do not prevent parenchymal adverse changes in kidneys. This causes a dissociation between renal function markers (such as serum creatinine level and urinary protein) and the real kidney function. Thus, the clinical renal prognosis does not improve despite seemingly better laboratory results.
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Protective Effects of Hydrogen Treatment Against High Glucose-Induced Oxidative Stress and Apoptosis via Inhibition of the AGEs/RAGE/NF-κB Signaling Pathway in Skin Cells
Authors: Pan Yu, Nan Hong, Qiong Wu and Zhipeng ZhaoAvailable online: 08 January 2025More LessBackgroundDiabetic wounds are major clinical challenges, often complicated by oxidative stress and free radical generation. Hydrogen (H2), a selective antioxidant, offers potential as a therapeutic agent for chronic diabetic wounds. However, its precise mechanisms remain underexplored.
ObjectiveThis study aimed to investigate the protective effects of H2 on high glucose-induced oxidative damage and apoptosis in human skin cells.
MethodsHaCaT keratinocytes and HSF fibroblasts were treated with high glucose or AGEs. Cell viability, oxidative stress markers, inflammatory cytokines, and apoptosis were analyzed. AGEs/RAGE/NF-κB signaling was evaluated via Western blot.
ResultsH2 treatment significantly reduced ROS, MDA, IL-1β, and TNF-α levels, while enhancing SOD and GSH activity. It also inhibited AGEs/RAGE/NF-κB signaling and apoptosis.
ConclusionHydrogen therapy protects against oxidative stress and inflammation induced by high glucose or AGEs, offering potential as an adjunctive treatment for diabetic wound healing.
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Acute Suppurative Thyroiditis Caused by Gemella Morbillorum: A Case Report
Available online: 09 December 2024More LessBackgroundAcute suppurative thyroiditis (AST) is a rare form of thyroid inflammation prevalently of bacterial origin that usually affects subjects with risk factors such as immunodeficiency, sepsis, and neck fistulas. The most prevalent pathogens associated with AST are gram-positive aerobic bacteria, followed by gram-negatives, while infections by anaerobic germs are exceptionally rare. Gemella morbillorum is a facultative anaerobic gram-positive bacterium that commonly populates the upper respiratory tract. Infections by Gemella Morbillorum have been previously documented in different regions (ie. lung, brain, bone, liver), but never in the thyroid.
Case presentationAn 18-year-old male with no previous medical history presented to the emergency department complaining of a rapidly enlarging painful neck mass in left anterior latero-cervical region progressively worsening over the last two weeks, accompanied by dysphagia and fever. Blood tests showed the presence of thyroiditis (suppressed TSH with increased free thyroxine, elevated inflammation markers and neutrophilic leucocytosis). Neck ultrasonography and CT showed a large abscess involving the left thyroid lobe and extending to the ipsilateral laterocervical region, suggesting the diagnosis of AST. Prompt antibiotic therapy was started and subsequent surgical drainage of the abscess was performed, resulting in a rapid clinical recovery and the restoration of normal thyroid function. The bacterial culture of the abscess showed exclusively the presence of Gemella morbillorum.
ConclusionWe present the first documented case of AST caused by Gemella morbillorum in an otherwise healthy young man. Although rare, AST in immunocompetent patients is possible; prompt diagnosis and treatment of this condition are fundamental to avoid severe complications.
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The Molecular Determinants of Erythrocyte Removal Impact the Development of Metabolic Dysfunction-Associated Steatohepatitis
Available online: 09 December 2024More LessMetabolic dysfunction-associated steatohepatitis (MASH) is a major cause of a worldwide clinical and financial burden. Despite the tremendous efforts for untangling the molecular mechanisms, there is still a need for defining specific therapeutic targets. In this editorial, the author will focus on the role of erythrocyte death and hepatic erythrophagocytosis in MASH. Evidence indicates that erythrolysis prior to erythrophagocytosis protects against the development of MASH, while phagocytosis of intact erythrocytes culminates in hepatic inflammation. Furthermore, understanding the balance between erythrolysis and intact erythrocyte engulfment could lead to the development of new strategies for the treatment of MASH.
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Asymptomatic Hypocalcemia Related to Denosumab Administration in Bone-Metastatic Patient Affected by Colorectal Cancer: A Case Report
Available online: 05 December 2024More LessBackgroundDenosumab, a fully humanized monoclonal neutralizing antibody inhibiting the RANK/RANKL/OPG signaling pathway, is widely used for treating patients with bone metastases. However, its use in cancer patients with bone metastases is burdened by the risk of all grades of hypocalcemia, with the severe grade being rare. In the literature, several cases of severe symptomatic hypocalcemia have been reported, particularly in patients with breast and prostate cancers. In this report, we present a rare case of asymptomatic hypocalcemia in a 78 years-old patient with sigmoid cancer and bone metastases.
Case PresentationHypocalcemia was detected two weeks after the first denosumab administration, during routine biochemical evaluation. The patient reported only a mild nonspecific paresthesia after medical questioning, without relevant clinical symptoms. Despite the severity of the hypocalcemia, serum calcium levels began to improve after a short period of low-dose calcium and calcitriol therapy, though complete stabilization and normalization occurred after several weeks.
ConclusionThis case highlight the importance to consider severe paucisymptomatic or asymptomatic hypocalcemia as a possible side effect in bone-metastatic patients treated with denosumab. It is advisable to monitor serum calcium levels even in the absence of typical hypocalcemia-related symptoms.
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