New Perspectives on Obesity-Associated Nephropathy from Pathophysiology to Therapeutics: Revealing the Promise of GLP-1 RA Therapy.

Obesity represents a substantial risk factor for a multitude of metabolic disorders, which seriously threatens human life and health. As the global obesity epidemic intensifies, obesity-related nephropathy (ORN) has attracted great attention. ORN arises from both physical/mechanical and non-physical insults to the glomerular and tubular structures precipitated by obesity, culminating in structural impairments and functional aberrations within the kidneys. Physical injury factors include changes in renal hemodynamics, renal compression, and mechanical stretching of podocytes. Non-physical injury factors include overactivation of the RAAS system, insulin resistance, lipotoxicity, inflammation, and dysregulation of bile acid metabolism. Exploring molecules that target modulation of physical or nonphysical injury factors is a potential approach to ORN treatment. ORN is characterized clinically by microproteinuria and pathologically by glomerulomegaly, which is atypical and makes early diagnosis difficult. Investigating early diagnostic markers for ORN thus emerges as a critical direction for future research. Additionally, there is no specific drug for ORN in clinical treatment, which mainly focuses on weight reduction, mitigating proteinuria, and preserving renal function. In our review, we delineate a progressive therapeutic approach involving enhancements in lifestyle, pharmacotherapy, and bariatric surgery. Our emphasis underscores glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as poised to emerge as pivotal therapeutic modalities for ORN in forthcoming clinical avenues.

Correlation between thyroid hormone sensitivity and diabetic peripheral neuropathy in euthyroid patients with type 2 diabetes mellitus.

Previous studies have revealed that thyroid hormone (TH) levels are associated with the risk of diabetic peripheral neuropathy (DPN) in euthyroid patients with type 2 diabetes mellitus (T2DM). However, the relationship between TH sensitivity, a complementary method for assessing thyroid function, and DPN remains unclear. This study aimed to investigate the correlation between DPN and TH sensitivity in euthyroid patients with T2DM. Exactly 708 euthyroid adults with T2DM were retrospectively enrolled. The FT3/FT4 ratio was used to estimate peripheral TH sensitivity. Central TH sensitivity was assessed using the Thyrotroph T4 Resistance Index (TT4RI), Thyroid-Stimulating Hormone Index (TSHI), Thyroid Feedback Quantile-based Index (TFQI), and Parametric TFQI (PTFQI). DPN was assessed using neurologic symptoms, signs, and nerve conduction velocity tests. The relationship between DPN and TH sensitivity was examined using logistic regression analysis. We observed that an elevated FT3/FT4 ratio was associated with DPN (OR = 1.36, 95%CI: 1.13-1.63, p = 0.0012). For each standard deviation (SD) increase in the TT4RI, TSHI, TFQI, and PTFQI, the OR of DPN was 0.80 (95%CI: 0.68-0.94, p = 0.0078), 0.72 (95%CI: 0.60-0.86, p = 0.0002), 0.69 (95%CI: 0.58-0.83, p < 0.0001), and 0.69 (95%CI: 0.58-0.82, p < 0.0001), respectively. These results suggested that reduced central and peripheral TH sensitivity is associated with a decreased risk of developing DPN.

Clinical features and risk factors for postoperative recurrence in patients with Cushing's syndrome of different etiologies.

The clinical characteristics of Cushing's syndrome (CS) vary with etiology, and few studies have investigated the risk factors affecting CS recurrence after surgery. This retrospective study involved 202 patients diagnosed with CS between December 2012 and December 2022. The patients were divided into three groups according to etiology: Cushing's disease (CD), adrenocortical adenoma (ACA), and ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). Of the patients with CS, 41.9% had hypokalemia and 15.0% had hypophosphatemia. The cortisol levels were negatively correlated with blood potassium, blood chlorine, and blood phosphorus. Moreover, 22.4% of patients had an abnormal heart structure, 11.2% had centripetal remodeling, 5.6% had centripetal hypertrophy, and 5.6% had centrifugal hypertrophy. The overall recurrence rate of CS caused by pituitary tumors and adrenal adenoma was 25.7%. The recurrence times were longer in the ACA group versus the CD group, in patients < 50 years of age versus in patients ≥ 50 years old group, and in patients with CD with tumors ≥ 1 cm versus tumors < 1 cm. Age, preoperative cortisol level, postoperative cortisol level, and absolute neutrophil value were closely related to postoperative recurrence, and etiology was an independent predictor of tumor recurrence in patients with CS. The results of this study showed that CS caused by different etiologies showed different clinical manifestations, blood electrolyte characteristics, and that CS could affect patient cardiac structure and function. Etiology is an independent predictor of tumor recurrence in patients with CS.

Bacteroidaceae, Bacteroides, and Veillonella: emerging protectors against Graves' disease.

Background: Graves' disease (GD) is the most common cause of hyperthyroidism, and its pathogenesis remains incompletely elucidated. Numerous studies have implicated the gut microbiota in the development of thyroid disorders. This study employs Mendelian randomization analysis to investigate the characteristics of gut microbiota in GD patients, aiming to offer novel insights into the etiology and treatment of Graves' disease. Methods: Two-sample Mendelian randomization (MR) analysis was employed to assess the causal relationship between Graves' disease and the gut microbiota composition. Gut microbiota data were sourced from the international consortium MiBioGen, while Graves' disease data were obtained from FINNGEN. Eligible single nucleotide polymorphisms (SNPs) were selected as instrumental variables. Multiple analysis methods, including inverse variance-weighted (IVW), MR-Egger regression, weighted median, weighted mode, and MR-RAPS, were utilized. Sensitivity analyses were conducted employing MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis as quality control measures. Results: The Mendelian randomization study conducted in a European population revealed a decreased risk of Graves' disease associated with Bacteroidaceae (Odds ratio (OR) [95% confidence interval (CI)]: 0.89 [0.89 ~ 0.90], adjusted P value: <0.001), Bacteroides (OR: [95% CI]: 0.555 [0.437 ~ 0.706], adjusted P value: <0.001), and Veillonella (OR [95% CI]: 0.632 [0.492 ~ 0.811], adjusted P value: 0.016). No significant evidence of heterogeneity, or horizontal pleiotropy was detected. Furthermore, the preliminary MR analysis identified 13 bacterial species including Eubacterium brachy group and Family XIII AD3011 group, exhibiting significant associations with Graves' disease onset, suggesting potential causal effects. Conclusion: A causal relationship exists between gut microbiota and Graves' disease. Bacteroidaceae, Bacteroides, and Veillonella emerge as protective factors against Graves' disease development. Prospective probiotic supplementation may offer a novel avenue for adjunctive treatment in the management of Graves' disease in the future.

Unraveling the mystery: a Mendelian randomized exploration of gut microbiota and different types of obesity.

Background: Numerous studies have demonstrated the influence of gut microbiota on the development of obesity. In this study, we utilized Mendelian randomization (MR) analysis to investigate the gut microbiota characteristics among different types of obese patients, aiming to elucidate the underlying mechanisms and provide novel insights for obesity treatment. Methods: Two-sample multivariable Mendelian randomization (MR) analysis was employed to assess causal relationships between gut microbiota and various obesity subtypes. Gut microbiota data were obtained from the international consortium MiBioGen, and data on obese individuals were sourced from the Finnish National Biobank FinnGen. Eligible single-nucleotide polymorphisms (SNPs) were selected as instrumental variables. Various analytical methods, including inverse variance weighted (IVW), MR-Egger regression, weighted median, MR-RAPS, and Lasso regression, were applied. Sensitivity analyses for quality control included MR-Egger intercept tests, Cochran's Q tests, and leave-one-out analyses and others. Results: Mendelian randomization studies revealed distinct gut microbiota profiles among European populations with different obesity subtypes. Following multivariable MR analysis, we found that Ruminococcaceae UCG010 [Odds Ratio (OR): 0.842, 95% confidence interval (CI): 0.766-0.926, Adjusted P value: 0.028] independently reduced the risk of obesity induced by excessive calorie intake, while Butyricimonas [OR: 4.252, 95% CI: 2.177-8.307, Adjusted P value: 0.002] independently increased the risk of medication-induced obesity. For localized adiposity, Pasteurellaceae [OR: 0.213, 95% CI: 0.115-0.395, Adjusted P value: <0.001] acted as a protective factor. In the case of extreme obesity with alveolar hypoventilation, lactobacillus [OR: 0.724, 95% CI: 0.609-0.860, Adjusted P value: 0.035] reduced the risk of its occurrence. Additionally, six gut microbiota may have potential roles in the onset of different types of obesity. Specifically, the Ruminococcus torques group may increase the risk of its occurrence. Desulfovibrio and Catenabacterium may serve as protective factors in the onset of Drug-induced obesity. Oxalobacteraceae, Actinomycetaceae, and Ruminiclostridium 9, on the other hand, could potentially increase the risk of Drug-induced obesity. No evidence of heterogeneity or horizontal pleiotropy among SNPs was found in the above studies (all P values for Q test and MR-Egger intercept > 0.05). Conclusion: Gut microbiota abundance is causally related to obesity, with distinct gut microbiota profiles observed among different obesity subtypes. Four bacterial species, including Ruminococcaceae UCG010, Butyricimonas, Pasteurellaceae and lactobacillus independently influence the development of various types of obesity. Probiotic and prebiotic supplementation may represent a novel approach in future obesity management.

Causality between sarcopenia and diabetic nephropathy: a bidirectional Mendelian randomization study.

Background and purpose: Observational studies have shown that sarcopenia and diabetic nephropathy (DN), are closely related; however, the causal relationship is unclear. This study aims to address this issue using a bidirectional Mendelian randomization (MR) study. Methodology: We data from genome-wide association studies including appendicular lean mass (n = 244,730), grip strength (right: n = 461,089, left: n = 461026), walking speed (n = 459,915), and DN (3283 cases and 181,704 controls) to conduct a bidirectional MR study. First, we conducted a Forward MR analysis to evaluate the causality of sarcopenia on the risk of DN from the genetic perspective with appendicular lean mass, grip strength, and walking speed as exposure and DN as the outcome. Then, DN as the exposure, we performed a Reverse MR analysis to determine whether DN impacted the appendicular lean mass, grip strength, and walking speed of the appendices. Finally, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and Leave-one-out analyses, were conducted to assess the MR analysis's accuracy further. Results: According to a forward MR analysis, a genetically predicted decrease in appendicular lean mass is associated with an increased risk of developing DN risk (inverse variance weighting[IVW]: odd ratio [OR] = 0.863, 95% confidence interval [CI] 0.767-0.971; P = 0.014). According to reverse MR results, grip strength decreased as DN progressed (IVW: right ß = 0.003, 95% CI: - 0.021 to - 0.009, P = 5.116e-06; left ß = 0.003, 95% CI: - 0.024 to - 0.012, P = 7.035e-09). However, the results of the other MR analyses were not statistically different. Conclusion: Notably, our findings suggest that the causal relationship between sarcopenia and DN cannot be generalized. According to analysis of the individual characteristic factors of sarcopenia, reducing in appendicular lean mass increases the risk of developing DN and DN is linked to reduced grip strength. But overall, there is no causal relationship between sarcopenia and DN, because the diagnosis of sarcopenia cannot be determined by one of these factors alone.

The role of lipotoxicity in kidney disease: From molecular mechanisms to therapeutic prospects.

Lipotoxicity is the dysregulation of the lipid environment and/or intracellular composition that leads to accumulation of harmful lipids and ultimately to organelle dysfunction, abnormal activation of intracellular signaling pathways, chronic inflammation and cell death. It plays an important role in the development of acute kidney injury and chronic kidney disease, including diabetic nephropathy, obesity-related glomerulopathy, age-related kidney disease, polycystic kidney disease, and the like. However, the mechanisms of lipid overload and kidney injury remain poorly understood. Herein, we discuss two pivotal aspects of lipotoxic kidney injury. First, we analyzed the mechanism of lipid accumulation in the kidney. Accumulating data indicate that the mechanisms of lipid overload in different kidney diseases are inconsistent. Second, we summarize the multiple mechanisms by which lipotoxic species affect the kidney cell behavior, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, dysregulated autophagy, and inflammation, highlighting the central role of oxidative stress. Blocking the molecular pathways of lipid accumulation in the kidney and the damage of the kidney by lipid overload may be potential therapeutic targets for kidney disease, and antioxidant drugs may play a pivotal role in the treatment of kidney disease in the future.

Structural Relationships between Counselors' Sense of Calling, Meaning of Work, Living a Calling, and Psychological Burnout.

This study examined the influence of counselors' sense of calling on psychological burnout, mediated by meaning of work and living a calling, based on the work as a calling theory (WCT) and preceding studies. Furthermore, the sequential mediating effects of meaning of work and living a calling were investigated. Data were collected from 420 Korean counselors working in counseling centers located nationwide and analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM). The results revealed that a sense of calling negatively impacted psychological burnout. Second, the sense of calling did not affect psychological burnout through the mediation of meaning of work. Third, the sense of calling negatively impacted psychological burnout through the mediation of living a calling. Fourth, the sense of calling negatively affected psychological burnout through the sequential mediation of meaning of work and living a calling. Based on this study's findings, implications can be provided to enhance counselors' professional calling and reduce psychological burnout, thereby aiding them in resolving their psychological issues during counseling practice and providing higher-quality psychological services to clients. Suggestions for improvements and future research are also discussed.

Pathogenesis, clinical features, and treatment of plurihormonal pituitary adenoma.

Plurihormonal pituitary adenoma (PPA) is a type of pituitary tumor capable of producing two or more hormones and usually presents as an aggressive, large adenoma. As yet, its pathogenesis remains unclear. This is the first study to systematically summarize the underlying pathogenesis of PPA. The pathogenesis is related to plurihormonal primordial stem cells, co-transcription factors, hormone co-expression, differential gene expression, and cell transdifferentiation. We conducted a literature review of PPA and analyzed its clinical characteristics. We found that the average age of patients with PPA was approximately 40 years, and most showed only one clinical symptom. The most common manifestation was acromegaly. Currently, PPA is treated with surgical resection. However, recent studies suggest that immunotherapy may be a potentially effective treatment.

Pathogenesis of central nervous system germ cell tumors.

Intracranial germ cell tumors (IGCTs) are clinically rare. They are more common in children and adolescents and the incidence in Asia is higher than in Western countries. Histologically, IGCTs are divided into germinoma and non-germinomatous germ cell tumor (NGGCT). Germinoma is sensitive to radiotherapy and chemotherapy and therefore, patients with germinoma have a good prognosis. However, NGGCTs, especially those with malignant components, are not sensitive to radiotherapy and chemoradiotherapy, leading to a poor prognosis. The pathogenesis of IGCTs is not fully understood. By summarizing previous literature, we found that the occurrence of IGCTs may be related to the following factors: chromosomal instability, MAPK and/or PI3K pathway changes, and DNA hypomethylation in pure germ cell tumors.