A Case of Autoimmune Hepatitis Initially Manifesting as Hepatic Encephalopathy.

Autoimmune hepatitis (AIH) is a T-cell-mediated liver disease characterized by elevated transaminases, circulating autoantibodies, hypergammaglobulinemia, and interface hepatitis. A 66-year-old female patient visited our department due to recurrent episodes of altered consciousness, sleep-wake inversion, and asterixis, indicating hepatic encephalopathy (HE). Her liver biopsy results clearly demonstrated interface hepatitis. The patient's severe HE does not parallel her relatively stable liver function and was attributed to a wide retroperitoneal collateral vein shunting blood directly into the inferior vena cava, bypassing the liver, and allowing excess neurotoxins to enter the central nervous system. Due to the unfavorable benefit-risk ratio of embolization and the patient's stable liver function, non-invasive treatments were adopted, and prednisolone was discontinued. The patient experienced no further episodes of HE thereafter. To the best of our knowledge, this is the first AIH case with a spontaneous portosystemic shunt directly shunting blood into the inferior vena cava. A crucial lesson from this case is that when HE cannot be fully explained by liver dysfunction, abdominal CT scans should be carefully inspected for possible anatomical variations. This case also underscores the importance of a multidisciplinary approach in managing AIH in elderly patients, who may benefit more from a tailored treatment regimen rather than strictly following standard treatment guidelines.

KLF13 restrains Dll4-muscular Notch2 axis to improve the muscle atrophy.

BACKGROUND: Muscle atrophy can cause muscle dysfunction and weakness. Krüppel-like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target. METHODS: The effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell-based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing. RESULTS: In a dexamethasone-induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P < 0.01), muscle weight (%) [gastrocnemius (Gas): 76.0 ± 5.69 vs. 60.7 ± 7.23, P < 0.001; tibialis anterior (TA): 75.8 ± 6.21 vs. 67.5 ± 5.01, P < 0.05], and exhaustive running distance (m) (495.5 ± 64.8 vs. 315.5 ± 60.9, P < 0.05) compared with the control group. KLF13 overexpression preserved muscle mass (Gas: 100 ± 6.38 vs. 120 ± 14.4, P < 0.01) and the exhaustive running distance (423.8 ± 59.04 vs. 530.2 ± 77.45, P < 0.05) in an in vivo diabetes-induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone-induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy-inducing glucocorticoid, were aggravated by KLF13 knockout, but anti-atrophic effects were achieved by inducing KLF13 overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta-like 4 (Dll4) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4-Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited KLF13 expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)-mediated KLF13 transcriptional activation and promoting F-Box and WD repeat domain containing 7 (i.e., FBXW7)-mediated KLF13 ubiquitination. CONCLUSIONS: This study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.

Multimorbidity measures associated with cognitive function among community-dwelling older Chinese adults.

INTRODUCTION: Older adults with multimorbidity are at high risk of cognitive impairment development. There is a lack of research on the associations between different multimorbidity measures and cognitive function among older Chinese adults living in the community. METHODS: We used the Chinese Longitudinal Healthy Longevity Survey from 2002 to 2018 and included data on dementia-free participants aged ≥65 years. Multimorbidity measures included condition counts, multimorbidity patterns, and trajectories. The association of multimorbidity measures with cognitive function was examined by generalized estimating equation and linear and logistic regression models. RESULTS: Among 14,093 participants at baseline, 43.2% had multimorbidity. Multimorbidity patterns were grouped into cancer-inflammatory, cardiometabolic, and sensory patterns. Multimorbidity trajectories were classified as "onset-condition," "newly developing," and "severe condition." The Mini-Mental State Examination scores were significantly lower for participants with more chronic conditions, with cancer-inflammatory/cardiometabolic/sensory patterns, and with developing multimorbidity trajectories. DISCUSSION: Condition counts, sensory pattern, cardiometabolic pattern, cancer-inflammatory pattern, and multimorbidity developmental trajectories were prospectively associated with cognitive function. HIGHLIGHTS: Elderly individuals with a higher number of chronic conditions were associated with lower MMSE scores in the Chinese Longitudinal Healthy Longevity Survey data. MMSE scores were significantly lower for participants with specific multimorbidity patterns. Individuals with developing trajectories of multimorbidity were associated with lower MMSE scores and a higher risk of mild cognitive impairment.

Research Hotspots and Trends of Interventions for Sarcopenic Obesity: A Bibliometric Analysis.

Sarcopenic obesity, characterized by both obesity and sarcopenia, significantly impacts health and independence of affected individuals. There is an urgent need to explore effective strategies for addressing or preventing sarcopenic obesity. An initial critical step is to promptly assess the impact of academic research in this field, considering factors such as geographical regions, authors, journals, and institutions. It is also essential to analyze current trends and identify potential areas that may inspire future researchers to conduct further studies, ultimately improving public health outcomes for individuals with sarcopenic obesity. To achieve this, bibliometric research was conducted using the Web of Science Core Collection database to identify English language articles and reviews focusing on sarcopenic obesity interventions published between January 1, 2004, and June 15, 2024, followed by a literature review. A total of 929 English-language articles were collected, consisting of 645 research articles and 284 reviews. Research output in the field has shown significant growth since 2017, reaching a peak of 139 papers in 2022. The United States leads in publication output with 234 papers and a total of 13,971 citations, highlighting substantial international collaboration. Both the United States and Europe are recognized as key academic hubs for sarcopenic obesity intervention research, characterized by robust academic interactions. Moreover, there has been a notable increase in publication volume from China, South Korea, and Japan. Noteworthy authors in this field include Boirie Y from Université Clermont Auvergne in France, Prado CM from the University of Alberta in Canada, Cruz-Jentoft AJ from Hospital Universitario Ramon y Cajal in Spain, and Prado CM from the University of Alberta, known for their high citation count. The University of Alberta leads in the number of publications, while the University of Verona in Italy leads in citation frequency. Journals with higher publication volumes in sarcopenic obesity intervention include Nutrients, Clinical Nutrition, and Journal of Cachexia Sarcopenia and Muscle. Among the top 20 keywords, the most relevant interventions for sarcopenic obesity are exercise, nutrition, resistance training, physical activity, and muscle strength. The primary evidence currently available suggests that resistance training is the most effective method for enhancing muscle strength in sarcopenic obesity patients. Additionally, combining protein supplementation with resistance exercise has shown encouraging results in reducing fat mass in these individuals. To progress in this field, it is crucial to foster collaboration among countries, regions, and academic institutions, promoting multidisciplinary partnerships.

Different prognosis in cutaneous early-onset and late-onset Merkel cell carcinoma: a population-based retrospective study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and highly aggressive form of skin cancer. However, there is limited research on the clinicopathological features of early-onset MCC (EOMCC) and the differences between EOMCC and late-onset MCC (LOMCC). Our objective was to evaluate the clinicopathological features and cancer-specific survival (CSS) of EOMCC. METHODS: Our cohort study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2018, to December 31, 2020. Data from 1941 patients who were diagnosed with primary cutaneous MCC were included. We then divided the patients with MCC into two groups: those with EOMCC (526 patients) and those with LOMCC (1415 patients). CSS is used as the primary outcome. RESULTS: The EOMCC group exhibited trends toward advanced tumor progression, an expanded surgical scope, increased lymph node retrieval, intensified radiotherapy, greater utilization of systemic therapy, and a better prognosis. Multivariate analysis revealed that LOMCC (HR 3.305 [2.002-5.456], P < 0.001), advanced T stage (HR 1.430 [1.139-1.797], P = 0.002), advanced N stage (HR 1.522 [1.221-1.897], P < 0.001), M1 stage (HR 2.587 [1.480-4.521], P < 0.001), and radiation (HR 0.586 [0.410-0.837], P = 0.003) were significantly associated with CSS. Among these factors, EOMCC/LOMCC was most strongly associated with CSS, indicating that LOMCC is an independent risk factor for CSS. Interestingly, we found that regional EOMCC and localized or in situ LOMCC had almost completely overlapping survival curves (Plog-rank = 0.620). Additionally, we observed that the TNM staging + age model was a more accurate predictor of CSS among MCC patients than using TNM staging alone. CONCLUSIONS: We found that EOMCC has distinct clinicopathological features compared to LOMCC. EOMCC is associated with better CSS. The combination of TNM staging and age was more accurate for predicting patient outcomes than TNM staging alone.

A Case of Pulmonary Actinomycosis With Concurrent Gastric Adenocarcinoma in an Older Adult.

Actinomycosis is a chronic granulomatous disease that can affect various parts of the body, including the head and neck, lungs, abdominal and pelvic cavities, and wounds. It is caused by different actinomycetes like Actinomyces sherdii, Actinomyces glasii, Actinomyces cariosa, Actinomyces zurichensis, and Actinomyces europaea. Reported infections caused by actinomycetes include pulmonary actinomycosis, pelvic and abdominal infections, bone or artificial joint infections, endocarditis, complicated urinary tract infections, and soft tissue abscesses. The combination of pulmonary actinomycosis with gastric cancer is exceptionally rare in clinical practice, and the presence of actinomycetal infection alongside tumors in elderly patients poses significant challenges in treatment. This article presents the diagnosis and treatment process of an elderly patient with pulmonary actinomycosis and gastric adenocarcinoma.

Albumin-bilirubin grade as a predictor of survival in hepatocellular carcinoma patients with thrombocytopenia.

BACKGROUND: The models for assessing liver function, mainly the Child-Pugh (CP), albuminbilirubin (ALBI), and platelet-ALBI (PALBI) classifications, have been validated for use in estimating the prognosis of hepatocellular carcinoma (HCC) patients. However, thrombocytopenia is a common finding and may influence the prognostic value of the three models in HCC. AIM: To investigate and compare the prognostic performance of the above three models in thrombocytopenic HCC patients. METHODS: A total of 135 patients with thrombocytopenic HCC who underwent radical surgery were retrospectively analyzed. Preoperative scores on the CP, ALBI and PALBI classifications were estimated accordingly. Kaplan-Meier curves with log-rank tests and Cox regression models were used to explore the significant factors associated with overall survival (OS) and recurrence-free survival (RFS). RESULTS: The preoperative platelet counts were significantly different among the CP, ALBI and PALBI groups. After a median follow-up of 28 mo, 39.3% (53/135) of the patients experienced postoperative recurrence, and 36.3% (49/135) died. Univariate analysis suggested that α-fetoprotein levels, tumor size, vascular invasion, and ALBI grade were significant predictors of OS and RFS. According to the multivariate Cox regression model, ALBI was identified as an independent prognostic factor. However, CP and PALBI grades were not statistically significant prognostic indicators. CONCLUSION: The ALBI grade, rather than CP or PALBI grade, is a significant prognostic indicator for thrombocytopenic HCC patients.

[Cell membrane-coated nanoparticles in disease therapy].

Nanotechnology has attracted increasing attention in the field of medical applications due to its significant potential for development. However, one major challenge that has emerged with nanoparticles is their tendency to activate the host immune clearance system, which hampers the achievement of desired therapeutic outcomes and may lead to harmful side effects. In recent years, membrane-coated nanoparticles have emerged as a promising solution, demonstrating their effectiveness in evading immune system clearance. These innovative nanoparticles inherit essential biological attributes from natural cell membranes, such as anchoring proteins and antigens. Consequently, membrane-coated nanoparticles exhibit unique capabilities such as immune evasion, prolonged circulation, targeted drug release, and immune modulation, substantially enhancing their versatility and prospects within the realm of biomedical applications. This review provides a comprehensive overview of the current applications of cell membrane-coated nanoparticles in disease therapy, highlighting their immense potential in this rapidly evolving platform. Additionally, the review outlines the promising prospects of this technology in disease therapy.

Radiotherapy and Anrotinib in Malignant Glomus Tumor of the Bladder: A Case Report and Literature Review.

Background: Malignant glomus tumors (MGTs) are rare malignancies, which grow rapidly and are aggressive. Surgical resection has been regarded as the standard management, but treatment options for those unresectable tumors are limited, resulting in a high recurrence rate and poor prognosis. Case Description: An 85-year-old man presented with gross hematuria and was diagnosed with MGTs of bladder. The patient achieved long-term local control after multimodal therapy comprising radiotherapy, iodine-125 seeds brachytherapy, transcatheter arterial chemoembolization, and antiangiogenic targeted therapy. Conclusion: MGTs occurring in the bladder are clinically rare and refractory. The case presented here highlights the importance of multidisciplinary diagnosis and treatment, providing evidence that radiotherapy and antiangiogenic therapy may play an important role in unresectable bladder MGT.

Magnesium Depletion Score and Metabolic Syndrome in US Adults: Analysis of NHANES 2003-2018.

BACKGROUND: The association between magnesium status and metabolic syndrome remains unclear. This study aimed to examine the relationship between the kidney reabsorption-related magnesium depletion score (MDS) and metabolic syndrome among US adults. METHODS: We analyzed data from 15,565 adults participating in the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Metabolic syndrome was defined according to the National Cholesterol Education Program's Adult Treatment Panel III report. The MDS is a scoring system developed to predict the status of magnesium deficiency that fully considers the pathophysiological factors influencing the kidneys' reabsorption capability. Weighted univariate and multivariate logistic regression were used to assess the association between MDS and metabolic syndrome. Restricted cubic spline analysis was conducted to characterize dose-response relationships. Stratified analyses by sociodemographic and lifestyle factors were also performed. RESULTS: In both univariate and multivariate analyses, higher MDS was significantly associated with increased odds of metabolic syndrome. Each unit increase in MDS was associated with approximately a 30% higher risk for metabolic syndrome, even after adjusting for confounding factors (OR 1.31; 95% CI 1.17-1.45). Restricted cubic spline graphs depicted a linear dose-response relationship across the MDS range. This positive correlation remained consistent across various population subgroups and exhibited no significant interaction by age, gender, race, adiposity, smoking status, or alcohol consumption. CONCLUSIONS: Higher urinary magnesium loss as quantified by MDS may be an independent linear risk factor for metabolic syndrome in US adults, irrespective of sociodemographic and behavioral factors. Optimizing magnesium nutritional status could potentially confer benefits to patients with metabolic syndrome.

Skeletal muscle extramedullary plasmacytoma transformed into plasmablastic plasmacytoma: a case report.

BACKGROUND: Extramedullary plasmacytoma (EMP) is a rare plasma cell malignancy, especially when the tumor originates in skeletal muscle. Plasmablastic plasmacytoma is an anaplastic round cell tumor with highly malignancy and poor prognosis. To date, there have been no reports on the transformation of skeletal muscle EMP into plasmablastic plasmacytoma. Therefore, the diagnosis, treatment, and prognosis of cases of this pathologic transformation are unclear. CASE PRESENTATION: This article reports a case of an elderly male patient who presented with a painless mass in the right calf and was diagnosed with EMP by puncture pathology. Complete remission was obtained after sequential chemoradiotherapy. 6 months later, another puncture was performed due to plasmablastic plasmacytoma multiple distant metastases, and the pathology showed that EMP was transformed to plasmablastic plasmacytoma. Despite aggressive antitumor therapy, the disease continued to deteriorate, and the patient ultimately died of respiratory failure. CONCLUSION: The transformation of EMP into plasmablastic plasmacytoma is very rare, and its diagnosis and treatment require the participation of both experienced pathologists and clinicians. We report this case in order to raise clinicians' awareness of the diagnosis and treatment of EMP and its transformation to plasmablastic plasmacytoma, and to avoid misdiagnosis and underdiagnosis.

Porphyrin Derivative with Binary Properties of Photodynamic Therapy and Water-Dependent Reversible Photoacidity Therapy for Treating Hypoxic Tumor.

Porphyrin photosensitizers are the classic drugs in clinical photodynamic therapy (PDT), but the hypoxia of tumor environment and the rapid oxygen consumption of PDT severely weaken their therapeutic effect. A recently reported water-dependent reversible photoacidity therapy (W-RPAT) is O2-independence, providing a solution for the treatment of hypoxic tumors. In this work, TPP-O-PEG5, a porphyrin derivative with binary properties of PDT and W-RPAT, is designed and synthesized for the first time. The nanoparticles (NPs) of TPP-O-PEG5 encapsulated with DSPE-mPEG2000, an amphiphilic polymer approved by Food and Drug Administration, can simultaneously produce reactive oxygen species and H+ under irradiation of a 660 nm laser, and revert the H+ back under darkness, presenting strong phototoxicity to multiple tumor cell lines with no obvious difference between the IC50 values tested under normoxic (≈20% O2) and hypoxic (<0.5% O2) conditions. Excitingly, in vivo experiments show that the therapeutic effect of TPP-O-PEG5 NPs on large hypoxic tumors is better than that of NPe6, a clinical porphin PDT drug. This work provides a novel strategy for porphyrin photosensitizers to break through the limitation of hypoxic environment, and significantly improve the phototherapeutic effect on hypoxic tumors.

Oral probiotics microgel plus Galunisertib reduced TGF-ß blockade resistance and enhanced anti-tumor immune responses in colorectal cancer.

Transforming growth factor ß (TGF-ß), a versatile immunosuppressive cytokine, has gained increasing attention as a potential target for cancer immunotherapy. However, current strategies are constrained by tumor heterogeneity and drug resistance. Therapeutic probiotics, such as Escherichia coli Nissle1917 (EcN), not only regulate the gut microbiota to increase beneficial bacteria with anti-tumor effects, but also modulate immune factors within the body, thereby enhancing immunity. In this study, we developed an oral microgel delivery system of EcN@(CS-SA)2 by electrostatic interaction between chitosan (CS) and sodium alginate (SA), aiming to enhance its bioavailability in the gastrointestinal tract (GIT). Notably, EcN@(CS-SA)2 microgel showed a synergistic enhancement of the anti-tumor efficacy of Galunisertib (Gal, a TGF-ß inhibitor) by inducing apoptosis and immunogenic cell death (ICD) in tumor cells, as well as promoting increased infiltration of CD8+ T cells into the tumor microenvironment (TME).

Photoacid Generators for Biomedical Applications.

Photoacid generators (PAGs) are compounds capable of producing hydrogen protons (H+ ) upon irradiation, including irreversible and reversible PAGs, which have been widely studied in photoinduced polymerization and degradation for a long time. In recent years, the applications of PAGs in the biomedical field have attracted more attention due to their promising clinical value. So, an increasing number of novel PAGs have been reported. In this review, the recent progresses of PAGs for biomedical applications is systematically summarized, including tumor treatment, antibacterial treatment, regulation of protein folding and unfolding, control of drug release and so on. Furthermore, a concept of water-dependent reversible photoacid (W-RPA) and its antitumor effect are highlighted. Eventually, the challenges of PAGs for clinical applications are discussed.

Post-transcriptional control of the essential enzyme MurF by a small regulatory RNA in Brucella abortus.

Brucella abortus is a facultative, intracellular, zoonotic pathogen that resides inside macrophages during infection. This is a specialized niche where B. abortus encounters various stresses as it navigates through the macrophage. In order to survive this harsh environment, B. abortus utilizes post-transcriptional regulation of gene expression through the use of small regulatory RNAs (sRNAs). Here, we characterize a Brucella sRNAs called MavR (for MurF- and virulence-regulating sRNA), and we demonstrate that MavR is required for the full virulence of B. abortus in macrophages and in a mouse model of chronic infection. Transcriptomic and proteomic studies revealed that a major regulatory target of MavR is MurF. MurF is an essential protein that catalyzes the final cytoplasmic step in peptidoglycan (PG) synthesis; however, we did not detect any differences in the amount or chemical composition of PG in the ΔmavR mutant. A 6-nucleotide regulatory seed region within MavR was identified, and mutation of this seed region resulted in dysregulation of MurF production, as well as significant attenuation of infection in a mouse model. Overall, the present study underscores the importance of sRNA regulation in the physiology and virulence of Brucella.

Polypyrrole regulates Active Sites in Co-based Catalyst in Direct Borohydride Fuel Cells.

Direct borohydride fuel cells (DBFCs) convert borohydride (NaBH4) chemical energy into clean electricity. However, catalytic active site deactivation in NaBH4 solution limits their performance and stability. We propose a strategy to regulate active sites in Co-based catalysts using polypyrrole modification (Co-PX catalyst) to enhance electrochemical borohydride oxidation reaction (eBOR). As an anode catalyst, the synthesized Co-PX catalyst exhibits excellent eBOR performance in DBFCs, with current density of 280 mA ⋅ cm-2 and power density of 151 mW ⋅ cm-2, nearly twice that of the unmodified catalyst. The Co-PX catalyst shows no degradation after 120-hour operation, unlike the rapidly degrading control. In-situ electrochemical attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIRS) and density functional theory (DFT) suggest that polypyrrole-modified carbon support regulate the charge distribution, increasing oxidation state and optimizing adsorption/desorption of intermediates. A possible reaction pathway is proposed. This work presents a promising strategy for efficient polymer-modulated catalysts in advanced DBFCs.

Validation and Comparison of Four Mortality Prediction Models in a Geriatric Ward in China.

Purpose: The efficacy of mortality risk prediction models among older patients in China remains uncertain. We aimed to validate and compare the performances of the Walter Index, Geriatric Prognostic Index (GPI), Charlson Comorbidity Index (CCI), and FRAIL Scale in predicting 1-year all-cause mortality post-discharge in geriatric inpatients in China. Patients and Methods: This study was conducted at a geriatric ward of a tertiary Hospital in Beijing, including patients aged 70 years or older with a documented comprehensive geriatric assessment, discharged between January 1, 2016, and December 31, 2021. Patients with a hospital stay ≤24 h or >60 days were excluded. All-cause mortality data within one year of discharge were collected from medical files and telephone interviews between August 2022 and February 2023. Multiple imputation, Logistic regression analysis, Brier scores, C-statistics, Hosmer-Lemeshow goodness-of-fit-test, and calibration plots were employed for statistical analysis. Results: We included 832 patients with a median (interquartile range) age of 77 (74-82) years. One-hundred patients (12.0%) died within one year. After adjusting for covariates-marital status, social support, cigarette use, length of stay, number of medications, hemoglobin levels, handgrip strength, and Short Physical Performance Battery-CCI scores of 3-4 and >4, and increased Walter Index, GPI, and FRAIL Scale scores were significantly associated with 1-year mortality risk. The Brier scores varied from 0.07 (Walter Index) to 0.10 (FRAIL Scale). The C-statistic ranged from 0.74 (95% confidence interval, 0.69-0.78) for FRAIL Scale to 0.88 (95% confidence interval, 0.84-0.91) for the Walter Index. Calibration curves showed that the Walter Index, GPI, and FRAIL Scale were well calibrated, while the CCI was poor. Conclusion: Combining the Brier score, discrimination and calibration, the Walter Index was confirmed for the first time to be the best model to predict the 1-year mortality risk of geriatric inpatients in China among the four models.

Inhibition of PFKP in renal tubular epithelial cell restrains TGF-ß induced glycolysis and renal fibrosis.

Metabolic reprogramming to glycolysis is closely associated with the development of chronic kidney disease (CKD). Although it has been reported that phosphofructokinase 1 (PFK) is a rate-limiting enzyme in glycolysis, the role of the platelet isoform of PFK (PFKP) in kidney fibrosis initiation and progression is as yet poorly understood. Here, we investigated whether PFKP could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells (PTECs). We induced PFKP overexpression or knockdown in renal tubules via an adeno-associated virus (AAV) vector in the kidneys of mice following unilateral ureteral occlusion. Our results show that the dilated tubules, the area of interstitial fibrosis, and renal glycolysis were promoted by proximal tubule-specific overexpression of PFKP, and repressed by knockdown of PFKP. Furthermore, knockdown of PFKP expression restrained, while PFKP overexpression promoted TGF-ß1-induced glycolysis in the human PTECs line. Mechanistically, Chip-qPCR revealed that TGF-ß1 recruited the small mothers against decapentaplegic (SMAD) family member 3-SP1 complex to the PFKP promoter to enhance its expression. Treatment of mice with isorhamnetin notably ameliorated PTEC-elevated glycolysis and kidney fibrosis. Hence, our results suggest that PFKP mediates the progression of kidney interstitial fibrosis by regulating glycolysis in PTECs.

Immunotherapy-Induced Hypophysitis Following Treatment With Tislelizumab in an Elderly Patient With Bladder Cancer and Prostate Cancer: A Case Report.

Immune checkpoint inhibitors represent a hopeful and emerging group of medications employed in the regulation of the immune response against cancer, displaying tremendous potential in cancer treatment. However, the administration of these drugs has been linked to the occurrence of adverse events, among which hypophysitis appears to be a prevailing complication affecting a substantial number of patients. Given the potential gravity of this condition, it is strongly recommended to actively monitor hormone levels throughout the treatment process, allowing for the prompt detection and provision of appropriate therapeutic measures. The present study showcases a case involving a 72-year-old individual afflicted with both bladder cancer and prostate cancer, who subsequently developed autoimmune hypophysitis and secondary adrenocortical insufficiency following the administration of programmed death protein 1 (PD-1) inhibitors.

MicroRNA-92b in the skeletal muscle regulates exercise capacity via modulation of glucose metabolism.

BACKGROUND: Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR-92b on the upregulation of exercise training-induced physical performance. METHODS: Adeno-associated virus (AAV)-mediated skeletal muscle miR-92b overexpression in C57BLKS/J mice, and global knockout of miR-92b mice were used to explore the function of miR-92b in glycogen and lactate metabolism in skeletal muscle. AAV-mediated UGP2 or MCT4 knockdown in WT or miR-92 knockout mice was used to confirm whether miR-92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass-related and function-related proteins were analysed by immunoblotting or immunostaining. RESULTS: Global knockout of miR-92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs. 1.043 ± 0.040, **P = 0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs. 3.207 ± 0.2511, *P = 0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs. 4231 ± 90.29, ***P = 0.0006; running time to exhaustion, 186.8 ± 8.027 vs. 220.8 ± 3.156, **P = 0.0028), as compared with those observed in the control mice. Mice skeletal muscle overexpressing miR-92b (both miR-92b-3p and miR-92b-5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs. 0.535 ± 0.0194, **P = 0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs. 5.467 ± 0.1892, *P = 0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs. 3228 ± 149.8, ***P<0.0001; running time to exhaustion, 225.5 ± 7.689 vs. 163 ± 6.476, **P = 0.001). Mechanistic analysis revealed that miR-92b-3p targets UDP-glucose pyrophosphorylase 2 (UGP2) expression to inhibit glycogen synthesis, while miR-92b-5p represses lactate extrusion by directly target monocarboxylate transporter 4 (MCT4). Knockdown of UGP2 and MCT4 reversed the effects observed in the absence of miR-92b in vivo. CONCLUSIONS: This study revealed regulatory pathways, including miR-92b-3p/UGP2/glycogen synthesis and miR-92b-5p/MCT4/lactate extrusion, which could be targeted to control exercise capacity.