Apelin is highly expressed in rat left ventricular hypertrophy Sprague Dawley rat models, and it plays a crucial role in the cardiovascular system. The aim this study was to clarify whether apelin-13 promotes hypertrophy in H9c2 rat cardiomyocytes and to investigate its underlying mechanism. The cardiomyocyte hypertrophy was observed by measuring the diameter, volume, and protein content of H9c2 cells. The activation of autophagy was evaluated by observing the morphology of autophagosomes by transmission electron microscopy, observing the subcellular localization of LC3 by light microscopy, and detecting the membrane-associated form of LC3 by western blot analysis. The phosphatidylinositol 3-kinase (PI3K) signaling pathway was identified and the proteins expression was detected using western blot analysis. The results revealed that apelin-13 increased the diameter, volume, and protein content of H9c2 cells and promoted the phosphorylation of PI3K, Akt, ERK1/2, and p70S6K. Apelin-13 activated the PI3K-Akt-ERK1/2-p70S6K pathway. PI3K inhibitor LY294002, Akt inhibitor 1701-1, ERK1/2 inhibitor PD98059 attenuated the increase of the cell diameter, volume, protein content induced by apelin-13. Apelin-13 increased the autophagosomes and up-regulated the expressions of beclin 1 and LC3-II/I both transiently and stably. The autophagy inhibitor 3MA ameliorated the increase of cell diameter, volume, and protein content that were induced by apelin-13. These results suggested that apelin-13 promotes H9c2 rat cardiomyocyte hypertrophy via PI3K-Akt-ERK1/2-p70S6K and PI3K-induced autophagy.

Spermatogonial stem cells (SSCs) play a crucial role in the male reproductive system, responsible for maintaining continuous spermatogenesis. The microenvironment or niche of SSCs is a key factor in regulating their self-renewal, differentiation and spermatogenesis. This microenvironment consists of multiple cell types, extracellular matrix, growth factors, hormones and other molecular signals that interact to form a complex regulatory network. This review aims to provide an overview of the main components of the SSCs microenvironment, explore how they regulate the fate decisions of SSCs, and discuss the potential impact of microenvironmental abnormalities on male reproductive health.

Background: Studies have shown that the expressions and working mechanisms of Dihydrolipoamide S-acetyltransferase (DLAT) in different cancers vary. It is necessary to analyze the expressions and regulatory roles of DLAT in tumors systematically. Methods: Online public-platform literature on the relationships between DLAT expression levels and tumor prognosis, methylation status, genetic alteration, drug sensitivity, and immune infiltration has been reviewed. The literature includes such documents as The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Tumor Immune Estimation Resource 2.0 (TIMER2.0), Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Receiver Operating Characteristic plotter (ROC plotter). The molecular mechanisms of DLAT were explored with the Gene Set Enrichment Analysis (GSEA). The relationship between down-regulated DLAT and autophagy in two liver hepatocellular carcinoma (LIHC) cell lines was confirmed with the western blot method, colony formation assay, and transmission electron microscopy. Tissue microarrays were validated through the immunohistochemical staining of DLAT. Results: DLAT is upregulated in the LIHC, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and stomach adenocarcinoma (STAD) tumors but is down-regulated in the head and neck squamous cell carcinoma (HNSC) and kidney renal clear cell carcinoma (KIRC) tumors in comparison with normal tissues. For LIHC patients treated with 5-Fluorouracil and Lenvatinib, the DLAT levels of those in the drug-resistant group are significantly high. In LIHC cells, autophagy will be inhibited, and cell death will be induced when DLAT breaks down. Moreover, there exist positive correlations between DLAT expression levels and infiltration of B cells, DC cells, Tregs, and CD8+ T cells in kidney chromophobe (KICH), breast invasive carcinoma (BRCA), prostate adenocarcinoma (PRAD), LIHC and HPV+ HNSC. In LIHC, markers of Tregs are positively correlated with DLAT. Compared with those of normal tissues, the staining intensity of DLAT and the amount of Tregs marker CD49d in LIHC increase. Conclusions: Through this study, the expressions of DLAT in various cancer types can be understood comprehensively. It suggests that DLAT may be a prognostic marker for LIHC, LUAD, LUSC, STAD and KIRC. A high DLAT expression in LIHC may promote tumorigenesis by stimulating autophagy and inhibiting anti-tumor immunity.

Background: Pembrolizumab, a programmed cell death protein 1 checkpoint inhibitor, is a novel drug used to treat a variety of advanced malignancies. However, it can also result in many immune-related adverse events, with cutaneous toxicities being the most frequent. Regarding pembrolizumab-induced skin adverse reactions, bullous pemphigoid (BP) has the worst effects on quality of life. Recently, there have been more and more reports of BP incidents resulting from pembrolizumab therapy in patients with cancer. This study aimed to define the clinical characteristics, diagnosis and management of pembrolizumab-induced BP and identify potential differences between classical BP and pembrolizumab-induced BP.Methods: Case reports, case series, and case analyses of pembrolizumab-induced BP up to 10 December 2022 were collected for retrospective analysis.Results: Our study included 47 patients (33 males and 14 females) from 40 studies. The median age was 72 years (range 42-86 years). The median time to cutaneous toxicity was 4 months (range 0.7-28 months), and the median time to bullae formation was 7.35 months (range 0.7-32 months). The most common clinical features were tense bullae and blisters (85.11%), pruritus (72.34%), and erythema (63.83%) on the limbs and trunk. In 20 of the 22 cases tested, the serum anti-BP180 autoantibodies were positive. However, in 10 cases (91.90%, 10/11) the circulating autoantibodies of anti-BP230 were negative. 40 patients had skin biopsies and the skin biopsy revealed subepidermal bullae or blister eosinophil infiltration in 75.00% of patients with pembrolizumab-induced BP, 10.00% of patients with lymphocyte infiltration and 20.00% of patients with neutrophil infiltration. There were 20 patients (50%) with eosinophilic infiltration around the superficial dermis vessels, 8 patients (20.00%) with lymphocyte infiltration around the superficial dermis vessels, and 4 patients (10.00%) with neutrophil infiltration around the superficial dermis vessels. Direct immunofluorescence detected linear immunoglobulin G (IgG) IgG and/or complement C3 along the dermo-epidermal junction in 36 patients (94.74%) with BP. IgG positivity was detected by indirect immunofluorescence in 81.82% of patients with BP. All patients were in complete remission (95.65%,44/46) or partial remission (4.35%, 2/46) of BP, whereas 9/46 patients had a relapse or refractory. The majority of patients achieved BP remission after discontinuation of pembrolizumab with a combination of topically and systemically administered steroid treatments, or other medications. The median duration of BP remission was 2 months (range 0.3-15 months).Conclusion: A thorough diagnosis of pembrolizumab-induced BP should be made using clinical signs, biochemical markers, histopathological and immunopathological tests. Pembrolizumab-induced BP had similar clinical characteristics to classic BP. Temporary or permanent discontinuation of pembrolizumab therapy may be required in patients with perbolizumab-induced BP depending on the severity of BP and the response to medication. Pembrolizumab-induced BP may be effectively treated using topical and systemic steroid treatments in combination with other medications (e.g., doxycycline, niacinamide, dapsone, rituximab, intravenous immunoglobulins, dupilumab, cyclophosphamide, methotrexate, mycophenolate mofetil, and infliximab). Clinicians should provide better management to patients with BP receiving pembrolizumab to prevent progression and ensure continuous cancer treatment.