Hunan Mawangdui Hospital

Microscopic polyangiitis (MPA), a severe antineutrophil cytoplasmic antibody associated vasculitis (ANCA-associated vasculitis, AAV), demonstrates strong clinical association with myeloperoxidase/perinuclear anti-neutrophilic cytoplasmic antibodies (MPO/P-ANCA). While genetic factors are known to contribute to MPA susceptibility, the potential roles of AKT signaling components remain incompletely characterized, with limited data available for AKT1 and even less for its homologous gene AKT2 in this specific disease context. This case-control analysis included 798 participants (202 MPA patients and 596 controls, the latter comprising 387 individuals from the 1,000 Genomes Project), with control groups pooled after confirmation of genetic homogeneity. Genotypes of seven single-nucleotidepolymorphisms (SNPs) (four in AKT1, three in AKT2) with divergent allele frequencies across populations were analyzed. Association analyses were conducted under multiple genetic models, with gene-level and set-based approaches employed to evaluate aggregate effects. Secondary analyses included haplotype reconstruction, SNP-SNP interaction testing, and functional characterization through expression quantitative trait locus (eQTL) mapping. Specific AKT1 variants (rs2498786 and rs1130233) demonstrated significant associations with reduced MPA risk, particularly in P-ANCA-positive patients. Gene-level analyses revealed a strong association for the AKT1 gene set (OR = 0.884, P=0.002) but not for AKT2. Haplotype analysis identified protective AKT1 haplotypes, while interaction testing revealed high-risk genotype combinations. eQTL analysis indicated that protective alleles correlate with enhanced AKT1 expression in immune-relevant tissues, suggesting a potential regulatory mechanism. AKT1 emerges from this study as a likely genetic contributor to MPA, with its influence potentially involving neutrophil regulatory functions and vascular maintenance. The consistent absence of association signals for AKT2 across all analytical approaches could be viewed as reinforcing the specificity of AKT1's involvement. These insights help refine the genetic architecture of MPA and position AKT1 signaling as a candidate pathway for future therapeutic exploration.

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Rationale: Although sepsis-associated encephalopathy (SAE) is a common psychiatric complication in septic patients, the underlying mechanisms remain unclear. Here, we explored the role of the hippocampus (HPC) - medial prefrontal cortex (mPFC) pathway in cognitive dysfunction in lipopolysaccharide-induced brain injury. Methods: Lipopolysaccharide (LPS, 5 mg/kg, intraperitoneal) was used to induce an animal model of SAE. We first identified neural projections from the HPC to the mPFC via a retrograde tracer and virus expression. The activation viruses (pAAV-CaMKIIα-hM3Dq-mCherry) were injected to assess the effects of specific activation of mPFC excitatory neurons on cognitive tasks and anxiety-related behaviors in the presence of clozapine-N-oxide (CNO). Activation of the HPC-mPFC pathway was evaluated via immunofluorescence staining of c-Fos-positive neurons in mPFC. Western blotting was performed to determine protein levels of synapse- associated factors. Results: We successfully identified a structural HPC-mPFC connection in C57BL/6 mice. LPS-induced sepsis induces cognitive impairment and anxiety-like behaviors. Chemogenetic activation of the HPC-mPFC pathway improved LPS-induced cognitive dysfunction but not anxiety-like behavior. Inhibition of glutamate receptors abolished the effects of HPC-mPFC activation and blocked activation of the HPC-mPFC pathway. The glutamate receptor-mediated CaMKII/CREB/BDNF/TrKB signaling pathway influenced the role of the HPC-mPFC pathway in sepsis-induced cognitive dysfunction. Conclusions: HPC-mPFC pathway plays an important role in cognitive dysfunction in lipopolysaccharide-induced brain injury. Specifically, the glutamate receptor-mediated downstream signaling appears to be an important molecular mechanism linking the HPC-mPFC pathway with cognitive dysfunction in SAE.

Oxalate-induced oxidative stress causes damage to cells, accompanied with renal deposition of calcium oxalate crystals. Recent studies have highlighted the extensive functions of microRNAs (miRNAs) in various processes, including cellular responses to oxidative stress. Hence, this study was intended to analyze the role of miR-204 in the calcium oxalate kidney-stone formation and the underlying mechanism. In silico analysis was performed to determine the miRNA/mRNA interaction involved in calculus, while dual-luciferase reporter assay was conducted for validation. A calcium oxalate kidney-stone model was established by H2O2 induction in RTEC HK-2 cells, in which the expression of miR-204 was examined. Gain- and loss-of-function approaches were employed to alter the expression of miR-204/MUC4 so as to assess the detailed role of miR-204 in oxidative stress injury in renal tubular epithelial cells (RTECs) and calcium oxalate kidney-stone formation. MUC4, an up-regulated gene in H2O2-induced HK-2 cells, was a target of MUC4. miR-204 functionally targeted MUC4 and blocked the ERK pathway activation. Furthermore, up-regulated miR-204 contributed to promotion of RTEC proliferation and suppression of ROS levels, RTEC apoptosis as well as formation of calcium oxalate crystal. Taken together, miR-204 impairs MUC4-dependent activation of the ERK signaling pathway and consequently ameliorates oxidative stress damage to RTECs and prevents calcium oxalate kidney-stone formation.

Aims and ObjectivesQuarantine during the COVID‐19 pandemic resulted in longer‐term sedentary behaviours and mental health problems. Our study aimed to evaluate the impact of the Otago exercise programme (OEP) on physical function and mental health among elderly with cognitive frailty during COVID‐19.BackgroundLockdowns and restrictions during the COVID‐19 pandemic result in longer‐term sedentary behaviours related disease and mental problem. Older people with cognitive frailty are more vulnerable to be influenced. Timely intervention may achieve better outcomes, OEP exercise was designed as a balance and muscle‐strengthening programme for elderly people.DesignA parallel‐group, assessor‐blinded randomised controlled trial was performed according to CONSORT guidelines.MethodsThis study was conducted from July 2020 to October 2020 among 62 elderly people with cognitive frailty from a nursing home. Participants were randomly divided into an OEP group (n = 31) or a control group (n = 31). Both groups received sleep‐ and diet‐related health education. The OEP group also received a 12‐week group exercise programme. The Five Times Sit to Stand Test (FTSST), Berg Balance Scale (BBS), and Timed Up and Go Test (TUGT) were used to assess physical function. The Geriatric Depression Scale‐15 (GDS‐15) and the 12‐Item Short Form Health Survey Mental Component Summary (SF‐12 MCS) were used to assess mental health. Outcomes were measured at 6 and 12 weeks.ResultsPhysical function and mental health were similar in the two groups at baseline. At 12 weeks, the OEP group (difference in change from baseline: FTSST, −2.78; TUGT, −3.73; BBS, 2.17; GDS‐15, −0.72; SF‐12 MCS, 2.58; all p < .001) exhibited significantly greater improvements than the control group (difference in change from baseline: FTSST, 1.55; TUGT, 1.66; BBS, −0.10; GDS‐15, 1.07; SF‐12 MCS, −5.95; all p < .001).ConclusionOur findings showed the OEP group had better physical function and mental health outcomes than the control group. OEP can be used to improve the physical and mental function among elderly people with cognitive frailty during the COVID‐19 pandemic.Relevance to clinical practiceOtago exercise program intervention programmes should be implemented to improve physical function for cognitive frailty elderly to reduce the harm of longer‐term sedentary behaviours, and to ruduce depression symptom and improve mental health, particularly during COVID‐19 pandemic period.

BackgroundEmerging evidence suggested that long intergenic noncoding RNA (lincRNA) 00887 (NR_024480) reduced the invasion and metastasis of non-small cell lung cancer by sponging miRNAs degradation. However, the role and regulatory mechanism of linc00887 in the progression of cervical cancer remain largely unknown.MethodsIn vivo or vitro, RT-qPCR assay was used to detect the expression of linc00887 in human normal (N = 30), cervical cancer tissues (N = 30), human normal cervical epithelial cells (Ect1/E6E7) and cervical cancer cell lines (HeLa, C33A). Then, CCK-8 and Transwell assays were used to examine cell proliferation and invasion when linc00887 was overexpressed or knocked down. In addition, bioinformatics, luciferase reporter gene and pull-down assays were used to predict and validate the relationship between linc00887 and miR-454-3p. Moreover, we detected the expression of miR-454-3p in Ect1/E6E7, HeLa and C33A cells when linc00887 was overexpressed or knocked down. Cell proliferation and invasion were also measured when pcDNA-linc00887 and miR-454-3p were transfected alone or together. Next, miR-454-3p target gene was predicted and validated by bioinformatics and luciferase reporter gene assays. Gain- and loss-of-function experiments were performed in HeLa cells to evaluate the effect of miR-454-3p or linc00887 on the expression of FERM domain containing protein 6 (FRMD6) protein and several key proteins in the FRMD6-Hippo signaling pathway.ResultsLinc00887 was downregulated in cervical cancer tissues or human cervical cancer cell lines (Hela, C33A) compared with normal tissues or cell lines. Overexpression of linc00887 inhibited proliferation and invasion HeLa and C33A cells, while linc00887 knockdown had the opposite effect. Linc00887 bound with miR-454-3p, and overexpression of miR-454-3p rescued linc00887-induced inhibition proliferation and invasion of HeLa cells. MiR-454-3p targeted and suppressed the expression of FRMD6, and linc00887 suppressed tumorigenesis of cervical cancer through activating the FRMD6-Hippo signaling pathway.ConclusionsLinc00887, sponging miR-454-3p, inhibited the progression of cervical cancer by activating the FRMD6-Hippo signaling pathway.