SNARE proteins: Core engines of membrane fusion in cancer.

Vesicles are loaded with a variety of cargoes, including membrane proteins, secreted proteins, signaling molecules, and various enzymes, etc. Not surprisingly, vesicle transport is essential for proper cellular life activities including growth, division, movement and cellular communication. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) mediate membrane fusion of vesicles with their target compartments that is fundamental for cargo delivery. Recent studies have shown that multiple SNARE family members are aberrantly expressed in human cancers and actively contribute to malignant proliferation, invasion, metastasis, immune evasion and treatment resistance. Here, the localization and function of SNARE proteins in eukaryotic cells are firstly mapped. Then we summarize the expression and regulation of SNAREs in cancer, and describe their contribution to cancer progression and mechanisms, and finally we propose engineering botulinum toxin as a strategy to target SNAREs for cancer treatment.

Combined effects of toxic Microcystis aeruginosa and high pH on antioxidant responses, immune responses, and apoptosis of the edible freshwater bivalve Corbicula fluminea.

Due to increasing anthropogenic perturbation and water eutrophication, cyanobacterial blooms (CYBs) have become a global ecological and environmental problem. Toxic CYBs and elevated pH are considered to be the two key stressors associated with eutrophication in natural waters, particularly in the event of CO2 depletion induced by dense blooms. However, previous research has been focused on investigating the impacts of toxic CYBs or pH changes in isolation, whereas the interactive effects of such stressors on edible bivalves that inhabit CYB waters still lack information. In this study, the combined effects of toxic Microcystis aeruginosa and pH shifts on the antioxidant responses, immune responses, and apoptosis of the edible freshwater bivalve Corbicula fluminea were explored. The results showed that the activity of antioxidant enzymes was significantly impacted by the interactive effects between toxic M. aeruginosa exposure and time course, yet pH shifts showed no significant effects on the activities of these antioxidant enzymes, implying that the antioxidant response in C. fluminea was mainly triggered by toxic M. aeruginosa exposure. Toxic M. aeruginosa also induced an increased production of reactive oxygen species and malondialdehyde in treated clams, particularly under high pH settings. The elevated lysosomal enzyme activity helped C. fluminea defend against toxic M. aeruginosa exposure under high pH conditions. The principal component analysis (PCA) and the integrated biomarker response (IBR) results suggested that the treated clams were subjected to the elevated toxicity of toxic M. aeruginosa in conditions of high pH. The heat shock proteins-related genes might be triggered to resist the oxidative damage in treated clams. Moreover, the upregulation of TNF and casp8 genes indicated the potential activation of the caspase8-mediated apoptotic pathway through TNF receptor interaction, potentially resulting in apoptosis. The TUNEL assay results further confirmed that apoptosis appeared in treated clams. These findings improve our understanding of the combined toxicological effects of harmful algae and pH shifts on bivalves, which will provide insights into a comprehensive ecological risk assessment of toxic CYBs to edible bivalve species.

Efficacy and safety of Piwei Peiyuan Prescription in the treatment of chronic atrophic gastritis: A multicenter, double-blind, double-simulated, randomized, controlled clinical trial.

The incidence of chronic atrophic gastritis (CAG) is on the rise due to the growing pressure in modern social life, increasing bad living habits and emotional disorders (such as anxiety and depression), and the aging of the population. Of note, digestive system diseases are the dominant diseases in the field of traditional Chinese medicine (TCM). Therefore, this study evaluated the efficacy and safety of Piwei Peiyuan Prescription, a TCM prescription, in the treatment of CAG through a multicenter, double-blind, randomized, controlled design. This research was organized by the Second Affiliated Hospital of Anhui University of TCM and simultaneously performed in 6 centers. A total of 120 CAG patients were included and randomized into 2 groups: group A (treatment with Piwei Peiyuan granules plus Weifuchun Simulant) and Group B (treatment with Weifuchun Tablets plus Piwei Peiyuan Simulant). These 2 groups were compared in terms of gastroscopy scores, TCM syndrome scores, and serological indicators at baseline and within 12 weeks after treatment. According to endoscopic biopsy for pathological observation, atrophy (2.56 ±â€…1.08 vs 3.00 ±â€…1.00, P = .028) and intestinal epithelial hyperplasia (1.00 ±â€…1.43 vs 1.69 ±â€…1.80, P = .043) scores were lower in group A than in group B. For the more, group A had higher effective rates for inflammation, atrophy, and intestinal metaplasia (IM) in various regions of the stomach, especially for atrophy/IM of the gastric angle (64%, P = .034) and atrophy/IM of the lesser curvature of gastric antrum (63%, P = .042) than group B. According to TCM syndrome scores, Piwei Peiyuan Prescription improved the scores of gastric distension (2.30 ±â€…1.13 vs 2.80 ±â€…0.99, P = .022), preference for warmth and pressure (1.44 ±â€…1.06 vs 1.36 ±â€…1.10, P = .041), and poor appetite and indigestion (0.78 ±â€…0.66 vs 1.32 ±â€…0.72, P = .018). GAS, MTL, and PGE2 expression was significantly elevated after treatment with Piwei Peiyuan Prescription (P < .001). Piwei Peiyuan Prescription is effective for CAG treatment with high safety.

The association between hematologic traits and aneurysm-related subarachnoid hemorrhage: a two-sample mendelian randomization study.

Several hematologic traits have been suggested to potentially contribute to the formation and rupture of intracranial aneurysms (IA). The purpose of this study is to explore the causal association between hematologic traits and the risk of IA. To explore the causal association between hematologic traits and the risk of IA, we employed two-sample Mendelian randomization (MR) analysis. Two independent summary-level GWAS data were used for preliminary and replicated MR analyses. The inverse variance weighted (IVW) method was employed as the primary method in the MR analyses. The stabilities of the results were further confirmed by a meta-analysis. In the preliminary MR analysis, hematocrit, hemoglobin concentration (p = 0.0047), basophil count (p = 0.0219) had a suggestive inverse causal relationship with the risk of aneurysm-associated subarachnoid hemorrhage (aSAH). The monocyte percentage of white cells (p = 0.00956) was suggestively positively causally correlated with the risk of aSAH. In the replicated MR analysis, only the monocyte percentage of white cells (p = 0.00297) remained consistent with the MR results in the preliminary analysis. The hematocrit, hemoglobin concentration, and basophil count no longer showed significant causal relationship (p > 0.05). Meta-analysis results further confirmed that only the MR result of monocyte percentage of white cells reached significance in the random effect model and fixed effect model. None of the 25 hematologic traits was causally associated with the risk of unruptured intracranial aneurysms (uIA). This study revealed a suggestive positive association between the monocyte percentage of white cells and the risk of aSAH. This finding contributes to a better understanding that monocytes/macrophages could participate in the risk of aSAH.

Causal association between lipid-lowering drugs and cancers: A drug target Mendelian randomization study.

Accumulating evidences have indicated that lipid-lowering drugs have effect for the treatment of cancers. However, causal associations between lipid-lowering drugs and the risk of cancers are still unclear. In our study, we utilized single nucleotide polymorphisms of proprotein convertase subtilis kexin 9 (PCSK9) inhibitors and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors and performed a drug target Mendelian randomization to explore the causal association between lipid-lowering drugs and the risk of cancers. Five regression methods were carried out, including inverse variance weighted (IVW) method, MR Egger, weighted median, simple mode and weighted mode methods, of which IVW method was considered as the main analysis. Our outcome dataset contained the risk of breast cancer (BC), colorectal cancer, endometrial cancer, gastric cancer (GC), hepatocellular carcinoma (HCC), lung cancer, esophageal cancer, prostate cancer (PC), and skin cancer (SC). Our results demonstrated that PCSK9 inhibitors were significant associated with a decreased effect of GC [IVW: OR = 0.482, 95% CI: 0.264-0.879, P = .017]. Besides, genetic inhibitions of HMGCR were significant correlated with an increased effect of BC [IVW: OR = 1.421, 95% CI: 1.056-1.911, P = .020], PC [IVW: OR = 1.617, 95% CI: 1.234-2.120, P = .0005] and SC [IVW: OR = 1.266, 95% CI: 1.022-1.569, P = .031]. For GC [IVW: OR = 0.559, 95% CI: 0.382-0.820, P = .0029] and HCC [IVW: OR = 0.241, 95% CI: 0.085-0.686, P = .0077], HMGCR inhibitors had a protective risk. Our method suggested that PCSK9 inhibitors were significant associated with a protective effect of GC. Genetic inhibitions of HMGCR were significant correlated with an increased effect of BC, PC and SC. Meanwhile, HMGCR inhibitors had a protective risk of GC and HCC. Subsequent studies still needed to assess potential effects between lipid-lowering drugs and the risk of cancers with clinical trials.

Dietary Intakes of Women with Gestational Diabetes Mellitus and Pregnancy Outcomes: A Prospective Observational Study.

Purpose: Nutrient intake for pregnant women with gestational diabetes mellitus (GDM) is important to ensure satisfactory birth outcomes. This study aims to explore the dietary profiles of patients with GDM, compare the results with the Chinese dietary guidelines or Dietary Reference Intakes (DRIs) from China and investigate the relationship between maternal dietary intake and pregnancy outcomes. Patients and Methods: A total of 221 patients with GDM in the second trimester were included in the cohort. Dietary intake data were collected using a 24-hour recall method for three consecutive days. The pregnancy outcomes of these participants were subsequently monitored. Both univariate logistic regression and multivariate logistic regression analyses were conducted to explore the associations between dietary intake variables or general characteristics variables and adverse pregnancy outcomes. Results: Participants with adverse pregnancy outcomes showed a lower intake of iodine and vitamin D, a lower percentage of dietary energy intake from carbohydrates and a higher percentage of dietary energy intake from fats, compared to participants without adverse pregnancy outcomes. The gestational weight gain and family history of diabetes were associated with an increased risk of adverse pregnancy outcomes. Conversely, regular exercise, the intake of iodine and Vitamin D, and the percentage of dietary energy intake from carbohydrates were associated with a decreased risk. Conclusion: The daily diet of pregnant women with GDM in China did not meet the dietary guidelines or DRIs. The low intake of Vitamin D and iodine, the low dietary carbohydrate ratio, family history of diabetes, lack of exercise, and high gestational weight gain were associated with increased risk of adverse pregnancy outcomes in pregnant women with GDM.

Study on the risk factors of postoperative wound complications in patients with ankle fracture.

Wound complications after surgery for ankle fractures can lead to catastrophic consequences. The purpose of this study was to evaluate the risk factors of postoperative wound complications in patients with ankle fracture and to determine their effects on prognosis. 200 patients with ankle fracture treated in our hospital from October 2021 to December 2023 were analysed retrospectively. The total incidence of postoperative wound complications was 19% (38/200). Type of complications: wound edge necrosis 15 cases (39.47%), dehiscence (reopening of wound) 13 cases (34.21%), delayed healing (>30 days) 10 cases (26.32%); Univariate analysis showed that patients' age, body mass index (BMI), current smoking, alcoholism, diabetes mellitus, injury mechanism, open fracture, wound classification, higher American Society of Anesthesiologists (ASA) score and operation time were all associated with postoperative wound complications. Multivariate Logistic regression model shows: age ≥60 years old OR3.671 (1.875-5.937), BMI OR1.198 (1.143-1.324), current smoking OR2.727 (1.251-5.602), alcoholism OR1.143 (1.034-1.267), complicated with diabetes OR2.763 (1.236-4.852), injury mechanism (high vs. low and medium energy) OR2.437 (1.238-4.786), open fracture OR1.943 (1.8262.139), wound classification (II vs. I) OR4.423 (1.73511.674), ASA score (III-IV vs. I-II) OR1.307 (1.113-2.194) was an independent risk factor for postoperative wound complications in patients with ankle fracture. Further, ROC curves showed that these nine independent influences had high accuracy and validity in predicting postoperative wound complications in patients with ankle fractures. In conclusion, independent risk factors for postoperative complications of ankle fracture were age >60 years, BMI, injury mechanism, open fracture, wound classification (II vs. I), ASA score, current smoking, and alcoholism. The wound classification (II vs. I) has the highest diagnostic value.

A rat model of adenoid hypertrophy constructed by using ovalbumin and lipopolysaccharides to induce allergy, chronic inflammation, and chronic intermittent hypoxia.

BACKGROUND: Adenoid hypertrophy (AH) is a common pediatric disease that significantly impacts the growth and quality of life of children. However, there is no replicable and valid model for AH. METHODS: An AH rat model was developed via comprehensive allergic sensitization, chronic inflammation induction, and chronic intermittent hypoxia (CIH). The modeling process involved three steps: female Sprague-Dawley rats (aged 4-5 weeks) were used for modeling. Allergen sensitization was induced via intraperitoneal administration and intranasal provocation using ovalbumin (OVA); chronic nasal inflammation was induced through intranasal lipopolysaccharide (LPS) administration for sustained nasal irritation; CIH akin to obstructive sleep apnea/hypopnea syndrome was induced using an animal hypoxia chamber. Postmodel establishment, behaviors, and histological changes in nasopharynx-associated lymphoid tissue (NALT) and nasal mucosa were assessed. Arterial blood gas analysis and quantification of serum and tissue levels of (interleukin) IL-4 and IL-13, OVA-specific immunoglobulin E (sIgE), eosinophil cationic protein (ECP), tumor necrosis factor (TNF-α), IL-17, and transforming growth factor (TGF)-ß were conducted for assessment. The treatment group received a combination of mometasone furoate and montelukast sodium for a week and then was evaluated. RESULTS: Rats exhibited notable nasal symptoms and hypoxia after modeling. Histopathological analysis revealed NALT follicle hypertrophy and nasal mucosa inflammatory cell infiltration. Elevated IL-4, IL-13, IL-17, OVA-sIgE, ECP, and TNF-α levels and reduced TGF-ß levels were observed in the serum and tissue of model-group rats. After a week of treatment, the treatment group exhibited symptom and inflammatory factor improvement. CONCLUSION: The model effectively simulates AH symptoms and pathological changes. But it should be further validated for genetic, immunological, and hormonal backgrounds in the currently used and other strains and species.

A natural compound melatonin enhances the effects of Nimotuzumab via inhibiting EGFR in glioblastoma.

Sleep disorders are prevalent and debilitating symptoms in primary brain tumor patients, notably those receiving radiation therapy. Nevertheless, the relationship between sleep disorders, melatonin - a circadian rhythm regulatory hormone, and gliomas is underexplored. Melatonin exhibits various biological functions, one of them being anti-tumor activity. In the context of gliomas, often overexpressing EGFR, the humanized monoclonal antibody Nimotuzumab targets this marker. Our research discovered that variations in circadian rhythm significantly influence tumor growth in mice through impacting melatonin secretion. Harnessing proteogenomic, we identified that melatonin could inhibit the phosphorylation of EGFR and its downstream effectors, key elements in angiogenesis and tumor progression. Building on structural simulations, we propose that melatonin may amplify Nimotuzumab's anti-glioma efficacy by inhibiting EGFR TK dimerization. This proposition was validated in our in vitro and in vivo studies where melatonin synergistically augmented cytotoxicity and apoptosis in Nimotuzumab-treated glioma cells. Thus, melatonin shows promise as a beneficial addition to Nimotuzumab treatment in glioma patients.

Interleukin-6 promotes visceral adipose tissue accumulation during aging via inhibiting fat lipolysis.

BACKGROUND: Age-related visceral obesity could contribute to the development of cardiometabolic complications. The pathogenesis of visceral fat mass accumulation during the aging process remains complex and largely unknown. Interleukin-6 (IL-6) has emerged as one of the prominent inflammaging markers which are elevated in circulation during aging. However, the precise role of IL-6 in regulating age-related visceral adipose tissue accumulation remains uncertain. RESULTS: A cross-sectional study including 77 older adults (≥65 years of age) was initially conducted. There was a significant positive association between serum IL-6 levels and visceral fat mass. We subsequently validated a modest but significant elevation in serum IL-6 levels in aged mice. Furthermore, we demonstrated that compared to wildtype control, IL-6 deficiency (IL-6 KO) significantly attenuated the accumulation of visceral adipose tissue during aging. Further metabolic characterization suggested that IL-6 deficiency resulted in improved lipid metabolism parameters and energy expenditure in aged mice. Moreover, histological examinations of adipose depots revealed that the absence of IL-6 ameliorated adipocyte hypertrophy in visceral adipose tissue of aged mice. Mechanically, the ablation of IL-6 could promote the PKA-mediated lipolysis and consequently mitigate lipid accumulation in adipose tissue in aged mice. CONCLUSION: Our findings identify a detrimental role of IL-6 during the aging process by promoting visceral adipose tissue accumulation through inhibition of lipolysis. Therefore, strategies aimed at preventing or reducing IL-6 levels may potentially ameliorate age-related obesity and improve metabolism during aging.

Causal relationships between gut microbrome and digestive system diseases: A two-sample Mendelian randomization study.

Growing evidences of recent studies have shown that gut microbrome are causally related to digestive system diseases (DSDs). However, causal relationships between the gut microbiota and the risk of DSDs still remain unclear. We utilized identified gut microbiota based on class, family, genus, order and phylum information and digestive system diseases genome-wide association study (GWAS) dataset for two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used to evaluate causal relationships between gut microbiota and 7 DSDs, including chronic gastritis, colorectal cancer, Crohn's disease, gastric cancer, gastric ulcer, irritable bowel syndrome and esophageal cancer. Finally, we verified the robustness of MR results based on heterogeneity and pleiotropy analysis. We discovered 15 causal associations with genetic liabilities in the gut microbiota and DSDs, such as genus Victivallis, genus RuminococcaceaeUCG005, genus Ruminococcusgauvreauiigroup, genus Oxalobacter and so on. Our MR analysis revealed that the gut microbiota is causally associated with DSDs. Further researches of the gut microbiota and the pathogenesis of DSDs are still significant and provide new methods for the prevention and treatment of DSDs.

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7+satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible 'response biomarkers' in pre-clinical and clinical studies.

A potassium-chloride co-transporter with altered genome architecture functions as a suppressor in glioma.

Gliomas, the most lethal tumours in brain, have a poor prognosis despite accepting standard treatment. Limited benefits from current therapies can be attributed to genetic, epigenetic and microenvironmental cues that affect cell programming and drive tumour heterogeneity. Through the analysis of Hi-C data, we identified a potassium-chloride co-transporter SLC12A5 associated with disrupted topologically associating domain which was downregulated in tumour tissues. Multiple independent glioma cohorts were included to analyse the characterization of SLC12A5 and found it was significantly associated with pathological features, prognostic value, genomic alterations, transcriptional landscape and drug response. We constructed two SLC12A5 overexpression cell lines to verify the function of SLC12A5 that suppressed tumour cell proliferation and migration in vitro. In addition, SLC12A5 was also positively associated with GABAA receptor activity and negatively associated with pro-tumour immune signatures and immunotherapy response. Collectively, our study provides a comprehensive characterization of SLC12A5 in glioma and supports SLC12A5 as a potential suppressor of disease progression.

Roles of ß-catenin in innate immune process and regulating intestinal flora in Qi river crucian carp (Carassius auratus).

In mammals, ß-catenin participates in innate immune process through interaction with NF-κB signaling pathway. However, its role in teleost immune processes remains largely unknown. We aimed to clarify the function of ß-catenin in the natural defense mechanism of Qi river crucian carp (Carassius auratus). ß-catenin exhibited a ubiquitous expression pattern in adult fish, as indicated by real-time PCR analysis. Following lipopolysaccharide (LPS), Polyinosinic-polycytidylic acid (polyI: C) and Aeromonas hydrophila (A. hydrophila) challenges, ß-catenin increased in gill, intestine, liver and kidney, indicating that ß-catenin likely plays a pivotal role in the immune response against pathogen infiltration. Inhibition of the ß-catenin pathway using FH535, an inhibitor of Wnt/ß-catenin pathway, resulting in pathological damage of the gill, intestine, liver and kidney, significant decrease of innate immune factors (C3, defb3, LYZ-C, INF-γ), upregulation of inflammatory factors (NF-κB, TNF-α, IL-1, IL-8), and downregulation of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) activities, increase of Malondialdehyde (MDA) content. Following A. hydrophila invasion, the mortality rate in the FH535 treatment group exceeded that of the control group. In addition, the diversity of intestinal microflora decreased and the community structure was uneven after FH535 treatment. In summary, our findings strongly suggest that ß-catenin plays a vital role in combating pathogen invasion and regulating intestinal flora in Qi river crucian carp.

ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway.

Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.

Progress in the study of intestinal microbiota involved in morphine tolerance.

Morphine is a widely used opioid for treatment of pain. The attendant problems including morphine tolerance and morphine dependence pose a major public health challenge. In recent years, there has been increasing interest in the gastrointestinal microbiota in many physiological and pathophysiological processes. The connectivity network between the gut microbiota and the brain is involved in multiple biological systems, and bidirectional communication between them is critical in gastrointestinal tract homeostasis, the central nervous system, and the microbial system. Many research have previously shown that morphine has a variety of effects on the gastrointestinal tract, but none have determined the function of intestinal microbiota in morphine tolerance. This study reviewed the mechanisms of morphine tolerance from the perspective of dysregulation of microbiota-gut-brain axis homeostasis, by summarizing the possible mechanisms originating from the gut that may affect morphine tolerance and the improvement of morphine tolerance through the gut microbiota.

Pan-cancer evaluation of regulated cell death to predict overall survival and immune checkpoint inhibitor response.

Regulated cell death (RCD) plays a pivotal role in various biological processes, including development, tissue homeostasis, and immune response. However, a comprehensive assessment of RCD status and its associated features at the pan-cancer level remains unexplored. Furthermore, despite significant advancements in immune checkpoint inhibitors (ICI), only a fraction of cancer patients currently benefit from treatments. Given the emerging evidence linking RCD and ICI efficacy, we hypothesize that the RCD status could serve as a promising biomarker for predicting the ICI response and overall survival (OS) in patients with malignant tumors. We defined the RCD levels as the RCD score, allowing us to delineate the RCD landscape across 30 cancer types, 29 normal tissues in bulk, and 2,573,921 cells from 82 scRNA-Seq datasets. By leveraging large-scale datasets, we aimed to establish the positive association of RCD with immunity and identify the RCD signature. Utilizing 7 machine-learning algorithms and 18 ICI cohorts, we developed an RCD signature (RCD.Sig) for predicting ICI response. Additionally, we employed 101 combinations of 10 machine-learning algorithms to construct a novel RCD survival-related signature (RCD.Sur.Sig) for predicting OS. Furthermore, we obtained CRISPR data to identify potential therapeutic targets. Our study presents an integrative framework for assessing RCD status and reveals a strong connection between RCD status and ICI effectiveness. Moreover, we establish two clinically applicable signatures and identify promising potential therapeutic targets for patients with tumors.

Characterization of insulin-like growth factor 3 and its potential role in the spotted steed Hemibarbus maculatus ovary development.

As a new member of the insulin-like growth factors (Igfs), Igf3 was reported to play a vital role in fish reproduction. However, in spotted steed, the function of Igf3 remains largely unknown. In the present study, we identified and characterized Igf3 gene in spotted steed. Structural analysis showed that Igf3 contained five domains (B, C, A, D, E) and six conserved cysteine residues. The expression of Igf3 mRNA and protein were increased during ovary development and peaked in the maturation stage. The subcellular localization of IGF3 was highly expressed in granulosa cells and theca cells. Furthermore, recombinant IGF3 protein was produced and in vitro treatment with ovarian follicles significantly promoted the germinal vesicle breakdown (GVBD) rates of spotted steed follicles. The mRNA expression of cdc2 and cyclinB genes were significantly increased after IGF3 treatment, which were main components of maturation promoting factor (MPF). In addition, transcription levels of 3ß-hsd, 20ß-hsd, Cyp17a and Cyp19a1a were also changed. Taken together, these findings suggest that Igf3 is essential for ovary steroidogenesis and maturation in spotted steed.

Mannanase improves the growth performance of broilers by alleviating inflammation of the intestinal epithelium and improving intestinal microbiota.

This experiment aimed to discuss and reveal the effect and mechanism of mannanase on intestinal inflammation in broilers triggered by a soybean meal diet. In this experiment, 384 Arbor Acres broilers at 1 d old were randomly divided into 3 treatment groups. The broilers were fed a corn-soybean meal basal diet, a low-energy diet (metabolizable energy reduced by 50 kcal/kg), and a low-energy diet supplemented with 100 mg/kg mannanase for 42 d. The low-energy diet increased feed conversion ratio from 0 to 42 d, reduced ileal villus height and villus height-to-crypt depth ratio and upregulated the expression of nuclear factor kappa B (NF-κB) in the ileum (P < 0.05). It also reduced cecal short-chain fatty acids (SCFA), such as acetic acid (P < 0.05). Compared with low-energy diets, the addition of mannanase increased body weight at 42 d, promoted the digestibility of nutrients, and maintained the morphology and integrity of the intestinal epithelium of broilers (P < 0.05). In addition, mannanase upregulated the expression of claudin-1 (CLDN1) and zonula occludens-1 (ZO-1) in the jejunum at 21 d, downregulated the expression of ileal NF-κB, and increased the content of isobutyric acid in the cecum of broilers (P < 0.05). The results for the ileal microbiota showed that a low-energy diet led to a decrease in the relative abundance of Lactobacillus reuteri in the ileum of broilers. The addition of mannanase increased the relative abundance of Lactobacillus-KC45b and Lactobacillus johnsonii in broilers. Furthermore, a low-energy diet reduced the relative abundance of Butyricicoccus in the intestine of broilers and inhibited oxidative phosphorylation and phosphoinositol metabolism. Mannanase increased the relative abundance of Odoribacter, promoted energy metabolism and N-glycan biosynthesis, and increased the activities of GH3 and GH18. It is concluded that mannanase could improve the growth performance of broilers by reducing the expression of NF-κB in the ileum, increasing the production of SCFA in the cecum, suppressing intestinal inflammation, balancing the intestinal microbiota, reducing damage to the intestinal barrier, and improving the efficiency of nutrient utilization to alleviate the adverse effects caused by the decrease in dietary energy level.

Machine learning-based investigation of regulated cell death for predicting prognosis and immunotherapy response in glioma patients.

Glioblastoma is a highly aggressive and malignant type of brain cancer that originates from glial cells in the brain, with a median survival time of 15 months and a 5-year survival rate of less than 5%. Regulated cell death (RCD) is the autonomous and orderly cell death under genetic control, controlled by precise signaling pathways and molecularly defined effector mechanisms, modulated by pharmacological or genetic interventions, and plays a key role in maintaining homeostasis of the internal environment. The comprehensive and systemic landscape of the RCD in glioma is not fully investigated and explored. After collecting 18 RCD-related signatures from the opening literature, we comprehensively explored the RCD landscape, integrating the multi-omics data, including large-scale bulk data, single-cell level data, glioma cell lines, and proteome level data. We also provided a machine learning framework for screening the potentially therapeutic candidates. Here, based on bulk and single-cell sequencing samples, we explored RCD-related phenotypes, investigated the profile of the RCD, and developed an RCD gene pair scoring system, named RCD.GP signature, showing a reliable and robust performance in predicting the prognosis of glioblastoma. Using the machine learning framework consisting of Lasso, RSF, XgBoost, Enet, CoxBoost and Boruta, we identified seven RCD genes as potential therapeutic targets in glioma and verified that the SLC43A3 highly expressed in glioma grades and glioma cell lines through qRT-PCR. Our study provided comprehensive insights into the RCD roles in glioma, developed a robust RCD gene pair signature for predicting the prognosis of glioma patients, constructed a machine learning framework for screening the core candidates and identified the SLC43A3 as an oncogenic role and a prediction biomarker in glioblastoma.