Discovery and genomic characterization of three double-stranded RNA viruses coinfecting Conidiobolus taihushanensis.

Conidiobolus sensu lato, a genus within the family Ancylistaceae, encompasses a diverse range of fungal species that are widely distributed in plant debris and soil. In this study, we identified three double-stranded RNA (dsRNA) viruses coinfecting a strain of Conidiobolus taihushanensis. These viruses were identified as Conidiobolus taihushanensis totivirus 1 (CtTV1), Conidiobolus nonsegmented RNA virus 1-2 (CNRV1-2), and Conidiobolus taihushanensis virus 1 (CtV1). Through high-throughput sequencing and RNA-ligase-mediated rapid amplification of cDNA ends (RLM-RACE), we determined their complete genome sequences. The genome of CtTV1 is 6,921 nucleotides in length, containing two open reading frames (ORFs). ORF1 encodes a 1,124-amino-acid capsid protein (CP) with a molecular weight of 125.07 kDa, and ORF2 encodes a 780-amino-acid RNA-dependent RNA polymerase (RdRp) with a molecular weight of 88.05 kDa. CNRV1-2, approximately 3.0 kb in length, also contains two ORFs, which are predicted to encode a 186-amino-acid hypothetical protein (HP) and a 758-amino-acid RdRp. CtV1 has a smaller genome consisting of 3,081 base pairs (bp) with two ORFs: one encoding a 244-amino-acid HP (26.85 kDa) and the other encoding a 707-amino-acid RdRp (80.64 kDa). Phylogenetic analysis based on RdRp sequences revealed that CtTV1 shows the highest similarity to Phytophthora pluvialis RNA virus 1, with 38.79% sequence identity, and clusters with members of the family Orthototiviridae, and it is most closely related to Utsjoki toti-like virus. In contrast, CtV1 formed a unique branch and might represent a new genus. The genome sequence of CNRV1-2 is 99.74% identical to that of the previously described Conidiobolus non-segmented RNA virus 1 (CNRV1). Our findings indicate that CtTV1 and CtV1 are distinct novel viruses, while CNRV1-2 appears to be a variant of CNRV1. This study enhances our understanding of the genetic diversity and evolutionary relationships among mycoviruses associated with C. taihushanensis.

High Carriage of tetA, sul1, sul2 and bla TEM Resistance Genes among the Multidrug-resistant Uropathogenic Escherichia coli (UPEC) Strains from Malaysian Patients.

The rapid emergence of multidrug-resistant (MDR) uropathogenic Escherichia coli (UPEC) strains pose a critical challenge in urinary tract infection (UTI) treatments. However, little work elucidated the resistance mechanisms of the MDR UPEC clinical strains in Malaysia. Therefore, this study aimed to determine the antimicrobial susceptibility profiles and the prevalence of antimicrobial resistance genes among the UPEC strains. Polymerase chain reactions were conducted to detect the presence of 6 antimicrobial resistance genes among 60 UPEC strains. Meanwhile, the antimicrobial resistance profiles against 9 antimicrobials were examined through the Kirby-Bauer disk diffusion method. In this study, the MDR isolates accounted for 40.0% (24/60), with the highest prevalence of resistance towards ampicillin (43/60; 71.7%), followed by tetracycline (31/60; 51.7%), nalidixic acid (30/60; 50.0%), co-trimoxazole (20/60, 33.3%), ciprofloxacin (19/60, 31.7%), levofloxacin (16/60, 21.6%) and chloramphenicol (10/60, 16.7%). In contrast, low resistance rates were observed among minocycline (1/60; 1.7%) and imipenem (0/60; 0.0%). bla TEM was the most prevalent gene (36/60; 60.0%), followed by tetA (27/60; 45.0%), sul2 (25/60; 41.7%), sul1 (13/60; 21.7%) and tetB (8/60; 13.3%). Surprisingly, bla SHV was not detected among the UPEC isolates. The MDR, ampicillin and tetracycline-resistant isolates were significantly associated with a higher prevalence of tetA, sul1, sul2 and bla TEM. In contrast, tetB displayed no significant relationship with any of the antimicrobials tested. The patient's age and gender were not the risk factors for the carriage of the resistance genes. Our findings identified the common resistance genes carried by the antimicrobial resistant UPEC isolates and provide valuable insights into developing the best antibiotic prescription regime to treat UTIs in our local scene.

Possible role of a malfunctioning immune system in discordant lymphoma with peripheral T­cell lymphoma secondary to classical Hodgkin lymphoma: A case report.

The present case report investigated the clinicopathological features and potential mechanisms underlying the transformation to peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), following treatment for classical Hodgkin lymphoma (CHL) in a 73-year-old man. The patient was admitted to hospital in 2012 and underwent a left cervical lymph node biopsy, which confirmed CHL of the nodular sclerosing type, with evident bone marrow involvement. The patient received four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy, after which they achieved complete remission. However, after 3 years, the patient presented with enlarged left inguinal lymph nodes and a biopsy revealed PTCL-NOS. Molecular studies indicated a T-cell receptor-γ gene rearrangement. A literature review, together with the current case, identified 11 patients with CHL that transformed into PTCL-NOS. Among these, nine patients (81.82%) were middle-aged or elderly (>45 years old), and eight (72.73%) experienced transformation within 3 years post-treatment of CHL. Among these eight patients, seven (87.50%) predominantly exhibited the nodular sclerosis subtype, with a median recurrence time of 26 months. Five (45.45%) patients died of the disease. The rare transformation of CHL to PTCL-NOS, primarily among men, underscores its clinical significance. Notably, nodular sclerosing-type CHL appears to be particularly prone to transformation into PTCL-NOS. The poor prognosis in such cases may be attributed to the complex tumor microenvironment of CHL.

Exploring phytoremediation potential of willow NJU513 for cadmium-contaminated soil with and without epibrassinolide treatment.

There has been a growing concern over soil cadmium (Cd) pollution, underscoring the importance of finding effective remediation strategies. Willow trees have emerged as promising candidates for phytoremediation of Cd-contaminated soils. Nevertheless, the specific potential of a novel willow genotype, NJU513, in remediating Cd-polluted soil remains unexplored. Hence, the primary objectives of this study were twofold: firstly, to ascertain the suitability of the willow genotype NJU513 for remediating Cd-contaminated soil; and secondly, to elevate its remediation efficciency with the application of epibrassinolide (Brs). In the pot-culture experiment without Brs, its leaf and stem Cd concentrations were 203 mg kg-1 and 65.1 mg kg-1, with a bioaccumulation factor (BCF) of 20.8 and 6.68, respectively. In the pot-culture experiment with Brs, the corresponding Cd concentrations were 226 mg kg-1 and 59.2 mg kg-1, with a BCF of 23.1 and 6.06, respectively. In addition, the extracted Cd contents were higher in the Brs treatments (1.11-1.37 mg plant-1) than in the no-Brs treatments (0.78-0.96 mg plant-1) because Brs increased the plant biomass and leaf BCF. The mechanism underlying the Cd accumulation of NJU513 leaves with and without Brs was revealed by a transcriptome analysis. The expression levels of genes related to metal ion binding, channel activity, and transporters in leaves were up-regulated, which contributed to the high Cd accumulation and stress tolerance. Analyses of soil metabolites and bacteria in the presence and absence of Brs spraying on willow leaves indicated that soil organic compounds with carboxyl and amino groups may induce Cd activation and passivation, respectively. This study provides valuable insights for developing woody plant varieties that can be used for remediating Cd-contaminated soil.

Differential impacts of organic and inorganic phosphorus on the growth and phosphorus utilization of Microcystis aeruginosa.

Phytoplankton growth in freshwater is often limited by the availability of phosphorus (P), and thorough understandings of P availability are essential to prevent algal blooms. However, the differences in bioavailability and utilization mechanisms of different P forms remain unclear, especially whether organophosphorus could be used as P sources. This study investigated the effects of 0.5, 1.0, and 2.0 mg/L P on Microcystis aeruginosa, including dissolved organic P (DOP) (1-hydroxyethane 1,1-diphosphonic acid) and dissolved inorganic P (DIP) (dipotassium phosphate). Compared with DIP, intracellular P content absorbed in DOP treatment was significantly lower. DOP was more conducive to the synthesis of soluble protein and the release of extracellular polymeric substances. Alkaline phosphatase activity was generally enhanced in response to DIP deficiency. Both DIP and DOP promoted carbon uptake to the same extent. DOP groups absorbed carbon to synthesize energy and proteins in response to stress, while DIP groups were mainly used carbon for growth. They all reduced the content of microcystin releasing into the aquatic environment and therefore reduced ecological risk caused by microcystin. Compared with DIP, the expressions of photosynthesis-related genes were significantly down-regulated in DOP group, while the expressions of nucleoside phosphate catabolism, P transporter, and amino acid biosynthesis and metabolism were significantly up-regulated in response to P deficiency environment and the stress of 1.0 mg/L DOP concentration. In summary, the bioavailability of different P forms on cyanobacteria is different, so it is not sufficient to only use total P for assessing environmental risk. P forms should also be considered for risk management of freshwater ecosystems.

Palladium-Catalyzed Denitrative α-Arylation of Heteroarenes with Nitroarenes via C-H and C-NO2 Bond Activations.

A general approach for the α-arylation of heteroarenes with nitroarenes via denitrative coupling is reported for the first time. Various heteroarenes, including derivatives of furan, benzofuran, pyrrole, indole, thiophene, and benzothiophene, can be arylated at the α-position in moderate to good yields. Mechanistic studies demonstrate that the reaction proceeds via a CMD pathway, with C-H bond activation as the rate-determining step. Furthermore, the scalability and applicability in the synthesis of a drug molecule exemplify the utility of this protocol.

Bioinspired deformation computational design method for muscle-driven soft robots using MPM.

In order to adapt to complex and changing environments, animals have a wide variety of locomotor forms, which has inspired the investigation of their deformation and driving mechanisms. In this paper, we propose a computational design method for muscle-driven soft robots to satisfy desired deformations, aiming to mimic the deformation behavior of muscle-driven animals in nature. In this paper, we generate the ideal muscle-driven layout for the soft robot by inputting an initial shape and a desired shape, so that it can closely achieve the desired deformation. The material point method is utilized to simulate the soft medium so as to achieve the effect of coupling and coordinated deformation of arbitrary shapes. Our method efficiently searches for muscle layouts corresponding to various deformations and realizes the deformation behaviors of a variety of bio-inspired robots, including soft robots such as bionic snakes, frogs, and human faces. Experimental results show that for both the bionic snake and frog soft robots, the overlap of the geometric contour regions between the actual and simulated deformations is more than 90%, which validates the effectiveness of the method. In addition, the global muscle distributions of the bionic snake and human face soft robots during motion are generated and validated by effective simulation.

Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8.

Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development.

A refined formula derived from Jiawei-Xiaoyao pill exerts rapid antidepressant-like effects in LPS-induced depression by reducing neuroinflammation and restoring neuroplasticity signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei-Xiaoyao Pill (JWX), a classic formula in traditional Chinese medicine, is derived from Xiaoyao Pill by adding significant amounts of Gardeniae Fructus (GF) and Moutan Cortex (MC). It is frequently used for the treatment of depression. JWX has been demonstrated to uniquely elicit rapid antidepressant-like effects within the prescribed dosage range. To date, GF has been shown to have rapid antidepressant-like effects, but a much higher dose is required than its proportion in JWX. It is assumed that the synergism of GF with a minimum number of other herbs in JWX serves as a refined formula that exerts these rapid antidepressant-like effects. Identification of a refined formula is important for prioritizing the herbs and ingredients to optimize the quality control of JWX. However, such a refined formula for JWX has not been identified yet. AIM OF THE STUDY: Here we aimed to identify a refined formula derived from JWX for optimized rapid antidepressant-like effects. Since the neuroinflammation mechanism involving in depression treatment has not been previously investigated for JWX, we tested the mechanism for both JWX and the refined formula. MATERIALS AND METHODS: Individual herbs (MC; ASR, Angelica Sinensis Radix; Bupleuri Radix; Paeonia Radix Alba) that show antidepressant-like responses were mixed with GF at the proportional dosage in JWX to identify the refined formula. Rapid antidepressant-like effects were assessed by using NSF (Novelty Suppressed Feeding Test) and other behavioral tests following a single administration. The identified formula was further tested in a lipopolysaccharide (LPS)-induced depressive model, and the molecular signaling mechanisms were investigated using Western blot analysis, immunofluorescence, and pharmacological inhibition of mTOR signaling. Scopolamine (Scop) was used as a positive control for induction of rapid antidepressant effects. RESULTS: A combination of GF, MC and ASR (GMA) at their dosages proportional to JWX induced behavioral signs of rapid antidepressant-like responses in both normal and LPS-treated mice, with the antidepressant-like effects sustained for 5 d. Similar to JWX or Scop, GMA rapidly reduced the neuroinflammation signaling of Iba-1-NF-кB, enhanced neuroplasticity signaling of CaMKII-mTOR-BDNF, and attenuated the upregulated expressions of the NMDAR sub-units GluN1 and GluN2B in the hippocampus of LPS-treated mice. GMA, JWX and Scop rapidly restored the number of BDNF-positive cells reduced by LPS treatment in the CA3 region of the hippocampus. Furthermore, rapamycin, a selective inhibitor of mTOR, blunted the rapid antidepressant-like effects and hippocampal BDNF signaling upregulation by GMA. CONCLUSION: GMA may serve as a refined formula from JWX, capable of inducing rapid antidepressant-like effects. In the LPS-induced depression model, the effects of GMA were mediated via rapidly alleviating neuroinflammation and enhancing neuroplasticity.

[Modular pharmacology: research progress and development of analysis platform].

Based on the systematic deconstruction of multi-dimensional and multi-target biological networks, modular pharmacology explains the complex mechanism of diseases and the interactions of multi-target drugs. It has made progress in the fields of pathogenesis of disease, biological basis of disease and traditional Chinese medicine(TCM) syndrome, pharmacological mechanism of multi-target herbs, compatibility of formulas, and discovery of new drug of TCM compound. However, the complexity of multi-omics data and biological networks brings challenges to the modular deconstruction and analysis of the drug networks. Here, we constructed the "Computing Platform for Modular Pharmacology" online analysis system, which can implement the function of network construction, module identification, module discriminant analysis, hub-module analysis, intra-module and inter-module relationship analysis, and topological visualization of network based on quantitative expression profiles and protein-protein interaction(PPI) data. This tool provides a powerful tool for the research on complex diseases and multi-target drug mechanisms by means of modular pharmacology. The platform may have broad range of application in disease modular identification and correlation mechanism, interpretation of scientific principles of TCM, analysis of complex mechanisms of TCM and formulas, and discovery of multi-target drugs.

Hippocampal PACAP signaling activation triggers a rapid antidepressant response.

BACKGROUND: The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response. METHODS: The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus. RESULTS: Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optogenetic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor (BDNF) signaling. Finally, acute ketamine treatment upregulated hippocampal PACAP expression, whereas intra-DG blockade of PACAP signaling attenuated ketamine's rapid antidepressant response. CONCLUSIONS: Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKII inhibition-governed eEF2-mTOR-BDNF signaling.

Application of Antioxidant Compounds in Bone Defect Repair.

Bone defects caused by trauma, tumor resection, and infections are significant clinical challenges. Excessive reactive oxygen species (ROS) usually accumulate in the defect area, which may impair the function of cells involved in bone formation, posing a serious challenge for bone repair. Due to the potent ROS scavenging ability, as well as potential anti-inflammatory and immunomodulatory activities, antioxidants play an indispensable role in the maintenance and protection of bone health and have gained increasing attention in recent years. This narrative review aims to give an overview of the main research directions on the application of antioxidant compounds in bone defect repair over the past decade. In addition, the positive effects of various antioxidants and their biomaterial delivery systems in bone repair are summarized to provide new insights for exploring antioxidant-based strategies for bone defect repair.

A novel betapartitivirus isolated from Cordyceps militaris, an edible-medicinal mushroom.

In this study, we identified a novel partitivirus, named "Cordyceps militaris partitivirus 1" (CmPV1), in Cordyceps militaris strain RCEF7506. The complete genome of CmPV1 comprises two segments, dsRNA1 and dsRNA2, each encoding a single protein. dsRNA1 (2,206 bp) encodes an RNA-dependent RNA polymerase (RdRp), and dsRNA2 (2,256 bp) encodes a coat protein (CP). Sequence analysis revealed that dsRNA1 has the highest similarity to that of Bipolaris maydis partitivirus 2 (BmPV2), whereas dsRNA2 shows the highest similarity to human blood-associated partitivirus (HuBPV). Phylogenetic analysis based on RdRp sequences suggests that CmPV1 is a new member of the genus Betapartitivirus of the family Partitiviridae. This is the first documentation of a betapartitivirus infecting the entomopathogenic fungus C. militaris.

Cathepsins and cancer risk: a Mendelian randomization study.

Background: Previous observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated the causal relationship between cathepsins and cancer using Mendelian randomization (MR) analysis. Methods: We used publicly available genome-wide association study (GWAS) data for bidirectional MR analysis. Inverse variance weighting (IVW) was used as the primary MR method of MR analysis. Results: After correction for the False Discovery Rate (FDR), two cathepsins were found to be significantly associated with cancer risk: cathepsin H (CTSH) levels increased the risk of lung cancer (OR = 1.070, 95% CI = 1.027-1.114, P = 0.001, PFDR = 0.009), and CTSH levels decreased the risk of basal cell carcinoma (OR = 0.947, 95% CI = 0.919-0.975, P = 0.0002, P FDR = 0.002). In addition, there was no statistically significant effect of the 20 cancers on the nine cathepsins. Some unadjusted low P-value phenotypes are worth mentioning, including a positive correlation between cathepsin O (CTSO) and breast cancer (OR = 1.012, 95% CI = 1.001-1.025, P = 0.041), cathepsin S (CTSS) and pharyngeal cancer (OR = 1.017, 95% CI = 1.001-1.034, P = 0.043), and CTSS and endometrial cancer (OR = 1.055, 95% CI = 1.012-1.101, P = 0.012); and there was a negative correlation between cathepsin Z and ovarian cancer (CTSZ) (OR = 0.970, 95% CI = 0.949-0.991, P = 0.006), CTSS and prostate cancer (OR = 0.947, 95% CI = 0.902-0.944, P = 0.028), and cathepsin E (CTSE) and pancreatic cancer (OR = 0.963, 95% CI = 0.938-0.990, P = 0.006). Conclusion: Our MR analyses showed a causal relationship between cathepsins and cancers and may help provide new insights for further mechanistic and clinical studies of cathepsin-mediated cancer.

Endothelial cell Piezo1 promotes vascular smooth muscle cell differentiation on large arteries.

Vascular stabilization is a mechanosensitive process, in part driven by blood flow. Here, we demonstrate the involvement of the mechanosensitive ion channel, Piezo1, in promoting arterial accumulation of vascular smooth muscle cells (vSMCs) during zebrafish development. Using a series of small molecule antagonists or agonists to temporally regulate Piezo1 activity, we identified a role for the Piezo1 channel in regulating klf2a levels and altered targeting of vSMCs between arteries and veins. Increasing Piezo1 activity suppressed klf2a and increased vSMC association with the cardinal vein, while inhibition of Piezo1 activity increased klf2a levels and decreased vSMC association with arteries. We supported the small molecule data with in vivo genetic suppression of piezo1 and 2 in zebrafish, resulting in loss of transgelin+ vSMCs on the dorsal aorta. Further, endothelial cell (EC)-specific Piezo1 knockout in mice was sufficient to decrease vSMC accumulation along the descending dorsal aorta during development, thus phenocopying our zebrafish data, and supporting functional conservation of Piezo1 in mammals. To determine mechanism, we used in vitro modeling assays to demonstrate that differential sensing of pulsatile versus laminar flow forces across endothelial cells changes the expression of mural cell differentiation genes. Together, our findings suggest a crucial role for EC Piezo1 in sensing force within large arteries to mediate mural cell differentiation and stabilization of the arterial vasculature.

The causal relationship between anti-diabetic drugs and gastrointestinal disorders: a drug-targeted mendelian randomization study.

BACKGROUND: The incidence of diabetic gastrointestinal diseases is increasing year by year. This study aimed to investigate the causal relationship between antidiabetic medications and gastrointestinal disorders, with the goal of reducing the incidence of diabetes-related gastrointestinal diseases and exploring the potential repurposing of antidiabetic drugs. METHODS: We employed a two-sample Mendelian randomization (TSMR) design to investigate the causal association between antidiabetic medications and gastrointestinal disorders, including gastroesophageal reflux disease (GERD), gastric ulcer (GU), chronic gastritis, acute gastritis, Helicobacter pylori infection, gastric cancer (GC), functional dyspepsia (FD), irritable bowel syndrome (IBS), ulcerative colitis (UC), Crohn's disease (CD), diverticulosis, and colorectal cancer (CRC). To identify potential inhibitors of antidiabetic drug targets, we collected single-nucleotide polymorphisms (SNPs) associated with metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, insulin, and its analogs, thiazolidinediones, sulfonylureas, and alpha-glucosidase inhibitors from published genome-wide association study statistics. We then conducted a drug-target Mendelian randomization (MR) analysis using inverse variance weighting (IVW) as the primary analytical method to assess the impact of these inhibitors on gastrointestinal disorders. Additionally, diabetes was selected as a positive control. RESULTS: Sulfonylureas were found to significantly reduce the risk of CD (IVW: OR [95% CI] = 0.986 [0.978, 0.995], p = 1.99 × 10- 3), GERD (IVW: OR [95% CI] = 0.649 [0.452, 0.932], p = 1.90 × 10- 2), and chronic gastritis (IVW: OR [95% CI] = 0.991 [0.982, 0.999], p = 4.50 × 10- 2). However, they were associated with an increased risk of GU development (IVW: OR [95%CI] = 2 0.761 [1.259, 6.057], p = 1 0.12 × 10- 2). CONCLUSIONS: The results indicated that sulfonylureas had a positive effect on the prevention of CD, GERD, and chronic gastritis but a negative effect on the development of gastric ulcers. However, our research found no causal evidence for the impact of metformin, GLP-1 agonists, SGLT2 inhibitors, DPP 4 inhibitors, insulin and its analogs, thiazolidinediones, or alpha-glucosidase inhibitors on gastrointestinal diseases.

Polydatin: a potential NAFLD therapeutic drug that regulates mitochondrial autophagy through SIRT3-FOXO3-BNIP3 and PINK1-PRKN mechanisms - a network pharmacology and experimental investigation.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder that is linked to metabolic syndrome, mitochondrial dysfunction and impaired autophagy. Polydatin (PD), a natural polyphenol from Polygonum cuspidatum, exhibits various pharmacological effects and protects against NAFLD. The aim of this study was to reveal the molecular mechanisms and therapeutic potential of PD for NAFLD, with a focus on the role of mitochondrial autophagy mediated by sirtuin 3 (SIRT3), fork-head box O3 (FOXO3) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), and by PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN). We combined network pharmacology analysis, animal models and cell culture experiments to show that PD could regulate the mitochondrial autophagy pathway by modulating several key genes related to mitochondrial function, and ameliorate the liver function, histopathology and mitochondrial biogenesis of NAFLD mice and hepatocytes by activating the SIRT3-FOXO3-BNIP3 axis and the PINK1-PRKN-dependent mechanism of mitochondrial autophagy. We also identified the core targets of PD, including SIRT3, FOXO3A, CASP3, PARKIN, EGFR, STAT3, MMP9 and PINK, and confirmed that silencing SIRT3 could significantly attenuate the beneficial effect of PD. This study provided novel theoretical and experimental support for PD as a promising candidate for NAFLD treatment, and also suggested new avenues and methods for investigating the role of mitochondrial autophagy in the pathogenesis and intervention of NAFLD.

Effect of ultraviolet aged polytetrafluoroethylene microplastics on copper bioavailability and Microcystis aeruginosa growth.

Microplastics (MPs) are ubiquitous in aquatic environments, which can act as carriers to affect the bioavailability of heavy metals. The aging process in the environment changes the physicochemical properties of MPs, thereby affecting their environmental behavior and co-toxicity with other pollutants. However, relevant research is limited. In this study, we compared the properties and Cu2+ adsorption capacity of pristine and aged polytetrafluoroethylene (PTFE) MPs and further explored the influence on copper bioavailability and bio-effects on Microcystis aeruginosa. Aging process induced surface oxidation and cracks of PTFE MPs, and decreased the stability of MPs in water by increasing zeta potential. PTFE MPs had a strong adsorption capacity for Cu2+ and increased the bioavailability of copper to microalgae, which was not affected by the aging process. Pristine and aged PTFE MPs adhered to cyanobacterium surfaces and caused shrinkage and deformation of cells. Inhibition of cyanobacterium growth, photosynthesis and reduction of total antioxidant capacity were observed in the treatment of PTFE MPs. Combined exposure of pristine MPs and Cu2+ had stronger toxic effects to cyanobacterium, and increased Microcystin-LR release, which could cause harm to aquatic environment. Aging reduced the toxic effects of PTFE MPs on microalgae. Furthermore, soluble exopolysaccharide (EPS) content was significantly higher in co-exposure of aged MPs and Cu2+, which could reduce the toxicity to cyanobacterium cells. These results indicate that aging process alleviates the toxicity to microalgae and environmental risks caused by PTFE MPs. This study improves understanding of the combined toxicity of aged MPs and metals in freshwater ecosystems.

Regulation of angiogenesis by endocytic trafficking mediated by cytoplasmic dynein 1 light intermediate chain 1.

Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, DYNC1LI1) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to regulate Rab-mediated endosomal recycling and lysosomal degradation. Defects in this gene are predicted to alter dynein motor function, Rab binding capabilities, and cytoplasmic cargo trafficking. Here, we have identified a dync1li1 zebrafish mutant, harboring a premature stop codon at the exon 12/13 splice acceptor site, that displays increased angiogenesis. In vitro, LIC1-deficient human endothelial cells display increases in cell surface levels of the pro-angiogenic receptor VEGFR2, SRC phosphorylation, and Rab11-mediated endosomal recycling. In vivo, endothelial-specific expression of constitutively active Rab11a leads to excessive angiogenesis, similar to the dync1li1 mutants. Increased angiogenesis is also evident in zebrafish harboring mutations in rilpl1/2, the adaptor proteins that promote Rab docking to Lic1 to mediate lysosomal targeting. These findings suggest that LIC1 and the Rab-adaptor proteins RILPL1 and 2 restrict angiogenesis by promoting degradation of VEGFR2-containing recycling endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting increases Rab11-mediated recycling endosome activity, promoting excessive SRC signaling and angiogenesis.

Time of exercise differentially impacts bone growth in mice.

Although physical training has been shown to improve bone mass, the time of day to exercise for optimal bone growth remains uncertain. Here we show that engaging in physical activity during the early active phase, as opposed to the subsequent active or rest phase, results in a more substantial increase in bone length of male and female mice. Transcriptomic and metabolomic methodologies identify that exercise during the early active phase significantly upregulates genes associated with bone development and metabolism. Notably, oxidative phosphorylation-related genes show a rhythmic expression in the chondrification centre, with a peak at the early active phase, when more rhythmic genes in bone metabolism are expressed and bone growth is synergistically promoted by affecting oxidative phosphorylation, which is confirmed by subsequent pharmacological investigations. Finally, we construct a signalling network to predict the impact of exercise on bone growth. Collectively, our research sheds light on the intricacies of human exercise physiology, offering valuable implications for interventions.