Exploring the Molecular Therapeutic Mechanisms of Gemcitabine through Quantitative Proteomics.

Gemcitabine (GEM) is widely employed in the treatment of various cancers, including pancreatic cancer. Despite their clinical success, challenges related to GEM resistance and toxicity persist. Therefore, a deeper understanding of its intracellular mechanisms and potential targets is urgently needed. In this study, through mass spectrometry analysis in data-dependent acquisition mode, we carried out quantitative proteomics (three independent replications) and thermal proteome profiling (TPP, two independent replications) on MIA PaCa-2 cells to explore the effects of GEM. Our proteomic analysis revealed that GEM led to the upregulation of the cell cycle and DNA replication proteins. Notably, we observed the upregulation of S-phase kinase-associated protein 2 (SKP2), a cell cycle and chemoresistance regulator. Combining SKP2 inhibition with GEM showed synergistic effects, suggesting SKP2 as a potential target for enhancing the GEM sensitivity. Through TPP, we pinpointed four potential GEM binding targets implicated in tumor development, including in breast and liver cancers, underscoring GEM's broad-spectrum antitumor capabilities. These findings provide valuable insights into GEM's molecular mechanisms and offer potential targets for improving treatment efficacy.

Quantitative Proteomics Reveal the Role of Matrine in Regulating Lipid Metabolism.

Hyperlipidemia (HLP) is a prevalent systemic metabolic disorder characterized by disrupted lipid metabolism. Statin drugs have long been the primary choice for managing lipid levels, but intolerance issues have prompted the search for alternative treatments. Matrine, a compound derived from the traditional Chinese medicine Kushen, exhibits anti-inflammatory and lipid-lowering properties. Nevertheless, the mechanism by which matrine modulates lipid metabolism remains poorly understood. Here, we investigated the molecular mechanisms underlying matrine's regulation of lipid metabolism. Employing quantitative proteomics, we discovered that matrine increases the expression of LDL receptor (LDLR) in HepG2 and A549 cells, with subsequent experiments validating its role in enhancing LDL uptake. Notably, in hyperlipidemic hamsters, matrine effectively lowered lipid levels without affecting body weight, which highlights LDLR as a critical target for matrine's impact on HLP. Moreover, matrine's potential inhibitory effects on tumor cell LDL uptake hint at broader applications in cancer research. Additionally, thermal proteome profiling analysis identified lipid metabolism-related proteins that may interact with matrine. Together, our study reveals matrine's capacity to upregulate LDLR expression and highlights its potential in treating HLP. These findings offer insights into matrine's mechanism of action and open new avenues for drug research and lipid metabolism regulation.

A novel conductive microtubule hydrogel for electrical stimulation of chronic wounds based on biological electrical wires.

Electrical stimulation (ES) is considered a promising therapy for chronic wounds via conductive dressing. However, the lack of a clinically suitable conductive dressing is a serious challenge. In this study, a suitable conductive biomaterial with favorable biocompatibility and conductivity was screened by means of an inherent structure derived from the body based on electrical conduction in vivo. Ions condensed around the surface of the microtubules (MTs) derived from the cell's cytoskeleton are allowed to flow in the presence of potential differences, effectively forming a network of biological electrical wires, which is essential to the bioelectrical communication of cells. We hypothesized that MT dressing could improve chronic wound healing via the conductivity of MTs applied by ES. We first developed an MT-MAA hydrogel by a double cross-linking method using UV and calcium chloride to improve chronic wound healing by ES. In vitro studies showed good conductivity, mechanical properties, biocompatibility, and biodegradability of the MT-MAA hydrogel, as well as an elevated secretion of growth factors with enhanced cell proliferation and migration ability in response to ES. The in vivo experimental results from a full-thickness diabetic wound model revealed rapid wound closure within 7d in C57BL/6J mice, and the wound bed dressed by the MT-MAA hydrogel was shown to have promoted re-epithelization, enhanced angiogenesis, accelerated nerve growth, limited inflammation phases, and improved antibacterial effect under the ES treatment. These preclinical findings suggest that the MT-MAA hydrogel may be an ideal conductive dressing for chronic wound healing. Furthermore, biomaterials based on MTs may be also promising for treating other diseases.

PROS1 is a crucial gene in the macrophage efferocytosis of diabetic foot ulcers: a concerted analytical approach through the prisms of computer analysis.

BACKGROUND: Diabetic foot ulcers (DFUs) pose a serious long-term threat because of elevated mortality and disability risks. Research on its biomarkers is still, however, very limited. In this paper, we have effectively identified biomarkers linked with macrophage excretion in diabetic foot ulcers through the application of bioinformatics and machine learning methodologies. These findings were subsequently validated using external datasets and animal experiments. Such discoveries are anticipated to offer novel insights and approaches for the early diagnosis and treatment of DFU. METHODS: In this work, we used the Gene Expression Omnibus (GEO) database's datasets GSE68183 and GSE80178 as the training dataset to build a gene model using machine learning methods. After that, we used the training and validation sets to validate the model (GSE134431). On the model genes, we performed enrichment analysis using both gene set variant analysis (GSVA) and gene set enrichment analysis (GSEA). Additionally, the model genes were subjected to immunological association and immune function analyses. RESULTS: In this study, PROS1 was identified as a potential key target associated with macrophage efflux in DFU by machine learning and bioinformatics approaches. Subsequently, the key biomarker status of PROS1 in DFU was also confirmed by external datasets. In addition, PROS1 also plays a key role in macrophage exudation in DFU. This gene may be associated with macrophage M1, CD4 memory T cells, naïve B cells, and macrophage M2, and affects IL-17, Rap1, hedgehog, and JAK-STAT signaling pathways. CONCLUSIONS: PROS1 was identified and validated as a biomarker for DFU. This finding has the potential to provide a target for macrophage clearance of DFU.

Exploring the mechanism of contact-dependent cell-cell communication on chemosensitivity based on single-cell high-throughput drug screening platform.

High-throughput drug screening (HTDS) has significantly reduced the time and cost of new drug development. Nonetheless, contact-dependent cell-cell communication (CDCCC) may impact the chemosensitivity of tumour cells. There is a pressing need for low-cost single-cell HTDS platforms, alongside a deep comprehension of the mechanisms by which CDCCC affects drug efficacy, to fully unveil the efficacy of anticancer drugs. In this study, we develop a microfluidic chip for single-cell HTDS and evaluate the molecular mechanisms impacted by CDCCC using quantitative mass spectrometry-based proteomics. The chip achieves high-quality drug mixing and single-cell capture, with single-cell drug screening results on the chip showing consistency with those on the 96-well plates under varying concentration gradients. Through quantitative proteomic analysis, we deduce that the absence of CDCCC in single tumour cells can enhance their chemoresistance potential, but simultaneously subject them to stronger proliferation inhibition. Additionally, pathway enrichment analysis suggests that CDCCC could impact several signalling pathways in tumour single cells that regulate vital biological processes such as tumour proliferation, adhesion, and invasion. These results offer valuable insights into the potential connection between CDCCC and the chemosensitivity of tumour cells. This research paves the way for the development of single-cell HTDC platforms and holds the promise of advancing tumour personalized treatment strategies.

Urea fertilization increased CO2 and CH4 emissions by enhancing C-cycling genes in semi-arid grasslands.

Global climate change is predicted to increase exogenous N input into terrestrial ecosystems, leading to significant changes in soil C-cycling. However, it remains largely unknown how these changes affect soil C-cycling, especially in semi-arid grasslands, which are one of the most vulnerable ecosystems. Here, based on a 3-year field study involving N additions (0, 25, 50, and 100 kg ha-1 yr-1 of urea) in a semi-arid grassland on the Loess Plateau, we investigated the impact of urea fertilization on plant characteristics, soil properties, CO2 and CH4 emissions, and microbial C cycling genes. The compositions of genes involved in C cycling, including C fixation, degradation, methanogenesis, and methane oxidation, were determined using metagenomics analysis. We found that N enrichment increased both above- and belowground biomasses and soil organic C content, but this positive effect was weakened when excessive N was input (N100). N enrichment also altered the C-cycling processes by modifying C-cycle-related genes, specifically stimulating the Calvin cycle C-fixation process, which led to an increase in the relative abundance of cbbS, prkB, and cbbL genes. However, it had no significant effect on the Reductive citrate cycle and 3-hydroxypropionate bi-cycle. N enrichment led to higher soil CO2 and CH4 emissions compared to treatments without added N. This increase showed significant correlations with C degradation genes (bglA, per, and lpo), methanogenesis genes (mch, ftr, and mcr), methane oxidation genes (pmoA, pmoB, and pmoC), and the abundance of microbial taxa harboring these genes. Microbial C-cycling genes were primarily influenced by N-induced changes in soil properties. Specifically, reduced soil pH largely explained the alterations in methane metabolism, while elevated available N levels were mainly responsible for the shift in C fixation and C degradation genes. Our results suggest that soil N enrichment enhances microbial C-cycling processes and soil CO2 and CH4 emissions in semi-arid ecosystems, which contributes to more accurate predictions of ecosystem C-cycling under future climate change.

Epidemiology and prognostic factors for new-onset deep venous thrombosis after unicompartmental knee arthroplasty: a retrospective study.

BACKGROUND: Patients who underwent knee joint arthroplasty were at risk of venous thromboembolic events (VTEs), however, less studies were conducted to demonstrate the epidemiology and risk factors of deep venous thrombosis (DVT) following unicompartmental knee arthroplasty (UKA). Objective of this study was to explore the incidence and prognostic factors of DVT after UKA. METHODS: Patients who underwent primary UKA from December 2018 to June 2022 were recruited in this study. Demographic characteristics, operation related variables and laboratory index were extracted and analyzed. Receiver operating characteristic analysis was performed to detect the optimum cut-off value for variables of interest. Univariate and multivariate logistic analysis were performed to identify risk factors of DVT. RESULTS: 351 UKAs with a mean age of 65.4 ± 7.1 years were reviewed. After 12.9 ± 11.2 months follow-up, 35 DVTs were confirmed which indicating an incidence of 9.9%. The results showed that occupation (agricultural laborer) (P = 0.008), disease duration > 8.5 years (P = 0.035), operation time > 169 min (P = 0.003), intraoperative blood loss > 102 ml (P < 0.001), BMI > 26.8 kg/m 2 (P = 0.001), preoperative D-dimer > 0.29 mg/L (P = 0.001), prothrombin time < 10.7 s (P = 0.033) and INR < 0.98 (P = 0.032) between DVT and Non-DVT group were significantly different. Multivariate logistic regression analysis showed intraoperative blood loss > 102 ml (OR, 3.707; P, 0.001), BMI > 26.8 kg/m 2 (OR, 4.664; P, 0.004) and D-dimer > 0.29 mg/L (OR, 2.882; P, 0.009) were independent risk factors of DVT after UKA. CONCLUSION: The incidence of DVT in the present study was 9.9%, extensive intraoperative blood loss, advanced BMI and high level of D-dimer would increase the risk of lower extremity thrombosis by 2-4 times.

Effect of total astragalosides on diabetic non-healing wound by regulating immune microenvironment.

Aim: The aim of the research was to analyse the regulatory effect of astragaloside (AST) on the immune microenvironment of diabetic non-healing wound (DNHW), and to analyse the clinical efficacy and mechanism of wound repair in multiple layers. Material and methods: Ninety adult male Wistar rats, which were kept healthy (SPF) under natural infection, were randomly divided into three groups, namely, blank, control and observation groups, with 30 rats in each group. After adaptive feeding for 7 days, the diabetes model was established. After the model was formed, the wounds were uniformly prepared, and then the blank group only was shaved. Both the control group and the observation group were treated with moist exposure therapy. The control group was covered with physiological saline gauze, while the observation group was covered with AST gauze. The healing status of the wounds in both groups was observed and recorded on the 1st, 7th, and 14th days after formation. And the levels of α-smooth muscle actin (α-SMA) and collagen I (COL-1) in the wound tissue were measured. Results: On the 1st day after wound formation, the wound healing area, α-SMA, and COL-1 levels in the three groups were consistent (p > 0.05). On the 7th and 14th days after wound formation, the wound healing area in the three groups increased compared within the group, but only the control and observation groups had significantly higher wound healing area than on the 1st day after wound formation (p < 0.05). In addition, the blank group had lower levels of α-SMA and COL-1, while the control and observation groups had higher levels of α-SMA and COL-1 (p < 0.05). In the comparison between groups, the wound healing area, α-SMA, and COL-1 levels in the control and observation groups were higher than those in the blank group, while the wound healing area, α-SMA, and COL-1 levels in the observation group were higher than those in the control group (p < 0.05). Conclusions: AST can regulate the immune microenvironment of DNHW, improve α-SMA and COL-1, and accelerate the wound healing of DNHW.

Full-length transcriptome characterization of Platycladus orientalis based on the PacBio platform.

As a unique and native conifer in China, Platycladus orientalis is widely used in soil erosion control, garden landscapes, timber, and traditional Chinese medicine. However, due to the lack of reference genome and transcriptome, it is limited to the further molecular mechanism research and gene function mining. To develop a full-length reference transcriptome, tissues from five different parts of P. orientalis and four cone developmental stages were sequenced and analyzed by single-molecule real-time (SMRT) sequencing through the PacBio platform in this study. Overall, 37,111 isoforms were detected by PacBio with an N50 length of 2,317 nt, an average length of 1,999 bp, and the GC content of 41.81%. Meanwhile, 36,120 coding sequences, 5,645 simple sequence repeats (SSRs), 1,201 non-coding RNAs (lncRNAs), and 182 alternative splicing (AS) events with five types were identified using the results obtained from the PacBio transcript isoforms. Furthermore, 1,659 transcription factors (TFs) were detected and belonged to 51 TF families. A total of 35,689 transcripts (96.17%) were annotated through the NCBI nr, KOG, Swiss-Prot and KEGG databases, and 385 transcript isoforms related to 8 types of hormones were identified incorporated into plant hormone signal transduction pathways. The assembly and revelation of the full-length transcriptome of P. orientalis offer a pioneering insight for future investigations into gene function and genetic breeding within Platycladus species.

Extracellular vesicles secreted by bone marrow stem cells mediate angiogenesis for the treatment of diabetic ulcers: A systematic review and meta-analysis of preclinical studies.

Background: Diabetic ulcers (DUs) typically occur in patients with vascular diseases and diabetes. Extracellular vesicles secreted by bone marrow-derived stem cells (BMSC-EVs) represent a cell-free therapy that has emerged as a promising alternative for treating DU, especially due to significant advancements in the understanding of their role in promoting angiogenesis; however, their application in DU treatment remains in the preclinical stage, and their effectiveness is still uncertain. Therefore, we conducted this meta-analysis to evaluate the therapeutic efficacy of BMSC-EVs in treating DU and to expedite the clinical translation of BMSC-EV therapy for DU. Methods: We conducted a comprehensive search of PubMed, Cochrane Library, MEDLINE, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database, and our self-constructed database of Chinese Biomedical Literature up to May 2023 to identify preclinical studies related to the therapeutic use of extracellular vesicles secreted by bone marrow-derived stem cells for treating diabetic ulcers. Outcome measures included wound healing rate, neovascularization density, a-sma, and CD31. RevMan 5 software was employed for all statistical analyses. Results: In this meta-analysis, a total of 11 studies involving 103 animals were identified. The pooled analysis indicated that BMSC-EV treatment showed a superior wound healing rate compared to that of the control group (SMD = 1.06, 95% CI [0.52, 1.60], P = 0.0001). In the subgroup analysis, EV combined with new materials or drug therapy performed better than the sole injection of extracellular vesicles (SMD = 1.85, 95% CI [0.87, 2.82], P < 0.00001). BMSC-EV treatment also resulted in a higher number of neovascular structures compared to the control group(SMD = 5.80, 95% CI[0.89,10.71], P = 0.006). In the subgroup analysis, EV combined therapy showed a significant difference in the number of blood vessels compared to the sole injection of extracellular vesicles (SMD = 4.90, 95% CI[2.64,7.15], P < 0.00001). However, BMSCs-EV treatment did not demonstrate any statistically significant difference in the angiogenesis-related indicators CD31 and α-SMA compared to the control group (SMD = 1.61, 95% CI[-0.51,3.74], P = 0.14). Conclusion: According to the current meta-analysis, BMSC-EV therapy can enhance the healing of diabetic ulcers and promote wound angiogenesis, particularly when used in combination with novel dressings or other drugs, which further accelerates the healing process of diabetic ulcers. To establish the most effective parameters for EV treatment in diabetic ulcers, future research should promptly progress into clinical trials.

Discovery of a PROTAC degrader for METTL3-METTL14 complex.

N6-methyladenosine (m6A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex. WD6305 suppresses m6A modification and the proliferation of AML cells, and promotes apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti-leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions.

A novel diabetic foot ulcer diagnostic model: identification and analysis of genes related to glutamine metabolism and immune infiltration.

BACKGROUND: Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes, with vascular changes, neuropathy, and infections being the primary pathological mechanisms. Glutamine (Gln) metabolism has been found to play a crucial role in diabetes complications. This study aims to identify and validate potential Gln metabolism biomarkers associated with DFU through bioinformatics and machine learning analysis. METHODS: We downloaded two microarray datasets related to DFU patients from the Gene Expression Omnibus (GEO) database, namely GSE134431, GSE68183, and GSE80178. From the GSE134431 dataset, we obtained differentially expressed Gln-metabolism related genes (deGlnMRGs) between DFU and normal controls. We analyzed the correlation between deGlnMRGs and immune cell infiltration status. We also explored the relationship between GlnMRGs molecular clusters and immune cell infiltration status. Notably, WGCNA to identify differentially expressed genes (DEGs) within specific clusters. Additionally, we conducted GSVA to annotate enriched genes. Subsequently, we constructed and screened the best machine learning model. Finally, we validated the predictions' accuracy using a nomogram, calibration curves, decision curve analysis (DCA), and the GSE134431, GSE68183, and GSE80178 dataset. RESULTS: In both the DFU and normal control groups, we confirmed the presence of deGlnMRGs and an activated immune response. From the GSE134431 dataset, we obtained 20 deGlnMRGs, including CTPS1, NAGS, SLC7A11, GGT1, GCLM, RIMKLA, ARG2, ASL, ASNS, ASNSD1, PPAT, GLS2, GLUD1, MECP2, ASS1, PRODH, CTPS2, ALDH5A1, DGLUCY, and SLC25A12. Furthermore, two clusters were identified in DFU. Immune infiltration analysis indicated the presence of immune heterogeneity in these two clusters. Additionally, we established a Support Vector Machine (SVM) model based on 5 genes (R3HCC1, ZNF562, MFN1, DRAM1, and PTGDS), which exhibited excellent performance on the external validation datasetGSE134431, GSE68183, and GSE80178 (AUC = 0.929). CONCLUSION: This study has identified five Gln metabolism genes associated with DFU, revealing potential novel biomarkers and therapeutic targets for DFU. Additionally, the infiltration of immune-inflammatory cells plays a crucial role in the progression of DFU.

Research progress and challenges in stem cell therapy for diabetic foot: Bibliometric analysis and perspectives.

BACKGROUND: Stem cell therapy has shown great potential for treating diabetic foot (DF). AIM: To conduct a bibliometric analysis of studies on the use of stem cell therapy for DF over the past two decades, with the aim of depicting the current global research landscape, identifying the most influential research hotspots, and providing insights for future research directions. METHODS: We searched the Web of Science Core Collection database for all relevant studies on the use of stem cell therapy in DF. Bibliometric analysis was carried out using CiteSpace, VOSviewer, and R (4.3.1) to identify the most notable studies. RESULTS: A search was conducted to identify publications related to the use of stem cells for DF treatment. A total of 542 articles published from 2000 to 2023 were identified. The United States had published the most papers on this subject. In this field, Iran's Shahid Beheshti University Medical Sciences demonstrated the highest productivity. Furthermore, Dr. Bayat from the same university has been an outstanding researcher in this field. Stem Cell Research & Therapy is the journal with the highest number of publications in this field. The main keywords were "diabetic foot ulcers," "wound healing," and "angiogenesis." CONCLUSION: This study systematically illustrated the advances in the use of stem cell therapy to treat DF over the past 23 years. Current research findings suggested that the hotspots in this field include stem cell dressings, exosomes, wound healing, and adipose-derived stem cells. Future research should also focus on the clinical translation of stem cell therapies for DF.

The Neuroprotective Effects of Electroacupuncture on Parkinson's Disease and the Underlying Molecular Mechanisms.

Parkinson's disease (PD) is a chronic neurodegenerative disease whose main pathological features are the degeneration of dopamine neurons and deposition of α-synuclein in neurons. At present, the most important treatment strategy for PD is drugs, and one of the most used drugs is levodopa. However, this therapy shows many problems, such as tolerance and long-term effects, so other treatment strategies need to be explored. As a traditional Chinese medicine treatment method with effective and few side effects, electroacupuncture is considered a non-drug therapy. It serves as a novel, promising therapeutic approach for the treatment of PD. In this review, the application and the effects of electroacupuncture on PD have been described. Besides, the underlying molecular mechanisms of electroacupuncture on PD that contribute to protecting dopaminergic neurons and reducing α-synuclein levels have been illustrated, including ① anti-oxidant stress response, ② anti-neuroinflammatory response, ③ up-regulation of neurotrophic factors and reduction of nerve cell apoptosis, ④ down-regulation of endoplasmic reticulum stress and improvement of mitochondrial function, ⑤ improvement of the function of the ubiquitin-proteasome system, ⑥ anti-excitatory toxicity response, ⑦ activation of autophagy, and ⑧ modulation of gut microbiota. Achieving a better understanding of the neuroprotective effects of electroacupuncture on PD will provide a theoretical basis and facilitate the application of electroacupuncture on PD.

Genetic support of the causal association between gut microbiota and peripheral artery disease: a bidirectional Mendelian randomization study.

BACKGROUND: The causal relationship between gut microbiota and peripheral artery disease (PAD) is still not clear. In this research, we employed the Mendelian randomization (MR) technique to explore the potential causal connection between 211 gut microbiota species and PAD. We also investigated whether the causal effects operate in both directions. METHODS: We used Genome-wide Association Studies (GWAS) summary statistics data from the MiBioGen and FinnGen consortia to conduct a two-sample MR analysis to explore the causal link between gut microbiota and PAD. Sensitivity analysis is conducted to assess the robustness of the MR results. In addition to that, reverse MR analysis was performed to examine the inverse causal relationship. RESULTS: The inverse variance weighted (IVW) method provided evidence supporting a causal relationship between 9 specific gut microbiota taxa and PAD. The study findings indicated that family Family XI (OR=1.11, CI 1.00-1.24, P=0.048), genus Lachnoclostridium (OR=1.24, 1.02-1.50, P=0.033), and genus Lachnospiraceae UCG001 (OR=1.17, 1.01-1.35, P=0.031) are risk factors associated with PAD. class Actinobacteria (OR=0.84, 0.72-0.99, P=0.034), family Acidaminococcaceae (OR=0.80, 0.66-0.98, P=0.029), genus Coprococcus2 (OR=0.79, 0.64-0.98, P=0.029), genus Ruminococcaceae UCG004 (OR=0.84, 0.72-0.99, P=0.032), genus Ruminococcaceae UCG010 (OR=0.74, 0.58-0.96, P=0.022), and order NB1n (OR=0.88, 0.79-0.98, P=0.02) may be associated with the risk factors of PAD. Moreover, our analysis did not uncover any evidence of a reverse causal relationship between PAD and the nine specific gut microbiota taxa investigated. CONCLUSIONS: Our MR research has confirmed the potential causal relationship between gut microbiota and PAD while also identifying specific gut bacterial communities associated with PAD.

Microglial NLRP3 inflammasome-mediated neuroinflammation and therapeutic strategies in depression.

Previous studies have demonstrated a bidirectional relationship between inflammation and depression. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes is closely related to the pathogenesis of various neurological diseases. In patients with major depressive disorder, NLRP3 inflammasome levels are significantly elevated. Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies. In this review, we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome. Moreover, we outlined various therapeutic strategies that target the NLRP3 inflammasome, including NLRP3 inflammatory pathway inhibitors, natural compounds, and other therapeutic compounds that have been shown to be effective in treating depression. Additionally, we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression. Currently, there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment. The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression. Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments.

Effect of aridity on the ß-diversity of alpine soil potential diazotrophs: insights into community assembly and co-occurrence patterns.

Microbial diversity plays a vital role in the maintenance of ecosystem functions. However, the current understanding of mechanisms that shape microbial diversity along environmental gradients at broad spatial scales is relatively limited, especially for specific functional groups, such as potential diazotrophs. Here, we conducted an aridity-gradient transect survey from 60 sites across the Tibetan Plateau, the largest alpine ecosystem of the planet, to investigate the ecological processes (e.g., local species pools, community assembly processes, and co-occurrence patterns) that underlie the ß-diversity of alpine soil potential diazotrophic communities. We found that aridity strongly and negatively affected the abundance, richness, and ß-diversity of soil diazotrophs. Diazotrophs displayed a distance-decay pattern along the aridity gradient, with organisms living in lower aridity habitats having a stronger distance-decay pattern. Arid habitats had lower co-occurrence complexity, including the number of edges and vertices, the average degree, and the number of keystone taxa, as compared with humid habitats. Local species pools explained limited variations in potential diazotrophic ß-diversity. In contrast, co-occurrence patterns and stochastic processes (e.g., dispersal limitation and ecological drift) played a significant role in regulating potential diazotrophic ß-diversity. The relative importance of stochastic processes and co-occurrence patterns changed with increasing aridity, with stochastic processes weakening whereas that of co-occurrence patterns enhancing. The genera Geobacter and Paenibacillus were identified as keystone taxa of co-occurrence patterns that are associated with ß-diversity. In summary, aridity affects the co-occurrence patterns and community assembly by regulating soil and vegetation characteristics and ultimately shapes the ß-diversity of potential diazotrophs. These findings highlight the importance of co-occurrence patterns in structuring microbial diversity and advance the current understanding of mechanisms that drive belowground communities.IMPORTANCERecent studies have shown that community assembly processes and species pools are the main drivers of ß-diversity in grassland microbial communities. However, co-occurrence patterns can also drive ß-diversity formation by influencing the dispersal and migration of species, the importance of which has not been reported in previous studies. Assessing the impact of co-occurrence patterns on ß-diversity is important for understanding the mechanisms of diversity formation. Our study highlights the influence of microbial co-occurrence patterns on ß-diversity and combines the drivers of community ß-diversity with drought variation, revealing that drought indirectly affects ß-diversity by influencing diazotrophic co-occurrence patterns and community assembly.