Tetrahydrofolate Attenuates Cognitive Impairment after Hemorrhagic Stroke by Promoting Hippocampal Neurogenesis via PTEN Signaling.

Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients. Hippocampal neurogenesis has been shown to play an essential role in cognitive function. Our previous study has shown that tetrahydrofolate (THF) promotes the proliferation of neural stem cells (NSCs). However, the effect of THF on cognition after ICH and the underlying mechanisms remain unclear. Here, we demonstrated that administration of THF could restore cognition after ICH. Using Nestin-GFP mice, we further revealed that THF enhanced the proliferation of hippocampal NSCs and neurogenesis after ICH. Mechanistically, we found that THF could prevent ICH-induced elevated level of PTEN and decreased expressions of phosphorylated AKT and mTOR. Furthermore, conditional deletion of PTEN in NSCs of the hippocampus attenuated the inhibitory effect of ICH on the proliferation of NSCs and abnormal neurogenesis. Taken together, these results provide molecular insights into ICH-induced cognitive impairment and suggest translational clinical therapeutic strategy for hemorrhagic stroke.

Both Hostile and Benevolent Sexism Predict Men's Infidelity.

Infidelity has destructive effects on romantic relationships. Several idiographic characteristics or experiences in an intimate relationship have been linked to unfaithfulness. Yet, relatively little research has been paid to investigate how sexist beliefs might sabotage relationships by incurring infidelity. The present research examined the association between men's ambivalent sexism - hostile sexism and benevolent sexism - and men's infidelity as well as women's perception of the likelihood of men's infidelity. The results showed that men's hostile sexism and benevolent sexism predicted their increased infidelity (Studies 1 and 2). In addition, the indirect association between ambivalent sexism (both hostile sexism and benevolent sexism) and infidelity was through the importance placed on power in one's intimate relationship in general (Study 2). Importantly, women were unaware of benevolently sexist men's increased infidelity, such that women rated benevolently sexist men as having a lower likelihood of engaging in infidelity than hostilely sexist men and believed benevolently sexist men's infidelity level was similar to nonsexist men (Study 3). Therefore, these findings contribute to the psychology of infidelity by revealing that ambivalent sexism, both hostile sexism and benevolent sexism, are significant predictors. Implications of the findings are discussed.

Chemogenetic stimulation of intact corticospinal tract during rehabilitative training promotes circuit rewiring and functional recovery after stroke.

BACKGROUND: Neuromodulatory techniques have been proven to enhance functional recovery after stroke in patients and animals, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). However, the success and feasibility of these approaches were often variable, largely due to a lack of target specificity. OBJECTIVE: We explored the effects of specific chemogenetic stimulation of intact corticospinal tract during rehabilitative training on functional recovery after stroke in mice. METHODS: We developed a viral-based intersectional targeting approach that allows specific chemogentic activation of contralateral hindlimb corticospinal neurons (CSNs) in a photothrombotic stroke model. RESULTS: We demonstrated that specific chemogenetic activation of CSNs, when combined with daily rehabilitation training, leads to significant skilled motor functional recovery via promoting corticospinal tract (CST) axons midline crossing sprouting from intact to the denervated spinal hemicord, and rewiring new functional circuits by new synapse formation. Mechanistically, we revealed that combined chemogenetic stimulation of CSNs and daily rehabilitation training significantly enhanced the mTOR activity of CSNs. CONCLUSIONS: Our findings highlight the great potential of specific neural activation protocols in combination with motor training for the recovery of skilled motor functions after stroke.

The impact of gut microbiota changes on the intestinal mucus barrier in burned mice: a study using 16S rRNA and metagenomic sequencing.

Background: The gut microbiota is a complex ecosystem that plays a critical role in human health and disease. However, the relationship between gut microbiota and intestinal damage caused by burns is not well understood. The intestinal mucus layer is crucial for maintaining intestinal homeostasis and providing a physiological barrier against bacterial invasion. This study aims to investigate the impact of gut microbiota on the synthesis and degradation of intestinal mucus after burns and explore potential therapeutic targets for burn injury. Methods: A modified histopathological grading system was employed to investigate the effects of burn injury on colon tissue and the intestinal mucus barrier in mice. Subsequently, 16S ribosomal RNA sequencing was used to analyze alterations in the gut microbiota at days 1-10 post-burn. Based on this, metagenomic sequencing was conducted on samples collected at days 1, 5 and 10 to investigate changes in mucus-related microbiota and explore potential underlying mechanisms. Results: Our findings showed that the mucus barrier was disrupted and that bacterial translocation occurred on day 3 following burn injury in mice. Moreover, the gut microbiota in mice was significantly disrupted from days 1 to 3 following burn injury, but gradually recovered to normal as the disease progressed. Specifically, there was a marked increase in the abundance of symbiotic and pathogenic bacteria associated with mucin degradation on day 1 after burns, but the abundance returned to normal on day 5. Conversely, the abundance of probiotic bacteria associated with mucin synthesis changed in the opposite direction. Further analysis revealed that after a burn injury, bacteria capable of degrading mucus may utilize glycoside hydrolases, flagella and internalins to break down the mucus layer, while bacteria that synthesize mucus may help restore the mucus layer by promoting the production of short-chain fatty acids. Conclusions: Burn injury leads to disruption of colonic mucus barrier and dysbiosis of gut microbiota. Some commensal and pathogenic bacteria may participate in mucin degradation via glycoside hydrolases, flagella, internalins, etc. Probiotics may provide short-chain fatty acids (particularly butyrate) as an energy source for stressed intestinal epithelial cells, promote mucin synthesis and accelerate repair of mucus layer.

Current status and prospect of ZIF-based materials for breast cancer treatment.

Breast cancer, one of the three most life-threatening cancers in modern times, must be explored for treatments with low side effects and practical efficacy. Metal organic framework materials (MOFs) is made by metal ions as the center for point and organic ligands as a bridge connecting a new type of porous nano-materials, among them, the zinc base zeolite imidazole skeleton material series (ZIFs) because of its excellent biocompatibility and pH slow controlled release ability, is widely used in the tumor microenvironment in basic research and achieved remarkable curative effect. Inspired by this, in this review, we focus on the recent research progress on the application of ZIFs in the treatment of breast cancer, mainly studying the structure of ZIFs such as ZIF-8, ZIF-90 and ZIF-67 and their application in novel therapies for breast cancer treatment, such as targeted drug delivery, photothermal therapy, immunotherapy and gene therapy.We will more fully demonstrate the potential of zif in breast cancer treatment, hoping to provide an avenue for exploring breast cancer treatment.

Leaf spot disease on Juglans regia caused by Ragnhildiana diffusa in China.

Juglans regia L. is commercially important for its edible nuts, which is a major species of walnut trees in Sichuan Province (Luo et al. 2020). In September 2021, brown leaf spot symptoms were observed on roughly 75% of 60 J. regia trees surveyed in an orchard of Chongzhou city (30°40'6''N, 103°40'18''E). Initially, the lesions measuring 2-10 mm were reddish to brown with a yellowish halo, then increased in size and coalesced to cover the whole leaf, eventually resulting in severe defoliation. Six symptomatic leaves from different trees were collected, and a single fungal isolate was obtained from each of the sampled leaves using single-spore isolation (Chomnunti et al. 2014). The isolates were incubated on potato dextrose agar (PDA) with a 12h photoperiod at 25 ℃, and deposited at the Culture Collection of Sichuan Agricultural University. Colonies were identical with black center and reddish-brown periphery, and the diameter reached 2 cm after 7 days. On the host, conidiophores were mostly reduced to conidiogenous cells, with prominent and thickened conidiogenous loci. Conidia were light green to light brown, and curved with a thickened and darked hilum at the base, 0-17 septate, tapering toward the distal end, and measuring 20-120 × 3-5 µm ((x ) ̅= 56 × 4, n = 30). Morphological characteristics fit the description of Ragnhildiana diffusa (Heald & F.A. Wolf) Videira & Crous (Synonym: Sirosporium diffusum (Heald & F. A. Wolf) Deighton) (Poletto et al. 2017). The internal transcribed spacer (ITS) region, the large subunit of the nrDNA (LSU), and RNA polymerase II second largest subunit (rpb2) were amplified by polymerase chain reaction and sequenced with primers ITS5/ITS4 (White et al. 1990), LR0R/LR5 (Vilgalys & Hester 1990), fRPB2-5F/Rpb2-R3 (Liu et al. 1999, Videira et al. 2017), respectively. The nucleotide blast of the two isolates (SICAUCC 22-0077, SICAUCC 22-0078) showed 99.7% and 99.5% (ITS, 472/473 bp, 471/473 bp), 100% (LSU, 725/725 bp, 725/725 bp), 99.8% (rpb2, 866/867 bp, 866/867 bp) identities with the ex-type strain of Ragnhildiana diffusa (CBS 106.14). The phylogenetic tree combined with ITS, LSU, and rpb2 genes and morphological characteristics confirmed the identification as R. diffusa. These sequences of the three gene regions of two isolates were deposited in GenBank with accession numbers ON409525 and ON409526 (ITS), ON409559 and ON409560 (LSU), ON417473 and ON417474 (rpb2), respectively. The isolate SICAUCC 22-0077 was used for pathogenicity test to fulfill Koch's postulates. Three leaves of each walnut seedlings (2-year-old seedlings) were inoculated by placing a mycelium plug onto fresh wounds on the upper leaf surface punctured via a fine needle (0.7 mm in diameter), and three replicate seedlings were inoculated. For the control, a sterile PDA plug was placed on the same number of replicate leaves on the plants. The inoculated and control plants were placed in a growth chamber at 25°C with relative humidity >80% and a 12-h photoperiod. Irregular light to dark brown spots developed on inoculated leaves after twenty days, and no symptoms were observed on controls. The re-isolation and examination of the fungus showed it to be morphologically and phylogenetically identical to the originally isolated pathogen. R. diffusa has been described on J. regia in Mexico (Farr & Rossman 2022). To our knowledge, this is the first report of R. diffusa causing brown leaf spot on J. regia in China. The identification of the pathogen will provide a basis for disease management in walnut planting areas.

Identification of three metabolic subtypes in gastric cancer and the construction of a metabolic pathway-based risk model that predicts the overall survival of GC patients.

Gastric cancer (GC) is highly heterogeneous and GC patients have low overall survival rates. It is also challenging to predict the prognosis of GC patients. This is partly because little is known about the prognosis-related metabolic pathways in this disease. Hence, our objective was to identify GC subtypes and genes related to prognosis, based on changes in the activity of core metabolic pathways in GC tumor samples. Differences in the activity of metabolic pathways in GC patients were analyzed using Gene Set Variation Analysis (GSVA), leading to the identification of three clinical subtypes by non-negative matrix factorization (NMF). Based on our analysis, subtype 1 showed the best prognosis while subtype 3 exhibited the worst prognosis. Interestingly, we observed marked differences in gene expression between the three subtypes, through which we identified a new evolutionary driver gene, CNBD1. Furthermore, we used 11 metabolism-associated genes identified by LASSO and random forest algorithms to construct a prognostic model and verified our results using qRT-PCR (five matched clinical tissues of GC patients). This model was found to be both effective and robust in the GSE84437 and GSE26253 cohorts, and the results from multivariate Cox regression analyses confirmed that the 11-gene signature was an independent prognostic predictor (p < 0.0001, HR = 2.8, 95% CI 2.1-3.7). The signature was found to be relevant to the infiltration of tumor-associated immune cells. In conclusion, our work identified significant GC prognosis-related metabolic pathways in different GC subtypes and provided new insights into GC-subtype prognostic assessment.

WZ35 inhibits gastric cancer cell metastasis by depleting glutathione to promote cellular metabolic remodeling.

This study aimed at elucidating the crosstalk between redox reaction and metabolic remodeling through uncovering the mechanism underlying WZ35-mediated reactive oxygen species (ROS) production and regulation of amino acid metabolism to inhibit gastric cancer (GC) cell metastasis. The activity and biosafety of curcumin analog, WZ35, were verified in vitro and in vivo. The potential molecular mechanism underlying WZ35-mediated enhanced radiotherapeutic sensitivity by reduced Glutathione (GSH) depletion was elucidated by RNA sequencing, single-cell sequencing (scRNA-seq), metabolic mass spectrometry, and other molecular experiments. Compared to curcumin, WZ35 proved more potent anti-proliferative and anti-metastasis properties. Importantly, we demonstrated that WZ35 could consume GSH in multiple ways, including by reduction of raw materials and consumption reserves, inhibition of reformation, and enhanced decomposition. Mechanistically, we identify that WZ35 maintains the GSH depletion phenotype through the ROS-YAP-AXL-ALKBH5-GLS2 loop, further backing the relevance of metabolic remodeling in the tumor microenvironment with tumor metastasis and the role of m6A in tumor metastasis. Collectively, our study identified WZ35 as a novel GSH depletion agent and a previously undiscovered GSH depletion loop mechanism in GC cell metastasis.

Glutamine promotes O-GlcNAcylation of G6PD and inhibits AGR2 S-glutathionylation to maintain the intestinal mucus barrier in burned septic mice.

Mucus forms the first line of defence of the intestinal mucosa barrier, and mucin is its core component. Glutamine is a vital energy substance for goblet cells; it can promote mucus synthesis and alleviate damage to the intestinal mucus barrier after burn injury, but its mechanism is not fully understood. This study focused on the molecular mechanisms underlying the effects of glutamine on the synthesis and modification of mucin 2 (MUC2) by using animal and cellular models of burn sepsis. We found that anterior gradient-2 (AGR2) plays a key role in the posttranslational modification of MUC2. Oxidative stress induced by burn sepsis enhanced the S-glutathionylation of AGR2, interfered with the processing and modification of MUC2 precursors by AGR2 and blocked the synthesis of mature MUC2. Further studies revealed that NADPH, catalysed by glucose-6-phosphate dehydrogenase (G6PD), is a key molecule in inhibiting oxidative stress and regulating AGR2 activity. Glutamine promotes O-linked N-acetylglucosamine (O-GlcNAc) modification of G6PD via the hexosamine pathway, which facilitates G6PD homodimer formation and increases NADPH synthesis, thereby inhibiting AGR2 S-glutathionylation and promoting MUC2 maturation, ultimately reducing damage to the intestinal mucus barrier after burn sepsis. Overall, we have demonstrated that the central mechanisms of glutamine in promoting MUC2 maturation and maintaining the intestinal mucus barrier are the enhancement of G6PD glycosylation and inhibition of AGR2 S-glutathionylation.

Acute exposure to gold nanoparticles aggravates lipopolysaccharide-induced liver injury by amplifying apoptosis via ROS-mediated macrophage-hepatocyte crosstalk.

BACKGROUND: Gold nanoparticles (AuNPs) are increasingly utilized in industrial and biomedical fields, thereby demanding a more comprehensive knowledge about their safety. Current toxicological studies mainly focus on the unfavorable biological impact governed by the physicochemical properties of AuNPs, yet the consequences of their interplay with other bioactive compounds in biological systems are poorly understood. RESULTS: In this study, AuNPs with a size of 10 nm, the most favorable size for interaction with host cells, were given alone or in combination with bacterial lipopolysaccharide (LPS) in mice or cultured hepatic cells. The results demonstrated that co exposure to AuNPs and LPS exacerbated fatal acute liver injury (ALI) in mice, although AuNPs are apparently non-toxic when administered alone. AuNPs do not enhance systemic or hepatic inflammation but synergize with LPS to upregulate hepatic apoptosis by augmenting macrophage-hepatocyte crosstalk. Mechanistically, AuNPs and LPS coordinate to upregulate NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) generation and activate the intrinsic apoptotic pathway in hepatic macrophages. Extracellular ROS generation from macrophages is then augmented, thereby inducing calcium-dependent ROS generation and promoting apoptosis in hepatocytes. Furthermore, AuNPs and LPS upregulate scavenger receptor A expression in macrophages and thus increase AuNP uptake to mediate further apoptosis induction. CONCLUSIONS: This study reveals a profound impact of AuNPs in aggravating the hepatotoxic effect of LPS by amplifying ROS-dependent crosstalk in hepatic macrophages and hepatocytes.

Glutamine mitigates murine burn sepsis by supporting macrophage M2 polarization through repressing the SIRT5-mediated desuccinylation of pyruvate dehydrogenase.

Background: Alternative (M2)-activated macrophages drive the anti-inflammatory response against sepsis, a leading cause of death in patients suffering from burn injury. Macrophage M2 polarization is intrinsically linked with dominant oxidative phosphorylation (OXPHOS). Glutamine serves as a major anaplerotic source to fuel OXPHOS, but it remains unknown whether glutamine can modulate metabolic checkpoints in OXPHOS that favour M2 polarization. The study aims to explore whether glutamine essentially supports M2 polarization in IL-4-stimulated murine macrophages by sustaining the activity of PDH and whether glutamine augments macrophage M2 polarization and thus alleviates inflammation and organ injury in a murine burn sepsis model. Methods: To understand how glutamine promotes M2 activation in interleukin (IL-4)-treated murine macrophages, we detected glutamine-dependent M2 polarization and its relationship with the pyruvate dehydrogenase (PDH) complex by RT-PCR, flow cytometry and western blot. To explore how glutamine modulates PDH activity and thus supports M2 polarization, we compared the expression, phosphorylation and succinylation status of PDHA1 and then examined sirtuin SIRT5-dependent desuccinylation of PDHA1 and the effects of SIRT5 overexpression on M2 polarization by RT-PCR, flow cytometry and western blot. To determine whether glutamine or its metabolites affect M2 polarization, macrophages were cocultured with metabolic inhibitors, and then SIRT5 expression and M2 phenotype markers were examined by RT-PCR, flow cytometry and western blot. Finally, to confirm the in vivo effect of glutamine, we established a burn sepsis model by injecting Pseudomonas aeruginosa into burn wounds and observing whether glutamine alleviated proinflammatory injuries by RT-PCR, flow cytometry, western blot, immunofluorescent staining, hematoxylin-eosin staining and enzyme-linked immuno sorbent assay. Results: We showed that consumption of glutamine supported M2 activation in IL-4-treated murine macrophages by upregulating the activity of PDH. Mechanistically, glutamine did not affect the expression or alter the phosphorylation status of PDHA1 but instead downregulated the expression of SIRT5 and repressed SIRT5-dependent desuccinylation on PDHA1, which in turn recovered PDH activity and supported M2 polarization. This effect was implemented by its secondary metabolite α-ketoglutarate (αKG) rather than glutamine itself. Finally, we demonstrated that glutamine promoted macrophage M2 polarization in a murine burn sepsis model, thereby repressing excessive inflammation and alleviating organ injury in model mice. Conclusions: Glutamine mitigates murine burn sepsis by essentially supporting macrophage M2 polarization, with a mechanism involving the repression of the SIRT5-mediated desuccinylation of pyruvate dehydrogenase that replenishes OXPHOS and sustains M2 macrophages.

Psychosomatic Symptoms and Neuroticism following COVID-19: The Role of Online Aggression toward a Stigmatized Group.

The present study investigated the effect of interpersonal mistreatment on the perpetrators' mental health. We proposed that the threat of COVID-19 will increase people's mental health problems through their on-line aggression toward stigmatized groups accused of spreading the disease and that there might be potential gender differences in such effects. We tested our predictions among a sample of U.S. residents (Study 1) and a large sample of Chinese residents living out of Hubei province (Study 2) during a heightened period of concern about COVID-19, February 2020. Specifically, we measured U.S. residents' on-line aggressive behaviors toward Chinese people (Study 1) and Chinese non-Hubei residents' on-line aggressive behaviors toward Hubei residents (Study 2) as well as their neuroticism (Study 1) and mental health states (Study 2). In line with our predictions, both studies showed that perceived infection of COVID-19 can induce on-line aggression toward stigmatized groups, thereby increasing people's mental health problems. Moreover, the relationship between COVID-19 vulnerability, on-line aggression, and psychosomatic symptoms was more prominent in men than in women. These results offer insights into people's responses toward COVID-19 and add to the understanding of people's mental and physical health during the epidemic stage of contagious diseases.

Impact of fertilization with reducing in nitrogen and phosphorous application on growth, yield and biomass accumulation of rice (Oryza sativa L.) under a dual cropping system.

The current farming system in China is heavily reliant on synthetic fertilizers, which adversely affect soil quality and crop production. Therefore, the aim of this study was to assess the effect of different nitrogen (N) and phosphorous (P) fertilizer application rate on the growth, yield, and yield components of rice cultivars in the Binyang, Beiliu and Liucheng sites of southern China in the early (March to July) and late season (August to December). The study consisted of three fertilization regimes-CK (N0P0); N180P90 (180 kg N + 90 kg P2O5 ha-1) and N90P45 (90 kg N ha-1 + 45 kg P2O5)-conducted at each of three different experimental sites with four cultivars (Baixang 139, Y Liangyou 1, Guiyu 9, and Teyou 582). Results showed that the leaf area index (LAI) was 38.8% found higher in Guiyu 9 compared with Baxiang at reduced fertilization (N90P45). N90P45 resulted higher dry matter production at the heading (9411.2 kg ha-1) and maturity (15319.5 kg ha-1) stages in Teyou 582 at Beiliu. Fertilization (N180P90) had higher effective panicle number (4,158,800 panicle ha-1) and grains panicle-1 (113.84 grains) compared with other treatments. Teyou 582 treated with N90P45 and Y Liangyou 1 treated with N180P90 improved seed setting rate average by 82.91% and 72.17% compared with other treatments at Beiliu in both seasons, respectively. N0P0 and N90P45 increased the thousand-grain weight (TGW) of Y Liangyou 1 at Binyang (27.07 g) and Liucheng (27.84 g) during the early and late seasons, respectively. In Beiliu, the N90P45 treatment (6611.7 kg ha-1) of Teyou 582 increased grain yield compared with other treatments. Overall, our results suggested that reducing N and P at the ratio of 90:45 kg ha-1 in Teyou 582 and Y Liangyou 1 could increase rice grain yield and yield components.

The complete chloroplast genome of Chimonobambusa hejiangensis.

Chimonobambusa hejiangensis is of the unique edible bamboo specie of high quality in China. We studied the complete chloroplast(cp) genome of C. purpurea in this study. The cp genome of C. hejiangensis (GenBank accession: MW186792) was 138,911 bp in length, including a large single-copy (LSC) region of 82,498 bp, a small single-copy (SSC) region of 12,743 bp and a pair of inverted repeated (IR) regions of 21,835 bp. The genome contained 133 genes, including 86 protein-coding genes, 39 tRNA genes, and 8 rRNA genes. Based on 39 cp genomes, we used the phylogenetic analysis to build phylogenetic tree, indicating that C. hejiangensis is closely related to C. tumidissinoda. Also, the phylogenetic relationship of lineages might be (Hsuehochloa + (((Shibataea clade + Arundinaria clade) + Indocalamus wilsonii) + ((Bergbambos + Indocalamus) + (((African alpine bamboos + Gaoligongshania) + (Chimonocalamus + Kuruna))+(Thamnocalamus + Phyllostachys clade))))). It could be devoted to phylogenetic analysis of Arundinarieae.

Awareness of societal emphasis on appearance decreases women's (but not men's) career aspiration: A serial mediation model.

This research examined the association between awareness of societal emphasis on physical appearance and people's career aspiration and the process that linked the two. Specifically, we proposed that perceived societal emphasis on physical attractiveness would decrease women's career aspiration through decreased authenticity and perceived opportunity. A total of 349 college students (227 females) participated in the study. The results revealed that awareness of societal emphasis on physical attractiveness negatively predicted women's authenticity, and authenticity positively predicted perception of opportunity, which in turn predicted their career aspiration. However, this serial mediational model was not found in men. These findings suggest that socially prioritization of attractiveness can undermine women's strive for occupational prospects and add to a better understanding of women's growth and development.

The complete chloroplast genome of Chimonobambusa purpurea (Bambusatae).

Chimonobambusa purpurea is one of the important bamboo species in southwest of China. We studied the complete chloroplast (cp) genome of C. purpurea in this study. The cp genome of C. purpurea (GenBank accession: MW030500) was 139,574 bp in length, including a large single-copy (LSC) region of 83,171 bp, a small single-copy (SSC) region of 12,811 bp, and a pair of inverted repeated (IR) regions of 21,796 bp. And the genome contained 133 genes, including 86 protein-coding genes, 39 tRNA genes, and 8 rRNA genes. Based on 30 cp genomes, we used the phylogenetic analysis to build phylogenetic tree, indicating that C. purpurea is closely related to C. tumidissinoda.

Diphenyleneiodonium enhances P2X7 dependent non-opsonized phagocytosis and suppresses inflammasome activation via blocking CX43-mediated ATP leakage.

The beneficial effects of antioxidants against oxidative stress have been well described. However, the pharmacological impacts of antioxidants other than inhibiting the production of reactive oxygen species (ROS) remain less understood. This study demonstrated that diphenyleneiodonium (DPI), a canonical NADPH oxidase 2 (NOX2) inhibitor, effectively promoted non-opsonized bacterial phagocytosis. Indeed, DPI abrogated the elevation in the extracellular ATP level of Escherichia coli (E. coli) -infected murine peritoneal macrophages, thereby restoring the association of the purinergic receptor P2X7 with non-muscle myosin heavy chain 9 (MYH9) to upregulate the P2X7 -dependent phagocytosis of E. coli. DPI also suppressed inflammasome activation and reduced necroptosis in E. coli-infected macrophages by decreasing extracellular ATP levels. Mechanistically, DPI upregulated p38 MAPK phosphorylation to suppress the expression and activity of the hemichannel protein connexin 43 (CX43), leading to the inhibition of CX43-mediated ATP efflux in E. coli-infected macrophages. In a murine E. coli infection model, DPI effectively reduced ATP release, decreased bacterial load and inhibited inflammasome activation, thereby improving survival and ameliorating organ injuries in model mice. In summary, our study demonstrates a previously unknown function of DPI in conferring protection against bacterial infection and suggests a putative antimicrobial strategy of modulating CX43 -dependent ATP leakage.

circRNA_010383 Acts as a Sponge for miR-135a, and Its Downregulated Expression Contributes to Renal Fibrosis in Diabetic Nephropathy.

Diabetic nephropathy (DN), a vascular complication of diabetes, is the leading cause of death in patients with diabetes. The contribution of aberrantly expressed circular RNAs (circRNAs) to DN in vivo is poorly understood. Integrated comparative circRNA microarray profiling was used to examine the expression of circRNAs in diabetic kidney of db/db mice. We found that circRNA_010383 expression was markedly downregulated in diabetic kidneys, mesangial cells, and tubular epithelial cells cultured in high-glucose conditions. circRNA_010383 colocalized with miRNA-135a (miR-135a) and inhibited miR-135a function by directly binding to miR-135a. In vitro, the knockdown of circRNA_010383 promoted the accumulation of extracellular matrix (ECM) proteins and downregulated the expression of transient receptor potential cation channel, subfamily C, member 1 (TRPC1), which is a target protein of miR-135a. Furthermore, circRNA_010383 overexpression effectively inhibited the high-glucose-induced accumulation of ECM and increased TRPC1 levels in vitro. More importantly, the kidney target of circRNA_010383 overexpression inhibited proteinuria and renal fibrosis in db/db mice. Mechanistically, we identified that a loss of circRNA_010383 promoted proteinuria and renal fibrosis in DN by acting as a sponge for miR-135a. This study reveals that circRNA_010383 may be a novel therapeutic target for DN in the future.

Gold nanoparticles synergize with bacterial lipopolysaccharide to enhance class A scavenger receptor dependent particle uptake in neutrophils and augment neutrophil extracellular traps formation.

Gold nanoparticles (AuNPs) are extensively utilized in biomedical fields. However, their potential interaction with host cells has not been comprehensively elucidated. In this study, we demonstrated a size-dependent effect of AuNPs to synergize with bacterial lipopolysaccharide (LPS) in promoting neutrophil extracellular traps (NETs) release in human peripheral neutrophils. Mechanistically, LPS was more efficient to contact with 10 nm AuNPs and promote their uptake in neutrophils compared to 40 and 100 nm AuNPs, leading to a synergistic upregulation of class A scavenger receptor (SRA) which mediated AuNPs uptake and triggered activation of extracellular regulated protein kinase (ERK) and p38. Blocking SRA or inhibiting ERK and p38 activation remarkably abrogated the effect of AuNPs and LPS to induce NETs formation. Further experiments demonstrated that AuNPs and LPS augmented the production of cytosolic reactive oxygen species (ROS) in p38 and ERK dependent manner, through upregulating and activating NADPH oxidase 2 (NOX2). Accordingly, scavenging of ROS or inhibiting the NOX2 dampened NETs release induced by combined AuNPs and LPS treatment. AuNPs and LPS also synergized to upregulate reactive oxygen species modulator 1 (ROMO1) via activating ERK, thereby increasing mitochondrial ROS generation and promoting the release of NETs. In summary, we provide new evidences about the synergy of AuNPs and LPS to augment cellular responses in neutrophils, which implicates the need to consider the amplifying effect by pathogenic stimuli when utilizing nanomaterials in infectious or inflammatory conditions.