Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence.

Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-ß-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.

Pan-Cancer Analysis Shows that KIFC2 is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Bladder Cancer.

KIFC2 plays an important role in prostate cancer progression and chemotherapy resistance, but the mechanism of its involvement in other malignancies remains unclear. Therefore, this study aimed to analyze and validate the mechanism of effect of KIFC2 in multiple tumors. Bioinformatic analysis was performed in conjunction with multiple databases (The Cancer Genome Atlas, Genotype-Tissue Expression Project, Human Protein Atlas, etc.) to fully explore the potential role of KIFC2 within individual tumors and to analyze the correlation with major research components such as prognosis, mutations, and the tumor microenvironment. The expression of KIFC2 demonstrates a significant correlation with the prognosis, clinical phenotype, tumor mutational burden, microsatellite instability, and tumor microenvironment across various malignancies and is associated with the modulation of diverse functional and signaling pathways. The differences in the expression of KIFC2 in the bladder cancer tissues (14 pairs) were statistically significant. The pan-cancer analysis in this study revealed the multifunctionality of KIFC2 in a variety of tumors, indicating a possible prognostic predictor and potential therapeutic target for tumors.

Perivascular fat tissue and vascular aging: a sword and a shield.

The understanding of the function of perivascular adipose tissue (PVAT) in vascular aging has significantly changed due to the increasing amount of information regarding its biology. Adipose tissue surrounding blood vessels is increasingly recognized as a key regulator of vascular disorders. It has significant endocrine and paracrine effects on the vasculature and is mediated by the production of a variety of bioactive chemicals. It also participates in a number of pathological regulatory processes, including oxidative stress, immunological inflammation, lipid metabolism, vasoconstriction, and dilation. Mechanisms of homeostasis and interactions between cells at the local level tightly regulate the function and secretory repertoire of PVAT, which can become dysregulated during vascular aging. The PVAT secretion group changes from being reducing inflammation and lowering cholesterol to increasing inflammation and increasing cholesterol in response to systemic or local inflammation and insulin resistance. In addition, the interaction between the PVAT and the vasculature is reciprocal, and the biological processes of PVAT are directly influenced by the pertinent indicators of vascular aging. The architectural and biological traits of PVAT, the molecular mechanism of crosstalk between PVAT and vascular aging, and the clinical correlation of vascular age-related disorders are all summarized in this review. In addition, this paper aims to elucidate and evaluate the potential benefits of therapeutically targeting PVAT in the context of mitigating vascular aging. Furthermore, it will discuss the latest advancements in technology used for targeting PVAT.

Apelin ameliorates sepsis-induced myocardial dysfunction via inhibition of NLRP3-mediated pyroptosis of cardiomyocytes.

Sepsis-induced myocardial dysfunction (SMD) is the major cause of death in sepsis. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis contributes to the occurrence and development of SMD. Although Apelin confers direct protection against SMD, the potential mechanisms remain unclear. This study aimed to determine whether Apelin protects against SMD via regulation of NLRP3-mediated pyroptosis of cardiomyocytes. Experimental SMD was induced in wild-type (WT) control mice and Apelin knockout (Apelin-/-) mice by cecal ligation and puncture (CLP). Neonatal mouse cardiomyocytes (NMCs) were treated with lipopolysaccharide (LPS) to simulate the physiological environment of SMD in vitro. The expression of Apelin was greatly decreased in the plasma from septic patients and septic mouse heart. Knockout of Apelin aggravated SMD, evidenced by decreased cardiac function, and increased cardiac fibrosis and NLRP3 inflammasome and pyroptosis levels in CLP-treated Apelin-/- mice compared with WT mice. Overexpression of Apelin activated the AMPK pathway and thereby inhibited NLRP3 inflammasome-mediated pyroptosis of NMCs induced by LPS in vitro These protective effects were partially abrogated by AMPK inhibitor. In conclusion, Apelin attenuated SMD by inhibiting NLRP3-mediated pyroptosis via activation of the AMPK pathway. Apelin may serve as a promising therapeutic target for SMD.

Transcriptome analysis reveals therapeutic potential of NAMPT in protecting against abdominal aortic aneurysm in human and mouse.

Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta, which has no effective therapeutic approaches due to unclear molecular mechanisms. Using single-cell RNA sequencing, we analyzed the molecular profile of individual cells within control and AAA abdominal aortas. We found cellular heterogeneity, with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells (VSMCs) in AAA. Up-regulated genes in AAA were associated with muscle tissue development and apoptosis. Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA. Additionally, VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation. Similar observations were made in a mouse model of AAA induced by Angiotensin II, further affirming the relevance of our findings to human AAA. The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention. Nicotinamide phosphoribosyltransferase (NAMPT, also named VISFATIN) signaling emerged as a signature event in AAA. NAMPT was significantly downregulated in AAA. NAMPT-extracellular vesicles (EVs) derived from mesenchymal stem cells restored NAMPT levels, and offered protection against AAA. Furthermore, NAMPT-EVs not only repressed injuries, such as cell senescence and DNA damage, but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models, suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment. These findings shed light on the cellular heterogeneity and injuries in AAA, and offered promising therapeutic intervention for AAA treatment.

RAS signalling genes can be used as host-induced gene silencing targets to control fungal diseases caused by Sclerotinia sclerotiorum and Botrytis cinerea.

Sclerotinia sclerotiorum causes white mold (also called stem rot, Sclerotinia blight, etc.) in many economically important plants. It is a notorious soilborne fungal pathogen due to its wide host range and ability to survive in soil for long periods of time as sclerotia. Although host-induced gene silencing (HIGS) was recently demonstrated to be an effective method for controlling white mold, limited gene targets are available. Here, using a forward genetics approach, we identified a RAS-GTPase activating protein, SsGAP1, which plays essential roles in sclerotia formation, compound appressoria production and virulence. In parallel, as revealed by our knockout analysis, the SsGAP1 ortholog in Botrytis cinerea, BcGAP1, plays similar roles in fungal development and virulence. By knocking down SsRAS1 and SsRAS2, we also revealed that both SsRAS1 and SsRAS2 are required for vegetative growth, sclerotia development, compound appressoria production and virulence in S. sclerotiorum. Due to the major roles these RAS signalling components play in Sclerotiniaceae biology, they can be used as HIGS targets to control diseases caused by both S. sclerotiorum and B. cinerea. Indeed, when we introduced HIGS constructs targeting SsGAP1, SsRAS1 and SsRAS2 in Nicotiana benthamiana and Arabidopsis thaliana, we observed reduced virulence. Taken together, our forward genetics gene discovery pipeline in S. sclerotiorum is highly effective in identifying novel HIGS targets to control S. sclerotiorum and B. cinerea.

Mitochondrial damage-associated molecular patterns: A new insight into metabolic inflammation in type 2 diabetes mellitus.

The pathogenesis of diabetes is accompanied by increased levels of inflammatory factors, also known as "metabolic inflammation", which runs through the whole process of the occurrence and development of the disease. Mitochondria, as the key site of glucose and lipid metabolism, is often accompanied by mitochondrial function damage in type 2 diabetes mellitus (T2DM). Damaged mitochondria release pro-inflammatory factors through damage-related molecular patterns that activate inflammation pathways and reactions to oxidative stress, further aggravate metabolic disorders, and form a vicious circle. Currently, the pathogenesis of diabetes is still unclear, and clinical treatment focuses primarily on symptomatic intervention of the internal environment of disorders of glucose and lipid metabolism with limited clinical efficacy. The proinflammatory effect of mitochondrial damage-associated molecular pattern (mtDAMP) in T2DM provides a new research direction for exploring the pathogenesis and intervention targets of T2DM. Therefore, this review covers the most recent findings on the molecular mechanism and related signalling cascades of inflammation caused by mtDAMP in T2DM and discusses its pathogenic role of it in the pathological process of T2DM to search potential intervention targets.

A MAP kinase cascade broadly regulates the lifestyle of Sclerotinia sclerotiorum and can be targeted by HIGS for disease control.

Sclerotinia sclerotiorum causes white mold or stem rot in a wide range of economically important plants, bringing significant yield losses worldwide. Control of this pathogen is difficult as its resting structure sclerotia can survive in soil for years, and no Resistance genes have been identified in S. sclerotiorum hosts. Host-induced gene silencing (HIGS) has shown promising effects in controlling many fungal pathogens, including S. sclerotiorum. However, better molecular genetic understanding of signaling pathways involved in its development and pathogenicity is needed to provide effective HIGS gene targets. Here, by employing a forward genetic screen, we characterized an evolutionarily conserved mitogen-activated protein kinase (MAPK) cascade in S. sclerotiorum, consisting of SsSte50-SsSte11-SsSte7-Smk1, which controls mycelial growth, sclerotia development, compound appressoria formation, virulence, and hyphal fusion. Moreover, disruption of the putative downstream transcription factor SsSte12 led to normal sclerotia but deformed appressoria and attenuated host penetration, as well as impaired apothecia formation, suggestive of diverged regulation downstream of the MAPK cascade. Most importantly, targeting SsSte50 using host-expressed double-stranded RNA resulted in largely reduced virulence of S. sclerotiorum on both Nicotiana benthamiana leaves and transgenic Arabidopsis thaliana plants. Therefore, this MAPK signaling cascade is generally needed for its growth, development, and pathogenesis and can serve as ideal HIGS targets for mitigating economic damages caused by S. sclerotiorum infection.

The prodomain of Arabidopsis metacaspase 2 positively regulates immune signaling mediated by pattern-recognition receptors.

Metacaspases (MCs) are structural homologs of mammalian caspases found in plants, fungi, and protozoa. Type-I MCs carry an N-terminal prodomain, the function of which is unclear. Through genetic analysis of Arabidopsis mc2-1, a T-DNA insertion mutant of MC2, we demonstrated that the prodomain of metacaspase 2 (MC2) promotes immune signaling mediated by pattern-recognition receptors (PRRs). In mc2-1, immune responses are constitutively activated. The receptor-like kinases (RLKs) BAK1/BKK1 and SOBIR1 are required for the autoimmune phenotype of mc2-1, suggesting that immune signaling mediated by the receptor-like protein (RLP)-type PRRs is activated in mc2-1. A suppressor screen identified multiple mutations in the first exon of MC2, which suppress the autoimmunity in mc2-1. Further analysis revealed that the T-DNA insertion at the end of exon 1 of MC2 causes elevated expression of the MC2 prodomain, and overexpression of the MC2 prodomain in wild-type (WT) plants results in the activation of immune responses. The MC2 prodomain interacts with BIR1, which inhibits RLP-mediated immune signaling by interacting with BAK1, suggesting that the MC2 prodomain promotes plant defense responses by interfering with the function of BIR1. Our study uncovers an unexpected function of the prodomain of a MC in plant immunity.

Sema4D as a biomarker for Predicting rheumatoid arthritis disease activity.

OBJECTIVE: The semaphorins are membrane or secreted proteins first identified in neural development. Semaphorin 4D (Sema4D) is the first family member found to have immune properties. We evaluated the potential of Sema4D as a marker for rheumatoid arthritis (RA) disease activity, singly and in combination with other known biomarkers including rheumatoid factor (RF) and C-reactive protein (CRP). METHODS: Three hundred and eleven RA patients were enrolled. The patients were divided into three groups based on their disease activity in 28 joints (DAS28): mild, moderate, and severe. The healthy group included 40 healthy individuals. SerumSema4D was measured by quantitative ELISA and the specificity and sensitivity of biomarkers were evaluated by generating a receiver operating characteristic (ROC) curve to analyze their diagnostic accuracy. RESULTS: Serum Sema4D levels in the moderate and severe RA groups were elevated significantly above those of the controls (P < 0.01), while levels in the mild RA and control groups did not differ significantly (P > 0.05). The Sema4D cutoff threshold was 15.7 ng/ml when the DAS28 was applied as a reference. Compared to the erythrocyte sedimentation rate (ESR and CRP, Sema4D had the highest specificity (96.8%) and area under the curve (0.80) for diagnosing RA activity. The highest specificity (100%) for the biomarker combinations was obtained when Sema4D was combined with CRP and anti-CCP, the combination of the Sema4D combined with ESR and anti-CCP had the highest sensitivity (99.35%). According to this result, a new model for jointly calculating RA activity of Sema4D,anti-CCP and CRP was constructed. Meanwhile another model is established by using the method of multivariate analysis.Model comparison results showed the the multiple regression algorithm method fitted the patients' disease activity better. CONCLUSION: The serum Sema 4D level effectively reflects moderate to severe RA activity. Sema4D levels can be used together with conventional RA biomarkers to increase the diagnostic power of RA activity. The multiple regression algorithm method is promising in disease activity calculation.

Revealing the mechanism of quinoa on type 2 diabetes based on intestinal flora and taste pathways.

To investigate the antidiabetic effects and mechanisms of quinoa on type 2 diabetes mellitus (T2DM) mice model. In this context, we induced the T2DM mice model with a high-fat diet (HFD) combined with streptozotocin (STZ), followed by treatment with a quinoa diet. To explore the impact of quinoa on the intestinal flora, we predicted and validated its potential mechanism of hypoglycemic effect through network pharmacology, molecular docking, western blot, and immunohistochemistry (IHC). We found that quinoa could significantly improve abnormal glucolipid metabolism in T2DM mice. Further analysis showed that quinoa contributed to the improvement of gut microbiota composition positively. Moreover, it could downregulate the expression of TAS1R3 and TRPM5 in the colon. A total of 72 active components were identified by network pharmacology. Among them, TAS1R3 and TRPM5 were successfully docked with the core components of quinoa. These findings confirm that quinoa may exert hypoglycemic effects through gut microbiota and the TAS1R3/TRPM5 taste signaling pathway.

Current status of Fe-based MOFs in biomedical applications.

Recently nanoparticle-based platforms have gained interest as drug delivery systems and diagnostic agents, especially in cancer therapy. With their ability to provide preferential accumulation at target sites, nanocarrier-constructed antitumor drugs can improve therapeutic efficiency and bioavailability. In contrast, metal-organic frameworks (MOFs) have received increasing academic interest as an outstanding class of coordination polymers that combine porous structures with high drug loading via temperature modulation and ligand interactions, overcoming the drawbacks of conventional drug carriers. FeIII-based MOFs are one of many with high biocompatibility and good drug loading capacity, as well as unique Fenton reactivity and superparamagnetism, making them highly promising in chemodynamic and photothermal therapy, and magnetic resonance imaging. Given this, this article summarizes the applications of FeIII-based MOFs in three significant fields: chemodynamic therapy, photothermal therapy and MRI, suggesting a logical route to new strategies. This article concludes by summarising the primary challenges and development prospects in these promising research areas.

Downregulation of ALKBH5 rejuvenates aged human mesenchymal stem cells and enhances their therapeutic efficacy in myocardial infarction.

Despite promising results in myocardial infarction (MI), mesenchymal stem cell (MSC)-based therapy is limited by cell senescence. N6-methyladenosine (m6A) messenger RNA methylation has been reported to be closely associated with cell senescence. Nonetheless, its role in the regulation of MSC senescence remains unclear. We examined the role of ALKB homolog 5 (ALKBH5) in regulating MSC senescence and determined whether ALKBH5 downregulation could rejuvenate aged MSCs (AMSCs) to improve their therapeutic efficacy for MI. RNA methylation was determined by m6A dot blotting assay. MSC senescence was evaluated by senescence-associated ß-galactosidase (SA-ß-gal) staining. A mouse model of acute MI was established by ligation of the left anterior decedent coronary artery (LAD). Compared with young MSCs (YMSCs), m6A level was significantly reduced but ALKBH5 was greatly increased in AMSCs. Overexpression of ALKBH5 reduced m6A modification and accelerated YMSC senescence. Conversely, ALKBH5 knockdown increased m6A modifications and alleviated AMSC senescence. Mechanistically, ALKBH5 regulated the m6A modification and stability of CDKN1C mRNA, which further upregulated CDKN1C expression, leading to MSC senescence. CDKN1C overexpression ameliorated the inhibition of cellular senescence of ALKBH5 siRNA-treated AMSCs. More importantly, compared with AMSCs, shALKBH5-AMSCs transplantation provided a superior cardioprotective effect against MI in mice by improving MSC survival and angiogenesis. We determined that ALKBH5 accelerated MSC senescence through m6A modification-dependent stabilization of the CDKN1C transcript, providing a potential target for MSC rejuvenation. ALKBH5 knockdown rejuvenated AMSCs and enhanced cardiac function when transplanted into the mouse heart following infarction.

Epigenetic regulation of N-hydroxypipecolic acid biosynthesis by the AIPP3-PHD2-CPL2 complex.

N-Hydroxypipecolic acid (NHP) is a signaling molecule crucial for systemic acquired resistance (SAR), a systemic immune response in plants that provides long-lasting and broad-spectrum protection against secondary pathogen infections. To identify negative regulators of NHP biosynthesis, we performed a forward genetic screen to search for mutants with elevated expression of the NHP biosynthesis gene FLAVIN-DEPENDENT MONOOXYGENASE 1 (FMO1). Analysis of two constitutive expression of FMO1 (cef) and one induced expression of FMO1 (ief) mutants revealed that the AIPP3-PHD2-CPL2 protein complex, which is involved in the recognition of the histone modification H3K27me3 and transcriptional repression, contributes to the negative regulation of FMO1 expression and NHP biosynthesis. Our study suggests that epigenetic regulation plays a crucial role in controlling FMO1 expression and NHP levels in plants.

CDK5R1 promotes Schwann cell proliferation, migration, and production of neurotrophic factors via CDK5/BDNF/TrkB after sciatic nerve injury.

Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) is necessary for central nervous system development and neuronal migration. At present, there are few reports about the role of CDK5R1 in peripheral nerve injury, and these need to be further explored. The CCK-8 and EdU assay was performed to examine cell proliferation. The migration ability of Schwann cells was tested by the cell scratch test. The apoptosis of Schwann cells was detected by flow cytometry. Sciatic nerve injury model in rats was established by crush injury. The sciatic function index (SFI) and the paw withdrawal mechanical threshold (PWMT) were measured at different time points. The results revealed that overexpression of CDK5R1 promoted the proliferation and migration of Schwann cells, and inhibited the apoptosis. Further studies found that pcDNA3.1-CDK5R1 significantly upregulated the expression of CDK5, BDNF and TrkB. More importantly, CDK5R1 promoted the recovery of nerve injury in rats. In addition, the CDK5 mediated BDNF/TrkB pathway was involved in the molecular mechanism of CDK5R1 on Schwann cells. It is suggested that the mechanism by which CDK5R1 promotes functional recovery after sciatic nerve injury is by CDK5 mediated activation of BDNF/TrkB signaling pathways.

TRAF3IP2 drives mesenchymal stem cell senescence via regulation of NAMPT-mediated NAD biosynthesis.

The cellular senescence of mesenchymal stem cells (MSCs) limits their application in regenerative medicine. This study aimed to clarify the role of TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a pro-inflammatory cytoplasmic adaptor protein, in regulating MSC senescence and to explore the potential mechanisms. Methods: MSC senescence was determined by senescence-associated ß-galactosidase (SA-ß-gal) staining. The expression of TRAF3IP2 and senescence-related proteins was detected by Western blotting. The nicotinamide adenine dinucleotide (NAD+) level and nicotinamide phosphoribosyl transferase (NAMPT) expression in MSCs was measured. Results: Compared with that in MSCs isolated from young donors (YMSCs), the expression of TRAF3IP2 was greatly increased in MSCs derived from aged donors (AMSCs). Overexpression of TRAF3IP2 accelerated YMSC senescence whereas downregulation significantly rescued cellular senescence. The protein level of NAMPT and the level of NAD+ were significantly decreased in AMSCs compared with YMSCs. Mechanistically, TRAF3IP2 induced MSC senescence via downregulation of NAMPT expression and NAD + level by inhibiting the AMPK signaling pathway. These effects were partially reversed by treatment with an AMPK or NAMPT activator. Conclusion: We revealed that TRAF3IP2 accelerated MSC senescence via downregulation of NAMPT-mediated NAD biosynthesis by mediation of the AMPK pathway, highlighting a novel means to rejuvenate senescent MSCs.

Erratum: Long-Distance Coherent Propagation of High-Velocity Antiferromagnetic Spin Waves [Phys. Rev. Lett. 130, 096701 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.096701.

Moderate altitude exposure impacts host fasting blood glucose and serum metabolome by regulation of the intestinal flora.

Moderate altitude exposure has shown beneficial effects on diabetes incidence but the underlying mechanisms are not understood. Our study aimed to investigate how the human gut microbiome impacted the serum metabolome and associated with glucose homeostasis in healthy Chinese individuals upon moderate-altitude exposure. Faecal microbiome composition was assessed using shotgun metagenomic sequencing. Serum metabolome was acquired by untargeted metabolomics technology, and amino acids (AAs) and propionic acid in serum were quantified by targeted metabolomics technology. The results indicated that the moderate-altitude exposed individuals presented lowered fasting blood glucose (FBG) and propionic acid, increased circulating L-Glutamine but decreased L-Glutamate and L-Valine, which correlated with enriched Bacteroidetes and decreased Proteobacteria. Additionally, the silico causality associations among gut microbiota, serum metabolome and host FBG were analyzed by mediation analysis. It showed that increased Bacteroides ovatus (B. ovatus) and decreased Escherichia coli (E. coli) were identified as the main antagonistic species driving the association between L-Glutamate and FBG in silico causality. Furthermore, the high-fat diet (HFD) fed mice subjected to faecal microbiota transplantation (FMT) were applied to validate the cause-in-fact effects of gut microbiota on the beneficial glucose response. We found that microbiome in the moderate-altitude exposed donor could predict the extent of the FBG response in recipient mice, which showed lowered FBG, L-Glutamate and Firmicutes/Bacteroidetes ratio. Our findings suggest that moderate-altitude exposure targeting gut microbiota and circulating metabolome, may pave novel avenues to counter dysglycemia.

Moringa oleifera leaf supplementation relieves oxidative stress and regulates intestinal flora to ameliorate polycystic ovary syndrome in letrozole-induced rats.

This study investigated the effects of supplementation Moringa oleifera leaf (MOL) on relieving oxidative stress, anti-inflammation, changed the relative abundance of multiple intestinal flora and blood biochemical indices during letrozole-induced polycystic ovary syndrome (PCOS). Previous studies have shown that MOL has anti-inflammatory, anti-oxidation, insulin-sensitizing effects. However, whether MOL has beneficial effects on PCOS remains to be elucidated. In the current study, 10-week-old female Sprague-Dawley rats received letrozole to induce PCOS-like rats, and subsequently were treated with a MOL diet. Then, the body weight and estrus cycles were measured regularly in this period. Finally, the ovarian morphology, blood biochemical indices, anti-oxidative, intestinal flora, and anti-inflammation were observed at the end of the experiment. We found that MOL supplementation markedly decreased the body weight, significantly upregulated the expression of Sirt1, FoxO1, PGC-1α, IGF1, and substantially modulated the sex hormone level and improved insulin resistance, which may be associated with the relieves oxidative stress. Moreover, the supplementation of MOL changed the relative abundance of multiple intestinal flora, the relative abundance of Fusobacterium, Prevotella were decreased, and Blautia and Parabacteroides were increased. These results indicate that MOL is potentially a supplementary medication for the management of PCOS.

A cAMP phosphodiesterase is essential for sclerotia formation and virulence in Sclerotinia sclerotiorum.

Sclerotinia sclerotiorum is a plant pathogenic fungus that causes white mold or stem rot diseases. It affects mostly dicotyledonous crops, resulting in significant economic losses worldwide. Sclerotia formation is a special feature of S. sclerotiorum, allowing its survival in soil for extended periods and facilitates the spread of the pathogen. However, the detailed molecular mechanisms of how sclerotia are formed and how virulence is achieved in S. sclerotiorum are not fully understood. Here, we report the identification of a mutant that cannot form sclerotia using a forward genetics approach. Next-generation sequencing of the mutant's whole genome revealed candidate genes. Through knockout experiments, the causal gene was found to encode a cAMP phosphodiesterase (SsPDE2). From mutant phenotypic examinations, we found that SsPDE2 plays essential roles not only in sclerotia formation, but also in the regulation of oxalic acid accumulation, infection cushion functionality and virulence. Downregulation of SsSMK1 transcripts in Sspde2 mutants revealed that these morphological defects are likely caused by cAMP-dependent inhibition of MAPK signaling. Moreover, when we introduced HIGS construct targeting SsPDE2 in Nicotiana benthamiana, largely compromised virulence was observed against S. sclerotiorum. Taken together, SsPDE2 is indispensable for key biological processes of S. sclerotiorum and can potentially serve as a HIGS target to control stem rot in the field.