Cuproptosis and copper deficiency in ischemic vascular injury and repair.

Ischemic vascular diseases are on the rise globally, including ischemic heart diseases, ischemic cerebrovascular diseases, and ischemic peripheral arterial diseases, posing a significant threat to life. Copper is an essential element in various biological processes, copper deficiency can reduce blood vessel elasticity and increase platelet aggregation, thereby increasing the risk of ischemic vascular disease; however, excess copper ions can lead to cytotoxicity, trigger cell death, and ultimately result in vascular injury through several signaling pathways. Herein, we review the role of cuproptosis and copper deficiency implicated in ischemic injury and repair including myocardial, cerebral, and limb ischemia. We conclude with a perspective on the therapeutic opportunities and future challenges of copper biology in understanding the pathogenesis of ischemic vascular disease states.

Linezolid dose adjustment according to therapeutic drug monitoring helps reach the goal concentration in severe patients, and the oldest seniors benefit more.

BACKGROUND: The elderly with severe infection increased dramatically in intensive care unit (ICU). Proper antimicrobial therapy help improve the prognosis. Linezolid, as an antimicrobial drug, is commonly utilized to treat patients infected with methicillin-resistant S. aureus and vancomycin-resistant enterococci. Clinical evidence suggests elderly patients prone to linezolid overexposure. Here, we describe the results of three years' linezolid adjustment experiences according to therapeutic drug monitoring (TDM), especially in the oldest old. METHODS: Linezolid therapeutic drug monitoring data were collected between January 2020 and November 2022 from patients who were admitted to ICU and treated with linezolid. All the patients started with a dosage of 600 mg, twice daily. The first TMD was carried out ten minutes before the seventh administration. The dosage adjustment was determined by the doctor according to the first TMD and patients' condition, and the repeated TDM was conducted as required. The dosage adjustment in different age group was recorded. Laboratory data were compared between the old and the oldest old. The high mortality risk of the oldest old was also explored. RESULTS: Data of 556 linezolid TDM from 330 patients were collected. Among which, 31.6%, 54.8%, and 75% of patients had supra-therapeutic linezolid trough concentrations at the first TDM assessment in different age group, leading to the dosage adjustment rate of 31.0%, 40.3%, 68.8% respectively. The linezolid dosage adjustments according to TDM help to reach therapeutic concentration. The oldest old was in high risk of linezolid overexposure with lowercreatinine clearance. The norepinephrine maximum dosage but not linezolid Cmin was associated with 28-day mortality in the oldest old. CONCLUSIONS: Elderly patients with linezolid conventional 600 mg twice-daily dose might be at a high risk of overexposure, especially in the oldest old. The linezolid dosage adjustments according to TDM help reach the therapeutic concentration. The high mortality of the oldest old was not related with initial linezolid overexposure.

Clinical characteristics of severe fever with thrombocytopenia syndrome (SFTS) sepsis and non-SFTS sepsis.

Severe fever with thrombocytopenia syndrome (SFTS) is a new infectious disease caused by bunyavirus, and the critically cases conform to the definition of sepsis. In order to compare the differences between SFTS sepsis and non-SFTS sepsis, a retrospective analysis was performed. Thirty-seven SFTS sepsis and 96 non-SFTS sepsis patients were enrolled. The clinical characteristics, laboratory results were compared between the two groups and independent prognostic risk of mortality were investigated respectively. Compared with non-SFTS sepsis, SFTS cases had lower white blood cell, neutrophil and platelet counts, prolonged activated partial thromboplastin time and decreased fibrinogen, slightly elevated inflammatory indicators. Interleukin-6 (IL-6), and acute physiology and chronic health evaluation Ⅱ (APACHE II) score were independent prognostic risk factors in non-SFTS sepsis. The mortality risk of STFS sepsis was related to the viral clearance. There was no difference in viral load between SFTS survivors and non-survivors on admission. However, the differences were significant on 5th, 7th, 10th, and 14th day, and all SFTS non-survivors died within 14 days. Viral clearance rate on 7th day was an independent risk factor for mortality in SFTS sepsis. The mortality risk of STFS sepsis was related to the viral clearance rate.

Mycobacteriaceae Phenome Atlas (MPA): A Standardized Atlas for the Mycobacteriaceae Phenome Based on Heterogeneous Sources.

The bacterial family Mycobacteriaceae includes pathogenic and nonpathogenic bacteria, and systematic research on their genome and phenome can give comprehensive perspectives for exploring their disease mechanism. In this study, the phenotypes of Mycobacteriaceae were inferred from available phenomic data, and 82 microbial phenotypic traits were recruited as data elements of the microbial phenome. This Mycobacteriaceae phenome contains five categories and 20 subcategories of polyphasic phenotypes, and three categories and eight subcategories of functional phenotypes, all of which are complementary to the existing data standards of microbial phenotypes. The phenomic data of Mycobacteriaceae strains were compiled by literature mining, third-party database integration, and bioinformatics annotation. The phenotypes were searchable and comparable from the website of the Mycobacteriaceae Phenome Atlas (MPA, https://www.biosino.org/mpa/). A topological data analysis of MPA revealed the co-evolution between Mycobacterium tuberculosis and virulence factors, and uncovered potential pathogenicity-associated phenotypes. Two hundred and sixty potential pathogen-enriched pathways were found by Fisher's exact test. The application of MPA may provide novel insights into the pathogenicity mechanism and antimicrobial targets of Mycobacteriaceae. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00101-5.

Analogous assembly mechanisms and functional guilds govern prokaryotic communities in mangrove ecosystems of China and South America.

As an important coastal "blue carbon sink," mangrove ecosystems contain microbial communities with an as-yet-unknown high species diversity. Exploring the assemblage and structure of sediment microbial communities therein can aid in a better understanding of their ecosystem functioning, such as carbon sequestration and other biogeochemical cycles in mangrove wetlands. However, compared to other biomes, the study of mangrove sediment microbiomes is limited, especially in diverse mangrove ecosystems at a large spatial scale, which may harbor microbial communities with distinct compositions and functioning. Here, we analyzed 380 sediment samples from 13 and 8 representative mangrove ecosystems, respectively, in China and South America and compared their microbial features. Although the microbial community compositions exhibited strong distinctions, the community assemblage in the two locations followed analogous patterns: the assemblages of the entire community, abundant taxa, rare taxa, and generalists were predominantly driven by stochastic processes with significant distance-decay patterns, while the assembly of specialists was more likely related to the behaviors of other organisms in or surrounding the mangrove ecosystems. In addition, co-occurrence and topological network analysis of mangrove sediment microbiomes underlined the dominance of sulfate-reducing prokaryotes in both the regions. Moreover, we found that more than 70% of the keystone and hub taxa were sulfate-reducing prokaryotes, implying their important roles in maintaining the linkage and stability of the mangrove sediment microbial communities. This study fills a gap in the large-scale analysis of microbiome features covering distantly located and diverse mangrove ecosystems. Here, we propose a suggestion to the Mangrove Microbiome Initiative that 16S rRNA sequencing protocols should be standardized with a unified primer to facilitate the global-scale analysis of mangrove microbiomes and further comparisons with the reference data sets from other biomes.IMPORTANCEMangrove wetlands are important ecosystems possessing valuable ecological functions for carbon storage, species diversity maintenance, and coastline stabilization. These functions are greatly driven or supported by microorganisms that make essential contributions to biogeochemical cycles in mangrove ecosystems. The mechanisms governing the microbial community assembly, structure, and functions are vital to microbial ecology but remain unclear. Moreover, studying these mechanisms of mangrove microbiomes at a large spatial scale can provide a more comprehensive insight into their universal features and can help untangle microbial interaction patterns and microbiome functions. In this study, we compared the mangrove microbiomes in a large spatial range and found that the assembly patterns and key functional guilds of the Chinese and South American mangrove microbiomes were analogous. The entire communities exhibited significant distance-decay patterns and were strongly governed by stochastic processes, while the assemblage of specialists may be merely associated with the behaviors of the organisms in mangrove ecosystems. Furthermore, our results highlight the dominance of sulfate-reducing prokaryotes in mangrove microbiomes and their key roles in maintaining the stability of community structure and functions.

Spatial transcriptomics of a lycophyte root sheds light on root evolution.

Plant roots originated independently in lycophytes and euphyllophytes, whereas early vascular plants were rootless. The organization of the root apical meristem in euphyllophytes is well documented, especially in the model plant Arabidopsis. However, little is known about lycophyte roots and their molecular innovations during evolution. In this study, spatial transcriptomics was used to detect 97 root-related genes in the roots of the lycophyte Selaginella moellendorffii. A high number of genes showed expression patterns similar to what has been reported for seed plants, supporting the idea of a highly convergent evolution of mechanisms to control root development. Interaction and complementation data of SHORTROOT (SHR) and SCARECROW (SCR) homologs, furthermore, support a comparable regulation of the ground tissue (GT) between euphyllophytes and lycophytes. Root cap formation, in contrast, appears to be differently regulated. Several experiments indicated an important role of the WUSCHEL-RELATED HOMEOBOX13 gene SmWOX13a in Selaginella root cap formation. In contrast to multiple Arabidopsis WOX paralogs, SmWOX13a is able to induce root cap cells in Arabidopsis and has functionally conserved homologs in the fern Ceratopteris richardii. Lycophytes and a part of the euphyllophytes, therefore, may share a common mechanism regulating root cap formation, which was diversified or lost during seed plant evolution. In summary, we here provide a new spatial data resource for the Selaginella root, which in general advocates for conserved mechanisms to regulate root development but shows a clear divergence in the control of root cap formation, with a novel putative role of WOX genes in root cap formation in non-seed plants.

Intestinal flora plays a role in the progression of hepatitis-cirrhosis-liver cancer.

The liver is a vital metabolism and detoxification organ of human body, which is involved in the biotransformation and metabolism of the organism. Hepatitis - cirrhosis - liver cancer are significant and common part of liver diseases. The pathogenesis of liver diseases is generally as followed: inflammation and other pathogenic factors cause persistent damage to the liver, leading to the activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix. Patients with chronic hepatitis have a high risk of developing into liver fibrosis, cirrhosis, and even life-threatening liver cancer, which poses a great threat to public health.As the first organ to come into contact with blood from the gut, the liver is profoundly affected by the intestinal flora and its metabolites, with leaky gut and flora imbalance being the triggers of the liver's pathological response. So far, no one has reviewed the role of intestinal flora in this process from the perspective of the progression of hepatitis-cirrhosis-liver cancer and this article reviews the evidence supporting the effect of intestinal flora in the progression of liver disease.

Role of the human solute carrier family 14 member 1 gene in hypoxia-induced renal cell carcinoma occurrence and its enlightenment to cancer nursing.

BACKGROUND: Hypoxia is considered a critical contributor to renal cell carcinoma progression, including invasion and metastasis. However, the potential mechanisms by which it promotes invasion and metastasis have not yet been clarified. The purpose of this study was to investigate the role and mechanism of hypoxia-induced renal cell carcinoma and provide evidence-based medical proof for improvements to postoperative nursing of renal cell carcinoma patients. A total of 64 patients with renal cell carcinoma were divided into the observation group (nursing based on oxygen administration) and the control group (conventional nursing). Renal function indexes, serum inflammatory factors, and tumor markers were evaluated. The human renal cell carcinoma cell line A498 under hypoxia/normoxia was used as an experimental model in vitro and the biological characteristics and mitochondrial function of the cells were assessed. RESULTS: Nursing based on oxygen administration decreased the value of renal function indexes, serum inflammatory factors, and tumor markers in renal cell carcinoma patients. Hypoxia was found to induce A498 cell invasion, migration, and the release of inflammatory cytokines, while repressing human solute carrier family 14 member 1 gene expression. Elevated levels of solute carrier family 14 member 1 expression induced mitochondrial reactive oxygen species accumulation, diminished the intracellular adenosine triphosphate level, and destroyed both mitochondrial membrane potential integrity and mitochondrial morphology. Overexpression of the solute carrier family 14 member 1 gene could abolish hypoxia-induced invasion, reduce the migration of A498 cells, inhibit the hypoxia-induced release of inflammatory cytokines, and arrest the cell cycle at the G1/S checkpoint. CONCLUSIONS: These data reveal that nursing based on oxygen administration can improve the clinical efficacy of renal cell carcinoma therapies, being safe and effective. The results elucidate a mechanism wherein the solute carrier family 14 member 1 gene participates in the occurrence and development of hypoxia-induced renal cell carcinoma in a mitochondria-dependent manner.

Bufalin alleviates acute kidney injury by regulating NLRP3 inflammasome-mediated pyroptosis.

BACKGROUND: Recently, there has been an increasing clinical incidence of acute kidney injury (AKI), which rapidly declines renal function and leads to massive tubular cell necrosis. Pyroptosis is an inflammatory process of cell death that is more rapid than apoptosis, which is accompanied by a massive release of inflammasome activation. In the study, we aim to explore whether Bufalin regulates the AKI through the pyroptosis pathway. METHODS: We have established gentamicin (GM)-induced AKI animal and cell models to simulate the pathological conditions of kidney injury. The expression of renal injury and pyroptosis-related indicators were detected by western blot. PAS staining and IHC staining were used to analyze renal function. CCK-8 assay was performed to detect cell viability after AKI with different treatments. TUNEL staining, flow cytometry and immunofluorescence assays were performed to measure pyroptosis. RESULTS: After intraperitoneal injection of GM in rats, renal function was significantly decreased, along with a significant increase of damaged and necrotic cells as suggested by renal tubular epithelial tissue sections. In addition, there was an increase in the pyroptosis-related markers expression and pyroptosis-induced cell death. Consistently, studies in vitro found that GM significantly induced pyroptosis and its associated protein expression in NRK52e cells. Whereas, the administration of Bufalin reversed these effects of GM in vivo and in vitro. Further, we found that Nigericin (NLRP3 agonist) could reversed the effects of bufalin on GM-induced pyroptosis. CONCLUSION: Bufalin attenuates pyroptosis generated AKI by inhibiting NLRP3 inflammasome.

KLF10 deficiency in CD4+ T cells promotes atherosclerosis progression by altering macrophage dynamics.

BACKGROUND AND AIMS: Accumulating evidence supports a critical role for CD4+ T cells as drivers and modifiers of the chronic inflammatory response in atherosclerosis. Effector T cells have pro-atherogenic properties, whereas CD4+ regulatory T cells (Tregs) exert suppressive activity in atherosclerosis through increased secretion of inhibitory cytokines such as transforming growth factor-ß or interleukin-10. In addition, Tregs have been shown to suppress inflammatory macrophages and promote the resolution of atherosclerosis plaques. Impaired Treg numbers and function have been associated with atherosclerosis plaque development. However, the underlying mechanisms remain unclear. METHODS AND RESULTS: Here, we investigated a cell-autonomous role of a transcription factor, Krüppel-like factor 10 (KLF10), in CD4+ T cells in regulating atherosclerosis progression. Using CD4+ T-cell-specific KLF10 knockout (TKO) mice, we identified exaggerated plaque progression due to defects in immunosuppressive functions of Tregs on macrophages. TKO mice exhibited increased lesion size as well as higher CD4+ T cells and macrophage content compared to WT mice. TKO plaques also showed increased necrotic cores along with defective macrophage efferocytosis. In contrast, adoptive cellular therapy using WT Tregs abrogated the accelerated lesion progression and deleterious effects in TKO mice. Intriguingly, RNA-seq analyses of TKO lesions revealed increased chemotaxis and cell proliferation, and reduced phagocytosis compared to WT lesions. Mechanistically, TKO-Tregs impaired the efferocytosis capacity of macrophages in vitro and promoted a pro-inflammatory macrophage phenotype via increased IFN-γ and decreased TGF-ß secretion. CONCLUSIONS: Taken together, these findings establish a critical role for KLF10 in regulating CD4+ Treg-macrophage interactions and atherosclerosis.

Cellular and gene expression patterns associated with root bifurcation in Selaginella.

The roots of lycophytes branch through dichotomy or bifurcation, during which the root apex splits into two daughter roots. This is morphologically distinct from lateral root (LR) branching in the extant euphyllophytes, with LRs developing along the root axis at different distances from the apex. Although the process of root bifurcation is poorly understood, such knowledge can be important, because it may represent an evolutionarily ancient strategy that roots recruited to form new stem cells or meristems. In this study, we examined root bifurcation in the lycophyte Selaginella moellendorffii. We characterized an in vitro developmental time frame based on repetitive apex bifurcations, allowing us to sample different stages of dichotomous root branching and analyze the root meristem and root branching in S. moellendorffii at the microscopic and transcriptomic level. Our results showed that, in contrast to previous assumptions, initial cells (ICs) in the root meristem are mostly not tetrahedral but rather show an irregular shape. Tracking down the early stages of root branching argues for the occurrence of a symmetric division of the single IC, resulting in two apical stem cells that initiate root meristem bifurcation. Moreover, we generated a S. moellendorffii root branching transcriptome that resulted in the delineation of a subset of core meristem genes. The occurrence of multiple putative orthologs of meristem genes in this dataset suggests the presence of conserved pathways in the control of meristem and root stem cell establishment or maintenance.

The Role of Nrf2 in D-Galactose-Induced Cardiac Aging in Mice: Involvement of Oxidative Stress.

INTRODUCTION: Cardiac aging is the major risk factor for advanced heart disease, which is the leading cause of death in developed countries, accounting for >30% of deaths worldwide. OBJECTIVE: To discover the detailed mechanism of cardiac aging and develop an effective therapeutic candidate drug to treat or delay cardiac aging. METHODS: We used D-galactose to induce cardiac aging in Nrf2+/+ and Nrf2-/- mice, and then treated these mice with vehicle or the Nrf2 activator, CDDO-imidazolide (CDDO-Im). RESULTS AND CONCLUSIONS: D-galactose injection significantly induced cardiac aging, cell apoptosis, and oxidative stress in Nrf2+/+ mice, all of which were further exacerbated in Nrf2-/- mice. CDDO-Im treatment can effectively weaken oxidative stress and enhance the activities of antioxidant enzymes, but CDDO-Im lost its antioxidative effect in the Nrf2-/- mice. Nrf2 activator CDDO-Im could therefore effectively protect against D-galactose-induced cardiac aging by inhibiting oxidative stress, suggesting that CDDO-Im might be a potential and promising therapeutic candidate drug to treat cardiac aging.

Magnesium lithospermate B improves pulmonary artery banding induced right ventricular dysfunction by alleviating inflammation via p38MAPK pathway.

BACKGROUD: Magnesium lithospermate B (MLB) is a major bioactive component of Slavia miltiorrhiza, which has been widely used in heart diseases on account of its anti-inflammatory, anti-oxidative, anti-proliferative and anti-fibrotic properties. Substance P(SP) is a small molecule neuropeptide, which was secreted much more during heart failure, and has an obvious function of immune enhancement and inflammation induction. This study aimed to investigate the protective effects of MLB on pulmonary artery banding (PAB) induced right ventricular (RV) dysfunction. METHODS: The mouse model of PAB was established. The mice were intraperitoneal (IP) injection treated with MLB (10 mg kg-1·d-1) for 4 weeks and p38 mitogen-activated protein kinase (MAPK) activator was given at the same time. Echocardiography were performed on day 28. Then the hearts were harvested, and substance P (SP), inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and cardiac fibrosis were detected. The macrophages and fibroblasts were stimulated by SP separately, and then treated with MLB as well as p38MAPK activator. The inflammatory cytokines from macrophage, the proliferation and fibrosis of cardiac fibroblasts were measured. The expression of p38MAPK proteins were confirmed by immunoblotting. FINDINGS: MLB preserved RV ejection fraction (EF), FS, RV/(LV + septum), HW/BW index and blunted RV inflammation as well as fibrosis. Phosphorylated-p38 (p-p38) MAPK was up-regulated, which was partially reversed by MLB treatment. However, p38MAPK activator abolished the effects of MLB on RV dysfunction, suggesting a key role of p38MPAK pathway in the effects of MLB reversing RV dysfunction. In external experiment, MLB reversed the increase of inflammatory cytokines from macrophage, the proliferation and fibrosis of cardiac fibroblasts which was simulated by SP. In accordance with in vivo study, p38MAPK activator abolished the effects of MLB on macrophage as well as fibroblasts. INTERPRETATION: MLB improves PAB induced right ventricular remodeling by alleviating inflammation via p38MAPK pathway. Thus, MLB may offer the therapeutic potential for the patients of RV dysfunction.

Phenotypic and genetic variation in phosphorus-deficiency-tolerance traits in Chinese wheat landraces.

BACKGROUND: Phosphorus deficiency is a major limiting factors for affecting crop production globally. To understand the genetic variation of phosphorus-deficiency-tolerance, a total of 15 seedling traits were evaluated among 707 Chinese wheat landraces under application of phosphorus (AP) and non-application of phosphorus (NP). A total of 18,594 single-nucleotide polymorphisms and 38,678 diversity arrays technology sequencing markers were used to detect marker-trait associations under AP and NP. RESULTS: Top ten genotypes with extremely tolerance and bottommost ten genotypes with extremely sensitivity were selected from 707 Chinese wheat landraces for future breeding and genetic analysis. A total of 55 significant markers (81 marker-trait associations) for 13 traits by both CMLM and SUPER method. These were distributed on chromosomes 1A, 1B, 2A, 2B, 2D, 3A, 4B, 5A, 5B, 6A, 6B, 6D, 7A and 7B. Considering the linkage disequilibrium decay distance, 25 and 12 quantitative trait loci (QTL) were detected under AP and NP, respectively (9 QTL were specific to NP). CONCLUSIONS: The extremely tolerant landraces could be used for breeding phosphorus-deficiency-tolerant cultivars. The QTL could be useful in wheat breeding through marker-assisted selection. Our findings provide new insight into the genetic analysis of P-deficiency-tolerance, and will be helpful for breeding P-deficiency-tolerant cultivars.

Identification and validation of stable quantitative trait loci for grain filling rate in common wheat (Triticum aestivum L.).

KEY MESSAGE: We identified and validated two stable grain filling rate (GFR) quantitative trait loci (QTL) in wheat that positively influenced several yield-related traits. Among them, QGfr.sicau-7D.1 was a novel GFR QTL. The grain filling rate (GFR) plays a crucial role in determining grain yield. To advance the current understanding of the genetic characteristics underlying the GFR in common wheat, three recombinant inbred line populations were used to map and validate GFR quantitative trait loci (QTL). Using a high-density genetic linkage map, 10 GFR QTL were detected. They were located on chromosomes 2D, 4A, 4B, 5B, 6D, 7A and 7D, explained 4.99-12.62% of the phenotypic variation. Two of them, QGfr.sicau-6D and QGfr.sicau-7D.1, were detected in all four environments tested and their genetic effect was validated by closely linked kompetitive allele specific PCR (KASP) markers in different genetic backgrounds. The effects of these two GFR QTL on other yield-related traits were also estimated. QGfr.sicau-6D had a significant positive influence (p < 0.01) on thousand kernel weight, kernel width, kernel volume, and kernel surface area. QGfr.sicau-7D.1 had a significant positive influence (p < 0.01) on thousand kernel weight and kernel length. Furthermore, QGfr.sicau-7D.1 was a completely novel QTL for GFR; several genes associated with grain growth and development were predicted in its physical interval. These results will facilitate molecular marker-assisted selection of wheat with high-confidence QTL for GFR and fine mapping of genes associated with GFR, thereby contributing to yield improvement.

Distinct Responses of Gut Microbiota to Jian-Pi-Yi-Shen Decoction Are Associated With Improved Clinical Outcomes in 5/6 Nephrectomized Rats.

Gut dysbiosis contributes to the development and progression of chronic kidney disease (CKD) and its complications. However, the effect of drugs on the gut microbiota of CKD patients and its influence on treatment outcomes remains to be explored. Here, we assessed whether the response of gut microbiota to the traditional Chinese medicine Jian-Pi-Yi-Shen (JPYS) decoction differed from that to piperazine ferulate (PF), a kidney-targeted drug, by 16S rDNA sequencing, and whether the difference could be linked with drug-specific clinical outcomes. We showed that both JPYS and PF improved renal function, but only JPYS was able to restore the blood reticulocyte counting and serum calcium level in CKD rats. We also found that weighted UniFrac beta-diversity of the gut microbiome of the JPYS treated rats was significantly different from that of PF. Microbiome markers of drug-specific response were identified and subjected to correlation network analysis, together with clinical parameters and KEGG pathways. Among the microbiome markers of CKD, Corynebacterium was found to form a network hub that was closely correlated with the JPYS responder Enterococcus, suggesting a potential indirect impact of JPYS on Corynebacterium via interspecies interactions. We also identified two network hubs of the PF responder Blautia and the JPYS-only marker Coprococcus, which were connected with many genera and clinical parameters. They might serve as keystone taxa driving the response of gut microbiota to the drugs and influence host outcomes. Moreover, the JPYS-only marker Clostridium_XIVb was found to be connected to many pathways that are associated with CKD progression and might account for the improved outcomes in the JPYS treated rats. At last, the identified keystone markers of drug response were validated by qPCR for their differential abundance between CKD and the two drugs. Taken together, our study revealed that the responses of gut microbiota to JPYS were distinct from that to PF, and pinpointed drug-specific keystone microbiome markers closely correlated to clinical parameters, which could serve as candidate microbiome targets for further studies on their roles in medicating the drug efficacy of TCM in CKD.

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit.

BACKGROUND: Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. In this study, we designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process. METHODS: Atherosclerosis was induced in the abdominal arteries of rabbits by balloon injury of the aorta supplemented by the atherogenic diet. Simultaneously, in the process of atherosclerosis, animals underwent either ruxolitinib treatment or not for 12 weeks. At the end of the experimental period, all rabbits were sacrificed. The plaque areas in abdominal artery, the lipid burden of plaque and the calcium burden of plaque were detected by H&E staining, Oil Red O staining and Alizarin Red staining, respectively. In addition, rabbit plasma lipids and inflammatory cytokines were measured by biochemical test kits or ELISA kits. Finally, the expression and phosphorylation levels of JAK2/STAT3/SOCS3 pathway-related proteins were detected by RT-qPCR, western blot and immunohistochemistry assays. RESULTS: H&E staining and CT scan analysis showed that rabbit atherosclerosis model was constructed successfully. Ruxolitinib, an inhibitor of the Janus kinase 2 (JAK2), substantially reduced the area of atherosclerotic plaques in rabbits treated with high fat diet and balloon injury of the aorta. Moreover, ruxolitinib significantly decreased IL-6, IL-1ß, IFN-γ and TNF-α, but increased IL-10 and IL-17 levels in plasma of atherosclerotic rabbits. Additionally, ruxolitinib reduced plasma TC, TG and LDL-C contents and AIP value, while enhanced HDL-C level in atherosclerotic rabbits. Furthermore, we found that JAK2 and STAT3 phosphorylation were up-regulated in rabbits with atherosclerosis when compared with those of the control group, followed by the expression of SOCS3 was also increased due to the activation of JAK2 and STAT3. Interestingly, ruxolitinib could inactivate JAK2 and STAT3 pathway and decrease SOCS3 expression. CONCLUSION: Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.

NLRP3 inflammasome inhibitor glyburide expedites diabetic-induced impaired fracture healing.

Localized inflammation is accompanied by the diabetic-induced fracture. The present study aims to investigate the therapeutic effects of glyburide, an NLRP3 inflammasome inhibitor, in a diabetic-induced fracture model. An animal model of diabetic-induced fracture was established and the mice were administrated with metformin or glyburide for 3 weeks. Quantitative polymerase chain reaction (qPCR) and Western blotting were used to evaluate the relative expressions of IFN-γ, TNF-α, and IL-6. Micro-computed tomography (µCT) scanning was applied to evaluate bone callus formation. Histopathology examinations of fractured femur sections were performed using Tartrate-resistant acid phosphatase (TRAP) staining and Alcian blue and orange G staining. Bone strength was evaluated using Torsional testing. Our results showed that treatment of glyburide significantly decreased the expressions of IFN-γ, TNF-α, and IL-6 in the fracture calluses in diabetic-induced fracture model, while bone callus volume and bone volume fraction were increased. Additionally, our results also demonstrated that treatment of glyburide rescued the increase of osteoclasts in the bone-cartilage interface. Apart from decreasing a percentage of cartilage area and increasing the percentage of bone and fibrotic tissue area, treatment of glyburide increased the maximum torque and yield torque of fractures. These results implied that glyburide might be used as a potential drug candidate for diabetic-induced fracture.

The viscosity behaviors of bacterial suspensions or extracellular polymeric substances and their effects on aerobic granular sludge.

Although the viscosity behavior of bacteria and extracellular polymeric substances (EPS) in flocculent activated sludge (FAS) and aerobic granular sludge (AGS) has been investigated, no studies have explored the role of viscosity in microbial attachment in pure culture. This study investigated the viscosity behavior of bacteria and EPS. The results showed that bacteria and their EPS exhibited non-Newtonian fluid and shear-thinning behavior. The viscosity of bacteria and EPS was 1.55-3.80 cP and 1.10-2.40 cP, respectively, while the attachment of bacteria (optical density at 600 nm) was 0.1426-3.1015. Bacteria with high attachment secreted EPS with a higher viscosity (2.40 cP), whereas those with weak attachment expressed EPS with a lower viscosity (1.10 cP). Viscosity and microbial attachment or extracellular polysaccharide (PS) content were significantly positively correlated. PS content was the source of bacterial viscosity, and ß-polysaccharide played a more important role in viscosity and microbial attachment than α-polysaccharide. Thus, viscosity plays a critical role in microbial attachment, and high viscosity and PS content result in high microbial attachment, which is beneficial to the granulation process of AGS.

A One-Dimensional Hemodynamic Model of the Coronary Arterial Tree.

One-dimensional (1D) hemodynamic models of arteries have increasingly been applied to coronary circulation. In this study, we have adopted flow and pressure profiles in Olufsen's 1D structured tree as coronary boundary conditions, with terminals coupled to the dynamic pressure feedback resulting from the intra-myocardial stress because of ventricular contraction. We model a trifurcation structure of the example coronary tree as two adjacent bifurcations. The estimated results of blood pressure and flow rate from our simulation agree well with the clinical measurements and published data. Furthermore, the 1D model enables us to use wave intensity analysis to simulate blood flow in the developed coronary model. Six characteristic waves are observed in both left and right coronary flows, though the waves' magnitudes differ from each other. We study the effects of arterial wall stiffness on coronary blood flow in the left circumflex artery (LCX). Different diseased cases indicate that distinct pathological reactions of the cardiovascular system can be better distinguished through Wave Intensity analysis, which shows agreement with clinical observations. Finally, the feedback pressure in terminal vessels and measurement deviation are also investigated by changing parameters in the LCX. We find that larger feedback pressure increases the backward wave and decreases the forward one. Although simplified, this 1D model provides new insight into coronary hemodynamics in healthy and diseased conditions. We believe that this approach offers reference resources for studies on coronary circulation disease diagnosis, treatment and simulation.