AMD3100 is a small molecule inhibitor of chemokine receptor type 4 (CXCR4), which is located in the cell membranes of CD34+ cells and a variety of inflammatory cells and has been reported to reduce organ fibrosis in the lung, liver and myocardium. However, the effect of AMD3100 on renal fibrosis is unknown. This study investigated the impact of AMD3100 on renal fibrosis. C57bl/6 mice were subjected to unilateral ureteral obstruction (UUO) surgery with or without AMD3100 administration. Tubular injury, collagen deposition and fibrosis were detected and analyzed by histological staining, immunocytochemistry and Western Blot. Bone marrow derived pro-angiogenic cells (CD45+, CD34+ and CD309+ cells) and capillary density (CD31+) were measured by flow cytometry (FACS) and immunofluorescence (IF). Inflammatory cells, chemotactic factors and T cell proliferation were characterized. We found that AMD3100 treatment did not alleviate renal fibrosis but, rather, increased tissue damage and renal fibrosis. Continuous AMD3100 administration did not improve bone marrow derived pro-angiogenic cells mobilization but, rather, inhibited the migration of bone marrow derived pro-angiogenic cells into the fibrotic kidney. Additionally, T cell infiltration was significantly increased in AMD3100-treated kidneys compared to un-treated kidneys. Thus, treatment of UUO mice with AMD3100 led to an increase in T cell infiltration, suggesting that AMD3100 aggravated renal fibrosis.

The influence of atrial fibrillation (AF) on the clinical outcomes of patients with ischemic stroke (IS) has not been completely determined. We aimed to perform a systematic review and meta-analysis to assess the relationship between AF and adverse events in patients with acute IS treated with thrombolysis.PubMed, EMBASE, and the Cochrane Library were searched for relevant studies regarding the association between AF and the outcomes of patients with IS treated with thrombolysis. Random and fixed effect models were used for pooling data.Twelve cohort studies involving 14,801 patients with acute IS were included. Meta-analysis revealed that patients with AF were more likely to die within 90 days after thrombolysis (odds ratio [OR], 2.13; 95% confidence interval [CI]: 1.68-2.70, P < 0.001), whereas this association was not observed in hospitalized patients (OR, 1.50; 95% CI, 0.86-2.60; P = 0.150). AF was associated with a reduced incidence of favorable outcomes (modified Rankin Scale ≤ 2) (OR, 1.95; 95% CI: 1.33-2.85, P = 0.001) and an increased risk of symptomatic intracerebral hemorrhage (OR, 1.28; 95% CI: 1.08-1.52, P = 0.006). No evident publication bias was found by Begg's test or Egger's test.Comorbidity of AF may increase the risk of adverse outcomes for patients with IS undergoing thrombolysis. Further well-designed trials are warranted to confirm this association.

Biliverdin reductase A is an enzyme, with serine/threonine/tyrosine kinase activation, converting biliverdin (BV) to bilirubin (BR) in heme degradation pathway. It has been reported to have anti-inflammatory and antioxidant effect in monocytes and human glioblastoma. However, the function of BVRA in polarized macrophage was unknown. This study aimed to investigate the effect of BVRA on macrophage activation and polarization in injured renal microenvironment. Classically activated macrophages (M1macrophages) and alternative activation of macrophages (M2 macrophages) polarization of murine bone marrow derived macrophage was induced by GM-CSF and M-CSF. M1 polarization was associated with a significant down-regulation of BVRA and Interleukin-10 (IL-10), and increased secretion of TNF-α. We also found IL-10 expression was increased in BVRA over-expressed macrophages, while it decreased in BVRA knockdown macrophages. In contrast, BVRA over-expressed or knockdown macrophages had no effect on TNF-α expression level, indicating BVRA mediated IL-10 expression in macrophages. Furthermore, we observed in macrophages infected with recombinant adenoviruses BVRA gene, which BVRA over-expressed enhanced both INOS and ARG-1 mRNA expression, resulting in a specific macrophage phenotype. Through in vivo study, we found BVRA positive macrophages largely existed in mice renal ischemia perfusion injury. With the treatment of the regular cytokines GM-CSF, M-CSF or LPS, excreted in the injured renal microenvironment, IL-10 secretion was significantly increased in BVRA over-expressed macrophages. In conclusion, the BVRA positive macrophage is a source of anti-inflammatory cytokine IL-10 in injured kidney, which may provide a potential target for treatment of kidney disease.

Glaucoma is one of the most common causes of irreversible blindness. It is acknowledged that lowering intraocular pressure (IOP) is the effective treatment to slow glaucoma disease progression. The main obstacle of existing drugs is that the effect of reducing IOP does not last long. Degradation of IκB stimulates the transcription of NF-κB, which could upregulate the expression of matrix metalloproteinases (MMPs). Whether a IκB-targeted gene therapy works in glaucoma is unclear. Here, we established a chronic ocular hypertension (COHT) model in rhesus monkey by laser photocoagulation and verified that intracameral delivery of IκBα-siRNA showed long-lasting and potent effects of reducing IOP without obvious inflammation in monkeys with COHT. We also verified that IκBα-siRNA could increase the expressions of MMP2 and MMP9 by knocking down IκBα in vitro and in vivo. Our results in nonhuman primates indicated that IκBα-siRNA may become a promising therapeutic approach for the treatment of glaucoma.

Objective: The relationship between combined healthy lifestyle and cardiovascular (CV) events in diabetes is unclear. We aim to investigate the association between a healthy lifestyle score (HLS) and the risk of mortality and CV events in diabetes. Methods: We examined the associations of six lifestyle factors scores (including healthy diet, moderate alcohol and regular coffee intakes, never smoking, physical activity, and normal weight) with diabetes in the Atherosclerosis Risk in Communities (ARIC) study of 3,804 participants with diabetes from the United States at baseline. Primary outcomes included all-cause mortality, CV mortality, and composite CV events (heart failure hospitalizations, myocardial infarction, fatal coronary heart disease, and stroke). Results: Among these diabetic participants, 1,881 (49.4%), 683 (18.0%), and 1,600 (42.0%) cases of all-cause mortality, CV mortality, and CV events were documented, respectively, during the 26 years of follow-up. Further, the prevalence of these adverse events became lower with the increase of HLS (all P < 0.001). In the risk-factors adjusted Cox regression model, compared to participants with HLS of 0, participants with HLS of 2 had significant lower risk of all-cause mortality (HR = 0.811, 95% CI: 0.687-0.957, P = 0.013), CV mortality (HR = 0.744, 95% CI: 0.576-0.962, P = 0.024), and CV events (HR = 0.789, 95% CI: 0.661-0.943, P = 0.009). The association of HLS with CV events was stronger for women than men (P for interaction <0.05). Conclusion: Adherence to a healthy lifestyle was associated with a lower risk of CV events and mortality in diabetics. Our findings suggest that the promotion of a healthy lifestyle would help reduce the increasing healthcare burden of diabetes. Clinical Trial Registration: https://clinicaltrials.gov, Identifier: NCT00005131.

Whether metabolites derived from injured renal tubular epithelial cells (TECs) participate in renal fibrosis is poorly explored. After TEC injury, various metabolites are released and among the most potent is adenosine triphosphate (ATP), which is released via ATP-permeable channels. In these hemichannels, connexin 43 (Cx43) is the most common member. However, its role in renal interstitial fibrosis (RIF) has not been fully examined. We analyzed renal samples from patients with obstructive nephropathy and mice with unilateral ureteral obstruction (UUO). Cx43-KSP mice were generated to deplete Cx43 in TECs. Through transcriptomics, metabolomics, and single-cell sequencing multi-omics analysis, the relationship among tubular Cx43, ATP, and macrophages in renal fibrosis was explored. The expression of Cx43 in TECs was upregulated in both patients and mice with obstructive nephropathy. Knockdown of Cx43 in TECs or using Cx43-specific inhibitors reduced UUO-induced inflammation and fibrosis in mice. Single-cell RNA sequencing showed that ATP specific receptors, including P2rx4 and P2rx7, were distributed mainly on macrophages. We found that P2rx4- or P2rx7-positive macrophages underwent pyroptosis after UUO, and in vitro ATP directly induced pyroptosis by macrophages. The administration of P2 receptor or P2X7 receptor blockers to UUO mice inhibited macrophage pyroptosis and demonstrated a similar degree of renoprotection as Cx43 genetic depletion. Further, we found that GAP 26 (a Cx43 hemichannel inhibitor) and A-839977 (an inhibitor of the pyroptosis receptor) alleviated UUO-induced fibrosis, while BzATP (the agonist of pyroptosis receptor) exacerbated fibrosis. Single-cell sequencing demonstrated that the pyroptotic macrophages upregulated the release of CXCL10, which activated intrarenal fibroblasts. Cx43 mediates the release of ATP from TECs during renal injury, inducing peritubular macrophage pyroptosis, which subsequently leads to the release of CXCL10 and activation of intrarenal fibroblasts and acceleration of renal fibrosis.

The prognostic nutritional index (PNI) has been applied in acute myocardial infarction (AMI) recently.However, the application of PNI in AMI needs verification. This was a prospective cohort study. Patients diagnosed with AMI were enrolled. PNI was calculated as (serum albumin (SA in g/L)) + (5 × total lymphocyte count (TLC) × 109/L). Modified PNI (mPNI) was analyzed by logistic regression analysis to reset the proportion of SA and TLC. The primary outcome was all-cause death. A total of 598 patients were enrolled; 73 patients died during follow-up. The coefficient of SA and TLC in the mPNI formula was approximately 2:1. The area under the receiver operating characteristic curve of SA, TLC, PNI, mPNI and GRACE in predicting death for patients with AMI was 0.718, 0.540, 0.636, 0.721 and 0.825, respectively. Net reclassification improvement (NRI) between PNI and mPNI was 0.230 (p < 0.001). Integrated discrimination improvement (IDI) was 0.042 (p = 0.001). Decision curve analysis revealed that mPNI had better prognostic value for patients with AMI than PNI; however, it was not superior to SA. Thus, PNI may not a reliable prognostic predictor of AMI; after resetting the formula, the value of PNI in predicting prognosis of AMI is almost entirely due to SA.

Background: Parkinson's disease (PD) and irritable bowel syndrome (IBS) are respectively one of the most common neurodegenerative diseases and functional bowel diseases in the world. Recent studies suggest that patients with IBS seem to have a higher risk of PD, which conflicts with the result of previous meta-analysis. Therefore, the purpose of this systematic review is to evaluate all available evidence, in order to clarify the association between PD and IBS. Methods: Two reviewers independently searched the PubMed, Embase, Web of Science, and Cochrane library on April 25, 2021 to identify all records that explore the association between IBS and PD. All reports that clearly define PD and IBS and analyze the relationship between the two were included. The Newcastle-Ottawa scale was used to assess the risk of bias of included studies. Results: Five studies from four articles involving 2,044,110 subjects were included in this analysis. The pooled results demonstrated a significant association between PD and IBS (1.48; 95% CI: 1.35-1.62, P < 0.001), with subtle heterogeneity (I 2 = 0.0%, p = 0.585). The association was observed across genders and increased with age. However, the available evidence cannot allow a reliable analysis of the causal relationship between IBS and PD. Conclusion: This study demonstrates a higher risk of PD among subjects with IBS. Future studies are required to further clarify the causation and underlying mechanism of the association.

Lupus nephritis (LN) is a common and severe glomerulonephritis that often occurs as an organ manifestation of systemic lupus erythematosus (SLE). However, the complex pathological mechanisms associated with LN have hindered the progress of targeted therapies.

Studies, including various meta-analyses, on the effect of Protein Diet Restriction on Glomerular Filtration Rate (GFR) in Chronic Kidney Disease (CKD) have reported conflicting results. In this paper, we have provided an update on the evidence available on this topic. We have investigated the reasons why the effect has been inconsistent across studies. We have also compared the effect on GFR in various subgroups including type 1 diabetics, type 2 diabetics and non-diabetics.

Computed tomography (CT) is commonly used in all stages of oesophageal squamous cell carcinoma (SCC) management. Compared to basic CT features, CT radiomic features can objectively obtain more information about intratumour heterogeneity. Although CT radiomics has been proved useful for predicting treatment response to chemoradiotherapy in oesophageal cancer, the best way to use CT radiomic biomarkers as predictive markers for determining resectability of oesophageal SCC remains to be developed. This study aimed to develop CT radiomic features related to resectability of oesophageal SCC with five predictive models and to determine the most predictive model.

Macrophages play an important role in renal injury and repair after acute kidney injury (AKI) and the subsequent chronic kidney disease (CKD) that often results. However, as macrophages have a high degree of plasticity and heterogeneity, the function(s) of macrophage subtypes in AKI-to-CKD progression are not fully understood. Here, we focused on Ly6C- macrophages, which are derived from the embryonic yolk sac and post-development become resident in the kidneys. We found that C-C chemokine receptor type 2 (CCR2) deficiency, which blocks the migration of Ly6C+ macrophages from the bone marrow to the sites of injury, alleviated ischemia-induced AKI in mice. Unexpectedly, though, CCR2 deficiency worsened the subsequent renal fibrosis, which was marked by notable intra-renal infiltration of Ly6C- macrophages. These Ly6C- macrophages were greater in number in both the acute and chronic phases after ischemia reperfusion (I/R) in kidneys of wild type (WT) mice, and we showed them to be derived from the bone marrow by bone marrow chimerism. Clodronate Liposomes (CLs)-mediated depletion of renal Ly6C- macrophages in CCR2-/- mice or in WT mice after I/R alleviated the renal injury and fibrosis. On the contrary, adoptive transfer of Ly6C- macrophages from injured kidneys of WT mice into immune-deficient mice was sufficient to induce renal injury and fibrosis. Transcriptome sequencing of Ly6C- macrophages from injured kidneys revealed that they secreted various cytokines and growth factors, which were associated with the transdifferentiation of fibroblasts into myofibroblasts. This transdifferentiation effect was further supported by in vitro studies showing that Ly6C- macrophages induced the secretion of extracellular matrix proteins from co-cultured fibroblasts. In conclusion, the presence of bone marrow-derived Ly6C- macrophages after ischemia induces AKI and worsens subsequent CKD.

Putative endothelial progenitor cells (pEPCs) have been confirmed to participate in alleviation of renal fibrosis in several ischaemic diseases. However, their mechanistic effect on renal fibrosis, which is characterized by vascular regression and further rarefaction-related pathology, remains unknown.

To investigate the protective effect of different atorvastatin doses on contrast-induced acute kidney injury and the related mechanism.

Astragalus mongholicus Bunge (Fabaceae) is an important plant source of the herbal drug known as Radix Astragali, which is used worldwide as a medicinal ingredient and a component of food supplement. Russian Federation, Mongolia, Kazakhstan, and China are the main natural distribution areas of A. mongholicus in the world. However, the quality of medicinal plant varies among different locations. As for A. mongholicus, limited literature focused on its biodiversity mechanism. Here, we combined the chemometric analysis of chemical components with genetic variation, as well as climatic and edaphic traits, to reveal the biodiversity mechanism of A. mongholicus. Results showed that the detected chemical, genetic and climatic traits comprehensively contributed to the quality diversity of A. mongholicus. The eight main chemical components, as well as the inorganic elements of P, B and Na were all significant chemical factors. The precipitation and sunshine duration were the main distinguishing climatic factors. The inorganic elements As, Mn, P, Se and Pb were the distinguishing edaphic factors. The systematic method was firstly established for this medicinal plant in order to illustrate the formation of diversity in terms of quality, and provide scientific evidence for geographic indications and climatic adaptation in production and in the clinical application of herbal medicinal plants.

The relationship between gut microbial dysbiosis and acute or chronic kidney disease (CKD) is still unclear. Here, we show that oral administration of the probiotic Lactobacillus casei Zhang (L. casei Zhang) corrected bilateral renal ischemia-reperfusion (I/R)-induced gut microbial dysbiosis, alleviated kidney injury, and delayed its progression to CKD in mice. L. casei Zhang elevated the levels of short-chain fatty acids (SCFAs) and nicotinamide in the serum and kidney, resulting in reduced renal inflammation and damage to renal tubular epithelial cells. We also performed a 1-year phase 1 placebo-controlled study of oral L. casei Zhang use (Chinese clinical trial registry, ChiCTR-INR-17013952), which was well tolerated and slowed the decline of kidney function in individuals with stage 3-5 CKD. These results show that oral administration of L. casei Zhang, by altering SCFAs and nicotinamide metabolism, is a potential therapy to mitigate kidney injury and slow the progression of renal decline.

Clam heparinoid G2 (60.25 kDa) and its depolymerized derivatives DG1 (24.48 kDa) and DG2 (6.75 kDa) prepared from Coelomactra antiquata have been documented to have excellent fibrinolytic and anticoagulant activity. In this study, to further explore the antithrombotic activity of G2, DG1 and DG2, azure A, sheep plasma, and clot lytic rate assays were used to determine their anticoagulant and thrombolytic activity in vitro. The results indicated that the anticoagulant titer of G2 was approximately 70% that of heparin and the thrombolytic activity of DG2 was greater than G2, DG1, and heparin activities. Moreover, in a carrageenan-induced venous thrombosis model, oral administration of G2 and DG1 each at 20 mg/kg and 40 mg/kg for 7 days significantly reduced blacktail thrombus formation, increased tissue-type plasminogen activator, fibrin degradation products, and D-dimer levels, decreased von Willebrand factor and thromboxane B2 levels, and restored phylum and genus abundance changes of intestinal bacteria. DG2 had no antithrombotic effect. At 20 mg/kg, G2, DG1, and heparin had comparable antithrombotic activities, and DG1 at 40 mg/kg had more muscular antithrombotic activity than G2. Thus, DG1 could be an antithrombotic oral agent owing to its more robust antithrombotic activity and lower molecular weight.

In this study, porous silica nanoparticles functionalized with a thiol group (SiO2-SH NPs) were synthesized via a one-pot method. Subsequently, iminodiacetic acid was modified, and further adsorption of Ni2+ ions was conducted to obtain a SiO2-S/NH-Ni nano-adsorbent. Then, transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TG) and X-ray diffraction (XRD) were employed to characterize its morphology and composition. The results indicate that the SiO2-S/NH-Ni nano-adsorbent is porous, has an average diameter of 77.1 nm and has a small porous structure of about 3.7 nm in the silica skeleton. The Brunauer-Emmett-Teller (BET) surface area and total pore volume were 537.2 m2 g-1 and 3.3 cm3 g-1, respectively, indicating a large BET surface area. The results indicate that the as-prepared SiO2-S/NH-Ni nano-adsorbent would be suitable to selectively and efficiently bind His-tagged proteins from an E. coli cell lysate. The SDS-PAGE results show that the as-prepared nano-adsorbent presents specifically to both His-tagged CPK4 and His-tagged TRX proteins, indicating the nano-adsorbent can be used to effectively separate His-tagged proteins and is universal to all His-tagged fusion proteins. We also found that the as-prepared nano-adsorbent exhibits a low detection limit (1.0 × 10-7 mol L-1) and a strong regeneration ability based on four regeneration experiments that were particularly suited to the separation of His-tagged proteins.

Background: Mutations in the collagen components of the glomerular basement membrane (GBM) often lead to hereditary glomerulonephritis. Previous studies have identified that autosomal dominant mutations of Col4A3, Col4A4 or Col4A5 are associated with thin basement membrane nephropathy (TBMN), Alport syndrome and other hereditary kidney diseases. However, the genetic mutations underlying other glomerulonephritis types have not been elucidated. Methods: In this study, we investigated a Chinese family with hereditary nephritis using the methods of genetic sequencing and renal biopsy. Genomic DNA was extracted from peripheral blood of the proband and her sister, and subsequently was performed genetic sequencing. They were found to have the similar mutation sites. Other family members were then validated using Sanger sequencing. The proband and her sister underwent renal puncture biopsies, and experienced pathologists performed PAS, Masson, immunofluorescence, and immunoelectron microscopic staining of the kidney tissue sections. Results: Through genetic sequencing analysis, we detected a novel heterozygous frameshift mutation c.1826delC in the COL4A4 (NM_000092.4) gene coding region, and 1 hybrid missense variation c.86G>A (p. R29Q) was also detected in the TNXB (NM_019105.6) gene coding region in several members of this Chinese family. Interestingly, we found that the same mutations caused different clinical features and distinct pathological changes in individual family members, which confirmed that pathological and genetic testing are crucial for the diagnosis and treatment of hereditary kidney diseases. Conclusion: In this study, we found a novel heterozygous mutation in Col4A4 and co-mutations of the TNXB gene in this Chinese family. Our study indicated that the same Col4A4 mutated variants produced different pathological and clinical changes in different family members. This discovery may provide novel insights into the study of hereditary kidney disease. In addition, new genetic biology techniques and renal biopsy of individual family members are essential.

Rationale: Capillaries are composed of endothelial cells and the surrounding mural cells, pericytes. Microvascular repair after injury involves not only the proliferation of endothelial cells but also pericyte-based vessel stabilization. Exogenous bone marrow derived-putative endothelial progenitor cells (b-pEPCs) have the potential for vascular repair; however, their effect on vascular structure stabilization and pericyte-related pathobiological outcomes in the injured kidney has not been fully examined. Methods: We applied ischemia-reperfusion (IR) to induce renal vascular injury and renal fibrosis in mice. Platelet-derived growth factor receptor β (PDGFR-β)-DTR-positive mice were generated to deplete pericytes, and exogenous b-pEPCs and the PDGFR-β ligand, PDGF chain B (PDGF-BB), were employed to explore the relationship among b-pEPCs, pericytes, vascular repair, and early renal fibrosis. Results: Administration of b-pEPCs reduced IR-induced pericyte-endothelial detachment, pericyte proliferation, and myofibroblast transition via a paracrine mode, which preserved not only vascular stabilization but also ameliorated IR-initiated renal fibrosis. PDGF-BB upregulated the expression of PDGFR-β, exacerbated vascular abnormality, and pericyte-myofibroblast transition, which were ameliorated by b-pEPCs administration. The exogenous b-pEPCs and their culture medium (CM) induced vascular injury protection, and renal fibrosis was blocked by selective deletion of pericytes. Conclusion: Exogenous b-pEPCs directly protect against IR-induced vascular injury and prevent renal fibrosis by inhibiting the activation of PDGFR-β-positive pericytes.