Urinary exosomal microRNA-145-5p and microRNA-27a-3p act as noninvasive diagnostic biomarkers for diabetic kidney disease

BACKGROUND Diabetic kidney disease(DKD),characterized by increased urinary microalbumin levels and decreased renal function,is the primary cause of end-stage renal di-sease.Its pathological mechanisms are complicated and multifactorial;Therefore,sensitive and specific biomarkers are needed.Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney.The microRNAs(miRNAs)in urinary exosome are remark-ably stable and highly tissue-specific for the kidney.METHODS Type 2 diabetic mellitus(T2DM)patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups:DM,diabetic pa-tients without albuminuria[urinary albumin to creatinine ratio(UACR)<30 mg/g]and DKD,diabetic patients with albuminuria(UACR≥30 mg/g).Healthy subjects were the normal control(NC)group.Urinary exosomal miR-145-5p,miR-27a-3p,and miR-29c-3p,were detected using real-time quantitative polymerase chain reaction.The correlation between exosomal miRNAs and the clinical in-dexes was evaluated.The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic(ROC)analysis.Biological functions of miR-145-5p were investigated by performing RESULTS Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group(miR-145-5p:4.54±1.45 vs 1.95±0.93,P<0.001;miR-27a-3p:2.33±0.79 vs 1.71±0.76,P<0.05)and the NC group(miR-145-5p:4.54±1.45 vs 1.55±0.83,P<0.001;miR-27a-3p:2.33±0.79 vs 1.10±0.51,P<0.001).The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate.miR-27a-3p was also closely related to blood glucose,gly-cosylated hemoglobin A1c,and low-density lipoprotein cholesterol.ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88[95%confidence interval(CI):0.784-0.985,P<0.0001]in diagnosing DKD than miR-27a-3p with 0.71(95%CI:0.547-0.871,P=0.0239).Bioinformatics analysis revealed that the target genes of miR-145-5p were located in the actin filament,cytoskeleton,and extracellular exosome and were involved in the pathological processes of DKD,including apoptosis,inflammation,and fibrosis.CONCLUSION Urinary exosomal miR-145-5p and miR-27a-3p may serve as novel noninvasive diagnostic biomarkers or promising therapeutic targets for DKD.

Systemic meta-analysis assessing the short term applicability of early conversion to mammalian target of rapamycin inhibitors in kidney transplant

AIM To consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin(m TOR) inhibitors with or without calcineurin inhibitors(CNIs) in renal transplant recipients.METHODS We analysed the current literature following PROSPERO approval describing the role of immunosuppressive agent, m TOR inhibitors as an alternative to CNI within six months of renal transplant by searching the Pub Med, EMBASE, Cochrane, Crossref, and Scopus using Me SH terms. RESULTS Six articles of early withdrawal of CNI and introduction of m TOR-inhibitors within six months of renal transplantation were sought. Glomerular filtration rate(GFR) and serum creatinine were significantly better in m TOR inhibitor group with equivalent survival at 12 mo, even though Biopsy Proven Acute rejection was significantly higher in m TOR-inhibitor group. CONCLUSION The evidence reviewed in this meta-analysis suggests that early introduction m TOR-inhibitors substantial CNI minimization. The m TOR inhibitors such as everolimus and sirolimus, due to their complementary mechanism of action and favourable nephrotoxicity profile; better glomerular filtration, lower serum creatinine with equivalent survival. Having said that, due to the higher rejection rate, may influence the use of these regimens to patients with moderate to high immunological risk patients.

Evaluating the evolving evidence: The challenges of molecular-targeted therapy in management of gastric cancer

Over the past decade, a multitude of molecular targeted agents have been explored in the treatment of advanced metastatic gastric. Recent advances in molecular signaling pathways that are dysregulated in gastric cancer lead to the development of new targeted therapies for the treatment of advanced and metastatic gastric cancer. The addition of trastuzumab to first-line chemotherapy is now a standard of care for the treatment of Human epidermal growth factor receptor (HER2-) positive advanced or metastatic disease, and other HER2-targeted therapies are in late-stage clinical development. Findings from recent major clinical trials provide important insight into the future of metastatic gastric cancer management, which may include the use of anti-angiogenesis, Mesenchymal epithelial transition factor (MET) and Hedgehog Pathways Inhibitortherapy across multiple treatment lines, in the salvage setting, and as part of novel regimens in combination with other targeted agents.

MiR-183-5p promotes the progression of non-small cell lung cancer through targeted regulation of FOXO1

Objective To investigate miR-183-5p targeting to forkhead box protein O1(FOXO1)and its corresponding effect on the proliferation,migration,invasion,and epithelial-mesenchymal transition(EMT)of non-small cell lung cancer(NSCLC)cells.Methods NSCLC tissues and adjacent normal tissues from 60 patients with NSCLC adenocarcinoma were obtained via pathological biopsy or intraoperative resection.Several cell lines were cultured in vitro,including the human normal lung epithelial cell line BEAS-2B and human NSCLC cell lines A549,SPCA-1,PC-9,and 95-D.miR-183-5p and FOXO1 mRNA expression in tissues and cells were detected by qRT-PCR;the corresponding correlations in NSCLC tissues were analyzed using the Pearson test,and the relationship between miR-183-5p expression and clinicopathological parameters was analyzed.The miR-183-5p-mediated regulation of FOXO1 was verified by bioinformatics prediction alongside double luciferase,RNA-binding protein immunoprecipitation(RIP)assay,and pull-down experiments.A549 cells were divided into control,anti-miR-NC,anti-miR-183-5p,miR-NC,miR-183-5p,miR-183-5p+pcDNA3.1,and miR-183-5p+pcDNA3.1-FOXO1 groups.Cell proliferation,invasion,migration,apoptosis,and cell cycle distribution were detected using an MTT assay,clone formation assay,Transwell assay,scratch test,and flow cytometry,respectively.The expression of EMT-related proteins in the cells was analyzed by western blotting.The effect of miR-185-3p silencing on the development of transplanted tumors was detected by analyzing tumor formation in nude mice.Results miR-183-5p expression was significantly higher in NSCLC tissues and cells than in adjacent normal tissues,whereas FOXO1 mRNA expression was significantly down-regulated.There was a significant negative correlation between miR-183-5p and FOXO1 mRNA in NSCLC tissues(P<0.05).Additionally,the expression of miR-183-5p was significantly correlated with tumor size,tumor differentiation,and tumor-node-metastasis stage in patients with NSCLC(P<0.05).miR-183-5p targeted and inhibited FOXO1 expression.Compared to the anti-miR-NC group,the cell proliferation,scratch healing rate,N-cadherin and vimentin protein expression,and the proportion of S phase cells were significantly lower in the anti-miR-183-5p group,whereas the protein expression of E-cadherin andα-catenin and the proportion of G0/G1 phase cells were significantly higher;additionally,the frequency of colony formation and invasion were significantly lower in the anti-miR-183-5p group(P<0.05).Compared to the miR-NC group,the cell proliferation,scratch healing rate,N-cadherin and vimentin protein expression,and the proportion of S phase cells in the miR-183-5p group were significantly higher,whereas the E-cadherin andα-catenin protein expression and the proportion of G0/G1 phase cells were significantly lower;furthermore,the frequency of colony formation and invasion were significantly higher in the miR-183-5p group(P<0.05).Compared with the miR-183-5p+pcDNA3.1 group,the OD value,scratch healing rate,N-cadherin and vimentin protein expression,and the proportion of S phase cells were significantly lower in the miR-183-5p+pcDNA3.1-FOXO1 group,whereas E-cadherin andα-catenin protein expression and the proportion of G0/G1 phase cells were significantly higher;additionally,the frequency of colony formation and invasion was significantly lower in the miR-183-5p+pcDNA3.1-FOXO1 group(P<0.05).Overall,silencing miR-185-3p inhibited the growth of transplanted tumors and promoted FOXO1 expression.Conclusion Overexpression of miR-183-5p can inhibit apoptosis and promote the proliferation,migration,invasion,and EMT,of NSCLC cells by down-regulating FOXO1 expression.

Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop

BACKGROUND Type 2 diabetes mellitus(T2DM)is significantly increasing worldwide,and the incidence of its complications is also on the rise.One of the main complications of T2DM is diabetic kidney disease(DKD).The glomerular filtration rate(GFR)and urinary albumin creatinine ratio(UACR)increase in the early stage.As the disease progresses,UACR continue to rise and GFR begins to decline until endstage renal disease appears.At the same time,DKD will also increase the incidence and mortality of cardiovascular and cerebrovascular diseases.At present,the pathogenesis of DKD is not very clear.Therefore,exploration of the pathogenesis of DKD to find a treatment approach,so as to delay the development of DKD,is essential to improve the prognosis of DKD.AIM To detect the expression of tenascin-C(TNC)in the serum of T2DM patients,observe the content of TNC in the glomerulus of DKD rats,and detect the expression of TNC on inflammatory and fibrotic factors in rat mesangial cells(RMCs)cultured under high glucose condition,in order to explore the specific molecular mechanism of TNC in DKD and bring a new direction for the treatment of DKD.METHODS The expression level of TNC in the serum of diabetic patients was detected by enzyme-linked immunosorbent assay(ELISA),the protein expression level of TNC in the glomerular area of DKD rats was detected by immunohistochemistry,and the expression level of TNC in the rat serum was detected by ELISA.Rat glomerular mesangial cells were cultured.Following high glucose stimulation,the expression levels of related proteins and mRNA were detected by Western blot and polymerase chain reaction,respectively.RESULTS ELISA results revealed an increase in the serum TNC level in patients with T2DM.Increasing UACR and hypertension significantly increased the expression of TNC(P<0.05).TNC expression was positively correlated with glycosylated haemoglobin(HbA1c)level,body mass index,systolic blood pressure,and UACR(P<0.05).Immunohistochemical staining showed that TNC expression in the glomeruli of rats with streptozotocin-induced diabetes was significantly increased compared with normal controls(P<0.05).Compared with normal rats,serum level of TNC in diabetic rats was significantly increased(P<0.05),which was positively correlated with urea nitrogen and urinary creatinine(P<0.05).The levels of TNC,Toll-like receptor-4(TLR4),phosphorylated nuclear factor-κB p65 protein(Ser536)(p-NF-κB p65),and miR-155-5p were increased in RMCs treated with high glucose(P<0.05).The level of TNC protein peaked 24 h after high glucose stimulation(P<0.05).After TNC knockdown,the levels of TLR4,p-NF-κB p65,miR-155-5p,connective tissue growth factor(CTGF),and fibronectin(FN)were decreased,revealing that TNC regulated miR-155-5p expression through the TLR4/NF-κB p65 pathway,thereby regulating inflammation(NF-κB p65)and fibrosis(CTGF and FN)in individuals with DKD.In addition,metformin treatment may relive the processes of inflammation and fibrosis in individuals with DKD by reducing the levels of the TNC,p-NF-κB p65,CTGF,and FN proteins.CONCLUSION TNC can promote the occurrence and development of DKD.Interfering with the TNC/TLR4/NF-κB p65/miR-155-5p pathway may become a new target for DKD treatment.

Analytical models for the penetration of semi-infinite targets by rigid,deformable and erosive long rods

A theoretical study is presented herein on the pen- etration of a semi-infinite target by a spherical-headed long rod for Yp 〉 S, where Yp is the penetrator strength and S is the static target resistance. For Yp 〉 S, depending upon initial impact velocity, there exist three types of penetration, namely, penetration by a rigid long rod, penetration by a deforming non-erosive long rod and penetration by an erosive long rod. If the impact velocity of the penetrator is higher than the hydrodynamic velocity （VH）, it will penetrate the target in an erosive mode; if the impact velocity lies between the hydrodynamic velocity （VH） and the rigid body velocity （VR）, it will penetrate the target in a deformable mode; if the impact velocity is less than the rigid body velocity （VR）, it will penetrate the target in a rigid mode. The critical conditions for the transition among these three penetration modes are proposed. It is demonstrated that the present model predictions correlate well with the experimental observations in terms of depth of penetration （DOP） and the critical transition conditions.

Synthesis Hexadecyl 3-{4-[2-Hydroxy-3(isopropylamino)propoxy] phenyl}propionate as Potential Ligand for Liposome Targeting to Ischemic Myocardium

Novel hexadecyl 3-{4-[2-hydroxy-3(isopropylamino)propoxy]phenyl}propionate(HPP)was synthesized and its effect on delivery of liposomes into cultured cardiomyocytes was examined.The structure of HPP was characterized by IH NMR,1R and MS.The amount of cardiomyocytes uptake of HPP-liposome was 3.9-fold higher than plain-liposome,and the increase was 6.2-fold when hypoxia happens.It indicated that HPP was a potential ligand for liposome targeting to ischemic myocardium.

Ticagrelor Protects against Sepsis-Induced Acute Kidney Injury through an Adenosine Receptor-Dependent Pathway

Objective Ticagrelor is a widely used anti-platelet drug.However,the mechanisms by which ticagrelor protects against sepsis-induced acute kidney injury(AKI)have not been clearly demonstrated.We designed this study to explore the protective effect of ticagrelor on sepsis-induced AKI and to explore the underlying mechanisms.Methods C57BL6J mice received oral ticagrelor(20 mg/kg and 50 mg/kg)for 7 days,and then caecal ligation and puncture(CLP)were performed.An adenosine receptor antagonist,CGS15943,was administered(10 mg/kg,intraperitoneal injection)to block the adenosine pathway 2 h before CLP.After 24 h,serum creatinine levels were measured.Periodic acid-Schiff(PAS)staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)staining were employed to analyze pathological changes and cell apoptosis.Serum concentrations of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and mRNA expression of tissue TNF-αand IL-1βwere detected.Western blotting analysis was used to determine AKT and mammalian target of rapamycin(mTOR)protein expression in the kidney.Results PAS staining showed less swelling of renal tubules,and TUNEL staining revealed less cell apoptosis in the ticagrelor group than in the CLP group.Serum creatinine levels were significantly lower in the ticagrelor group than in the CLP group.Moreover,significantly lower serum and kidney levels of TNF-αand IL-1βwere observed in the ticagrelor group.CGS15943 blocked the effects of ticagrelor.Western blotting analysis showed increased phosphorylation of AKT and mTOR in the kidneys of the 50 mg/kg ticagrelor group.The adenosine receptor antagonist inhibited the activation of AKT and mTOR.Conclusion This study demonstrates that the protective effect of ticagrelor on sepsis-induced AKI depends on adenosine receptor activation and the subsequent increase of AKT and mTOR phosphorylation.

The accurate localization of fluorescent nanoparticle Au-Ft in nu/nu mice kidney

Au-Ft,as a green synthesized nanoparticle,is composed of a ferritin nanocage enclosing a pair of Au nanoclusters inside.Our previous study has demonstrated that Au-Ft can be an excellentfluorescent probe for whole body imaging of mice with kidney specific targeting.But,the accuratelocalization of Au-Ft in kidney is still absent.In the current study,we detected and assessed the cellular and subcellular localization of Au-Ft in renal cortex and medulla of nu/nu mice after tailvein injection by using Nuance optical system(CRi,Woburn,USA)and inForm intelligent image analysis soft ware based on single cell segmentation.We obtained the fluorescence intensity and cellular location of kidney-targeting Au-Ft probe in particular cell of renal glomerulus or renaltubules,which provided valuable proofs to clarify the mechanism of Au-Ft selective enrichment in kidney and the associated metabolic processes.

The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.

Potential role of long noncoding RNA RP5-881L22.5 as a novel biomarker and therapeutic target of colorectal cancer

BACKGROUND The incidence of colorectal cancer in humans is high,and it is in the top five for cancer-related morbidity and mortality.It is one of the main threats to human health.The function of long noncoding RNAs in tumor occurrence and development has gradually gained attention in recent years.In increasing numbers of studies,researchers have demonstrated that it plays an important role in the pathogenesis of colorectal cancer.AIM To find out if long noncoding RNA RP5-881L22.5 played a role in the pathogenesis of colorectal cancer in relation to the tumor microenvironment.METHODS We analyzed the transcriptome data and clinical data in The Cancer Genome Atlas-colon adenocarcinoma.The CIRBERSORT algorithm was applied to evaluate these tumor-infiltrating immune cells in The Cancer Genome Atlas-colon adenocarcinoma cancer tissue samples.Using the“estimate”package in R,we assessed the tumor immune microenvironment.The expression level of RP5-881L22.5 in tumor tissue and adjacent normal tissue samples from 4 pairs of colorectal cancer patients was determined by quantitative reverse transcription PCR.Colorectal cancer cells were tested for invasiveness using a transwell invasion assay after RP5-881L22.5 expression was knocked down.RESULTS The expression of lncRNA RP5-881L22.5 was related to the clinical characteristics of the tumors,and it was negatively related to the infiltration level of immune cells in the tumor microenvironment and the expression of T cell inhibitory receptors.A major function of its coexpressed mRNA was to regulate tumor immunity,such as the immune response.When quantitative reverse transcription PCR was performed on tumor tissues from 4 pairs of colorectal cancer patients,the results showed that RP5-881L22.5 was highly expressed.Subsequently,knocking down the expression of RP5-881L22.5,the invasiveness of colorectal cancer cell lines was reduced,and the apoptosis rate was increased.CONCLUSION RP5-881L22.5 plays a crucial role in the microenvironment of tumors as well as in the pathogenesis of colorectal cancer.The relationship between RP5-881L22.5 and the tumor immune microenvironment deserves further study.

Biological function of miRNA-145-5p in angiotensin II induced renal inflammation

Objective:Chronic kidney disease(CKD)is a progressive disorder characterized by intricate structural and functional alterations in the kidneys,attributable to diverse causative factors.Notably,the therapeutic promise of miR-145-5p in addressing renal pathologies has been discerned.This investigation seeks to elucidate the functional role of miR-145-5p in injured kidneys by subjecting human glomerular mesangial cells(HGMCs)to stimulation with Angiotensin II(AngII).Materials and Methods:Cellular viability and the levels of inflammatory mediators were evaluated utilizing Cell Counting Kit-8(CCK-8),quantitative real-time polymerase chain reaction(qRT-PCR),and western blot methodologies,both in the presence of AngII incubation and in scenarios of miR-145p overexpression and downregulation.Furthermore,the cell cycle dynamics were elucidated through Fluorescence-activated Cell Sorting(FACS)analysis.Results:AngII incubation induced an upregulation of miR-145-5p and inflammatory factors including Intercellular Adhesion Molecule 1(ICAM-1),Interleukin 6(IL-6),Interleukin 8(IL-8),and Interleukin 1β(IL-1β).Additionally,it elevated the expression of Cyclin A2,Cyclin D1,and the G2/M cell cycle ratio.Conversely,inhibition of miR-145-5p heightened the levels of inflammatory factors and cell cycle regulators induced by AngII incubation.Reduced expression of miR-145-5p correlated with a downregulation of Interleukin 10(IL-10)expression,concurrently promoting HGMC proliferation under AngII stimulation.Moreover,ectopic miR-145-5p expression demonstrated a reduction in inflammatory factors,cell cyclin regulators,G2/M cell cycle ratio,and overall proliferation.Conclusion:MiR-145-5p exhibited inhibitory effects on the inflammatory response and proliferation induced by Angiotensin II in HGMCs,showcasing its potential as a therapeutic avenue for the treatment of kidney injury.

环孢素引起肾小管上皮细胞培养液中肾损伤分子-1水平升高的机制

目的:探讨环孢素(CsA)引起人肾小管上皮细胞(HKC)培养液中肾损伤分子-1(KIM-1)水平升高的作用机制,阐明KIM-1表达与p38 MAPK通路和EKR1/2 MAPK通路的关系。方法:将处于对数生长期的HKC分为空白组、CsA损伤组、CsA与p38激酶抑制剂合用组、p38激酶抑制剂组、CsA与ERK1/2激酶抑制剂合用组和ERK1/2激酶抑制剂组。MTT法检测各组HKC增殖抑制率,ELISA法测定各组HKC上清液中KIM-1水平,流式细胞术检测各组细胞存活率、细胞凋亡率和细胞坏死率。结果:与空白组比较,CsA损伤组细胞上清液中KIM-1水平显著升高(P<0.05),细胞存活率显著降低(P<0.05),细胞凋亡率和细胞坏死率显著升高(P<0.05);p38激酶抑制剂组和ERK1/2激酶抑制剂组中细胞存活率、细胞凋亡率和细胞坏死率比较差异无统计学意义(P>0.05)。与CsA损伤组比较,CsA与p38激酶抑制剂合用组、CsA与ERK1/2激酶抑制剂合用组细胞上清液中KIM-1水平显著降低(P<0.05),细胞存活率显著升高(P<0.05),细胞凋亡率和细胞坏死率显著降低(P<0.05)。结论:p38 MAPK通路和ERK1/2 MAPK通路参与CsA素引起肾小管上皮细胞培养液中KIM-1水平升高的过程,KIM-1的表达可能成为临床监测CsA肾毒性的生化指标。

体外循环心脏不停跳二尖瓣置换术围术期肾损伤分子-1的变化

目的研究体外循环(CPB)心脏不停跳与停跳二尖瓣置换术(MVR)围术期尿肾损伤分子-1(KIM-1)的变化规律,探讨心脏不停跳手术对患者肾功能的影响。方法选择需行MVR患者40例,按随机数字表分为不停跳组和停跳组,每组各20例。检测术前(T1)、CPB后30 min(T2)、2 h(T3)、术后24 h(T4)、72 h(T5)的KIM-1浓度。结果组内不同时间点的KIM-1浓度差异有统计学意义(P<0.05),随着时间延长两组KIM-1浓度上升,但不停跳组术后72 h恢复至正常水平,而停跳组72 h后仍未能恢复至术前水平。不停跳组KIM-1浓度低于停跳组(P<0.05)。结论 CPB心脏不停跳MVR患者围术期尿KIM-1浓度变化较小,心脏不停跳手术或可减少肾功能损害。

Role of triggering receptor expressed on myeloid cells-1 in kidney diseases:A biomarker and potential therapeutic target

Triggering receptor expressed on myeloid cells-1(TREM-1)is a member of the immunoglobulin superfamily.As an amplifier of the inflammatory response,TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival.TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders.More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases.There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease.This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury,renal fibrosis,diabetic nephropathy,immune nephropathy,and renal cell carcinoma.

Targeted therapy of kidney disease with nanoparticle drug delivery materials

With the development of nanomedicine,nanomaterials have been widely used,offering specific drug delivery to target sites,minimal side effects,and significant therapeutic effects.The kidneys have filtration and reabsorption functions,with various potential target cell types and a complex structural environment,making the strategies for kidney function protection and recovery after injury complex.This also lays the foundation for the application of nanomedicine in kidney diseases.Currently,evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials.The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility,including nanoparticles,hydrogels,liposomes,micelles,dendrimer polymers,adenoviruses,lysozymes,and elastin-like polypeptides.These carriers have precise renal uptake,longer half-life,and targeted organ distribution,protecting and improving the efficacy of the drugs they carry.Additionally,attention should also be paid to the toxicity and solubility of the carriers.While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro,extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body.This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases,provide a more comprehensive catalog of nanocarrier materials,and offer prospects for their drug-loading efficacy and clinical applications.

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

14-3-3 proteins—an update

14-3-3 is a highly conserved acidic protein family, composed of seven isoforms in mammals. 14-3-3 protein caninteract with over 200 target proteins by phosphoserine-dependent and phosphoserine-independent manners. Little isknown about the consequences of these interactions, and thus are the subjects of ongoing studies. 14-3-3 controls cellcycle, cell growth, differentiation, survival, apoptosis, migration and spreading. Recent studies have revealed newmechanisms and new functions of 14-3-3, giving us more insights on this fascinating and complex family of proteins.Of all the seven isoforms, 14-3-3σ seems to be directly involved in human cancer. 14-3-3σ itself is subject to regulationby p53 upon DNA damage and by epigenetic deregulation. Gene silencing of 14-3-3σ by CpG methylation has beenfound in many human cancer types. This suggests that therapy-targeting 14-3-3σ may be beneficial for future cancertreatment.

Gut microbiota and diabetic kidney diseases: Pathogenesis and therapeutic perspectives

Diabetic kidney disease(DKD)is one of the major chronic complications of diabetes mellitus(DM),as well as a main cause of end-stage renal disease.Over the last few years,substantial research studies have revealed a contributory role of gut microbiota in the process of DM and DKD.Metabolites of gut microbiota like lipopolysaccharide,short-chain fatty acids,and trimethylamine N-oxide are key mediators of microbial–host crosstalk.However,the underlying mechanisms of how gut microbiota influences the onset and progression of DKD are relatively unknown.Besides,strategies to remodel the composition of gut microbiota or to reduce the metabolites of microbiota have been found recently,representing a new potential remedial target for DKD.In this minireview,we will address the possible contribution of the gut microbiota in the pathogenesis of DKD and its role as a therapeutic target.

Recent advances in nanotherapeutics for the treatment and prevention of acute kidney injury

Acute kidney injury(AKI)is a serious kidney disease without specific medications currently except for expensive dialysis treatment.Some potential drugs are limited due to their high hydrophobicity,poor in vivo stability,low bioavailability and possible adverse effects.Besides,kidney-targeted drugs are not common and small molecules are cleared too quickly to achieve effective drug concentrations in injured kidneys.These problems limit the development of pharmacological therapy for AKI.Nanotherapeutics based on nanotechnology have been proved to be an emerging and promising treatment strategy for AKI,which may solve the pharmacological therapy dilemma.More and more nanotherapeutics with different physicochemical properties are developed to efficiently deliver drugs,increase accumulation and control release of drugs in injury kidneys and also directly as effective antioxidants.Here,we discuss the recent nanotherapeutics applied in the treatment and prevention of AKI with improved effectiveness and few side effects.