Regardless of the underlying etiology, renal fibrosis is the final histological outcome of progressive kidney disease. Unilateral ureteral obstruction (UUO) is an ideal and reproducible experimental rodent model of renal fibrosis, which is characterized by tubulointerstitial inflammatory responses, accumulation of extracellular matrix, tubular dilatation and atrophy, and fibrosis. The magnitude of UUO-induced renal fibrosis is experimentally manipulated by the species chosen, animal age, and the severity and duration of the obstruction, while relief of the obstruction allows the animal to recover from fibrosis. The pathogenesis of renal fibrosis is complex and multifactorial and is orchestrated by activation of renin-angiotensin system (RAS), oxidative stress, inflammatory response, transforming growth factor beta 1-Smad pathway, activated myofibroblasts, cell death (apoptosis, autophagy, ferroptosis, and necroptosis), destruction of intracellular organelles, and signaling pathway. The current therapeutic approaches have limited efficacy. Inhibition of RAS and use of antioxidants and antidiabetic drugs, such as inhibitors of sodium-glucose cotransporter 2 and dipeptidyl peptidase-4, have recently gained attention as therapeutic strategies to prevent renal scarring. This literature review highlights the state of the art regarding the molecular mechanisms relevant to the management of renal fibrosis caused by UUO.

Regardless of the underlying etiology, renal fibrosis is the final histological outcome of progressive kidney disease. Unilateral ureteral obstruction (UUO) is an ideal and reproducible experimental rodent model of renal fibrosis, which is characterized by tubulointerstitial inflammatory responses, accumulation of extracellular matrix, tubular dilatation and atrophy, and fibrosis. The magnitude of UUO-induced renal fibrosis is experimentally manipulated by the species chosen, animal age, and the severity and duration of the obstruction, while relief of the obstruction allows the animal to recover from fibrosis. The pathogenesis of renal fibrosis is complex and multifactorial and is orchestrated by activation of renin-angiotensin system (RAS), oxidative stress, inflammatory response, transforming growth factor beta 1-Smad pathway, activated myofibroblasts, cell death (apoptosis, autophagy, ferroptosis, and necroptosis), destruction of intracellular organelles, and signaling pathway. The current therapeutic approaches have limited efficacy. Inhibition of RAS and use of antioxidants and antidiabetic drugs, such as inhibitors of sodium-glucose cotransporter 2 and dipeptidyl peptidase-4, have recently gained attention as therapeutic strategies to prevent renal scarring. This literature review highlights the state of the art regarding the molecular mechanisms relevant to the management of renal fibrosis caused by UUO.

Objective:To evaluate the efficacy and safety of antaitasvir phosphate 100 mg or 200 mg combined with yiqibuvir for 12 weeks in patients with various genotypes of chronic hepatitis C, without cirrhosis or compensated stage cirrhosis.Methods:Patients with chronic hepatitis C (without cirrhosis or compensated stage cirrhosis) were randomly assigned to the antaitasvir phosphate 100 mg+yiqibuvir 600 mg group (100 mg group) or the antaitasvir phosphate 200 mg+yiqibuvir 600 mg group (200 mg group) in a 1∶1 ratio. The drugs were continuously administered once a day for 12 weeks and observed for 24 weeks after drug withdrawal. The drug safety profile was assessed concurrently with the observation of the sustained virological response (SVR12) in the two patient groups 12 weeks following the drug cessation. The intention-to-treat concept was used to define as closely as possible a full analysis set, including all randomized cases who received the experimental drug at least once. The safety set was collected from all subjects who received the experimental drug at least once (regardless of whether they participated in the randomization group) in this study. All efficacy endpoints and safety profile data were summarized using descriptive statistics. The primary efficacy endpoint was SVR12. The primary analysis was performed on a full analysis set. The frequency and proportion of cases were calculated in the experimental drug group (antaitasvir phosphate capsules combined with yiqibuvir tablets) that achieved "HCV RNA

AIM:To explore the possible mechanism of Yiqi-Huoxue formula(YQHXF)in treating cerebral ischemia-reperfusion injury.METHODS:Male SD rats were randomly divided into six groups,namely,the sham,mod-el,nimodipine,and low-,middle-and high-dose YQHXF groups.The middle cerebral artery occlusion/reperfusion(MCAO/R)model was established in all groups except the sham group.After successful modeling,the YQHXF low-,me-dium-,and high-dose groups were given 3.8,7.5,and 15 g?kg-1?d-1 of YQHXF,respectively,by gavage,while the ni-modipine group was given 12 mg?kg-1?d-1 of nimodipine tablets by gavage.The sham and model groups were given 10 mL?kg-1?d-1 of distilled water by gavage.After 14 days of drug intervention,the rats were euthanized and the neurological func-tion was evaluated.The infarct volume was assessed using 2,3,5-triphenyltetrazolium chloride(TTC)staining and brain histopathological changes were determined by hematoxylin-eosin(HE)staining.Transmission electron microscopy was used to investigate changes in autophagosomes,with immunofluorescence used to assess expression of microtubule-associ-ated protein 1 light chain 3(LC3)protein in the cerebral cortex,Western blot was used to measure protein levels of p-PI3K,PI3K,p-Akt,Akt,p-mTOR,mTOR,LC3B,p62,beclin-1,and Atg5,and RT-qPCR was used to determined LC3 and P62 mRNA expression.RESULTS:Compared with the sham group,the neural function scores of rats in the model group rats were significantly increased,and TTC staining revealed large areas of white cerebral infarction.There was severe pathological damage to the cerebral tissue in the ischemic cortical area,and large numbers of autophagosomes were seen inside the cells.Immunofluorescence staining showed significant numbers of LC3B-positive cells(P<0.01).Protein expression of beclin-1,Atg5,and LC3-Ⅱ/LC3-Ⅰ was significantly upregulated(P<0.01),while that of p62 was markedly downregulated(P<0.01).The expression of p-PI3K/PI3K,p-Akt/Akt,and p-mTOR/mTOR proteins was also significantly reduced(P<0.01).In addition,the mRNA expression of LC3 was significantly upregulated(P<0.01),with downregulation of P62 mRNA levels(P<0.01).Compared with the model group,both the YQHXF medium-and high-dose groups showed upregulated LC3-Ⅱ/LC3-Ⅰ values after 12 h of reperfusion(P<0.01),followed by downregulation of the ratios(P<0.05)after 3,7,and 14 days of reperfusion.Furthermore,after 14 days of reperfusion,compared with the model group,the middle-and high-dose YQHXF groups and the nimodipine group showed reduced neurological function scores(P<0.01),reduced cerebral infarction volumes(P<0.01),improvements in the pathological damage to cortical tis-sue,and reduced autophagosome formation to varying degrees.At the same time,the number of LC3B-positive cells was reduced(P<0.01).Protein expression of beclin-1,Atg5,and LC3-Ⅱ/LC3-Ⅰ was significantly downregulated,while that of p62 was upregulated(P<0.01).The mRNA expression of LC3 and p62 was consistent with the protein levels(P<0.01).In addition,the expression of p-PI3K/PI3K,p-Akt/Akt,and p-mTOR/mTOR proteins was upregulated(P<0.01).CONCLUSION:YQHXF can dynamically regulate autophagy in ischemic brain tissue,with inhibition of excess autophagy by activation of the PI3K/Akt/mTOR signaling pathway,thus reducing the infarct volume,alleviating brain dam-age,and promoting the recovery of neurological function.

Regardless of the underlying etiology, renal fibrosis is the final histological outcome of progressive kidney disease. Unilateral ureteral obstruction (UUO) is an ideal and reproducible experimental rodent model of renal fibrosis, which is characterized by tubulointerstitial inflammatory responses, accumulation of extracellular matrix, tubular dilatation and atrophy, and fibrosis. The magnitude of UUO-induced renal fibrosis is experimentally manipulated by the species chosen, animal age, and the severity and duration of the obstruction, while relief of the obstruction allows the animal to recover from fibrosis. The pathogenesis of renal fibrosis is complex and multifactorial and is orchestrated by activation of renin-angiotensin system (RAS), oxidative stress, inflammatory response, transforming growth factor beta 1-Smad pathway, activated myofibroblasts, cell death (apoptosis, autophagy, ferroptosis, and necroptosis), destruction of intracellular organelles, and signaling pathway. The current therapeutic approaches have limited efficacy. Inhibition of RAS and use of antioxidants and antidiabetic drugs, such as inhibitors of sodium-glucose cotransporter 2 and dipeptidyl peptidase-4, have recently gained attention as therapeutic strategies to prevent renal scarring. This literature review highlights the state of the art regarding the molecular mechanisms relevant to the management of renal fibrosis caused by UUO.

Regardless of the underlying etiology, renal fibrosis is the final histological outcome of progressive kidney disease. Unilateral ureteral obstruction (UUO) is an ideal and reproducible experimental rodent model of renal fibrosis, which is characterized by tubulointerstitial inflammatory responses, accumulation of extracellular matrix, tubular dilatation and atrophy, and fibrosis. The magnitude of UUO-induced renal fibrosis is experimentally manipulated by the species chosen, animal age, and the severity and duration of the obstruction, while relief of the obstruction allows the animal to recover from fibrosis. The pathogenesis of renal fibrosis is complex and multifactorial and is orchestrated by activation of renin-angiotensin system (RAS), oxidative stress, inflammatory response, transforming growth factor beta 1-Smad pathway, activated myofibroblasts, cell death (apoptosis, autophagy, ferroptosis, and necroptosis), destruction of intracellular organelles, and signaling pathway. The current therapeutic approaches have limited efficacy. Inhibition of RAS and use of antioxidants and antidiabetic drugs, such as inhibitors of sodium-glucose cotransporter 2 and dipeptidyl peptidase-4, have recently gained attention as therapeutic strategies to prevent renal scarring. This literature review highlights the state of the art regarding the molecular mechanisms relevant to the management of renal fibrosis caused by UUO.

Background/Aims: Accumulating evidence indicates that L-carnitine (LC) protects against multiorgan damage through its antioxidant properties and preservation of the mitochondria. Little information is available about the effects of LC on renal fibrosis. This study examined whether LC treatment would provide renoprotection in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Methods: Sprague-Dawley rats that underwent UUO were treated daily with LC for 7 or 14 days. The influence of LC on renal injury caused by UUO was evaluated by histopathology, and analysis of gene expression, oxidative stress, mitochondrial function, programmed cell death, and phosphatidylinositol 3-kinase (PI3K)/ AKT/forkhead box protein O 1a (FoxO1a) signaling. In addition, H2O2-exposed human kidney cells (HK-2) were treated with LC. Results: LC treatment inhibited expression of proinflammatory and profibrotic cytokines, and was followed by a significant attenuation of tubulointerstitial inflammation and fibrosis. The increased oxidative stress caused by UUO was associated with mitochondrial dysfunction and excessive apoptosis and autophagy via PI3K/AKT/FoxO1a-dependent signaling, and this was abrogated by administration of LC. In H2O2-exposed HK-2 cells, LC decreased intracellular production of reactive oxygen species, and suppressed expression of profibrotic cytokines and reduced the number of apoptotic cells. Conclusions LC protects against the progression of tubulointerstitial fibrosis in an obstructed kidney.

Background/Aims: Cigarette smoking is an important modifiable risk factor in kidney disease progression. However, the underlying mechanisms for this are lacking. This study aimed to assess whether nicotine (NIC), a major toxic component of cigarette smoking, would exacerbates tacrolimus (TAC)-induced renal injury. Methods: Sprague-Dawley rats were treated daily with NIC, TAC, or both drugs for 4 weeks. The influence of NIC on TAC-caused renal injury was examined via renal function, histopathology, oxidative stress, mitochondria, endoplasmic reticulum (ER) stress, and programmed cell death (apoptosis and autophagy). Results: Both NIC and TAC significantly impaired renal function and histopathology, while combined NIC and TAC treatment aggravated these parameters beyond the effects of either alone. Increased oxidative stress, ER stress, mitochondrial dysfunction, proinf lammatory and profibrotic cytokine expressions, and programmed cell death from either NIC or TAC were also aggravated by the two combined. Conclusions Our observations suggest that NIC exacerbates chronic TAC nephrotoxicity, implying that smoking cessation may be beneficial for transplant smokers taking TAC.

BACKGROUND/AIMS: Evidence suggests that Shen-Kang (SK), a traditional Chinese herbal medicine, protects against various types of renal injury. In this study, we evaluated whether SK treatment confers renoprotection in a rat model of chronic tacrolimus (TAC) nephropathy. METHODS: Rats were treated daily with TAC (1.5mg/kg, subcutaneously) and SK (450 mg/kg, intravenously) for 4 weeks. The effects of SK on TAC-induced renal injury were assessed by measuring renal function, urine albumin excretion, histopathology, inflammatory cell infiltration, expression of profibrotic (transforming growth factor β1 [TGF-β1] and TGF-β inducible gene-h3 [βig-h3]) and proinflammatory cytokines, oxidative stress, and apoptotic cell death. RESULTS: Administration of SK preserved glomerular integrity (fractional mesangial area and Wilms tumor 1-positive glomeruli), attenuated tubulointerstitial fibrosis, and reduced the number of ectodermal dysplasia 1-positive cells, and this was paralleled by improved urine albumin excretion and renal dysfunction. At the molecular level, SK treatment suppressed expression of TGF-β1/Smad2/3, βig-h3, and proinflammatory cytokines. Oxidative stress and apoptotic cell death were significantly decreased with SK treatment, and apoptosis-related genes were regulated toward cell survival (active caspase-3 and the B-cell lymphoma-2/Bcl2-associated X [Bcl-2/Bax] ratio). CONCLUSIONS SK protects against TAC-induced renal injury.

OBJECTIVETo investigate the risk factors for the failure in treating periprosthetic infection of coagulase-negative staphylococci by two-stage revision.

METHODSFrom January 2005 to June 2015, 57 patients with periprosthetic hip and knee joint infection of coagulase-negative staphylococcus by two-stage revision were retrospectively reviewed with an average age of (61.3±11.9) years old. According to the drug resistance of methicillin, the patients were divided into methicillin sensitive group(MSCoN) and methicillin resistance(MRCoN) group, 25 cases in MSCoN group(9 knees and 16 hips) included 12 males and 13 females, 32 cases in MRCoN group(11 knees and 21 hips) included 14 males and 18 females. Follow-up for at least 2 years, the inflammatory markers, incidence rate of sinus and the duration of the symptoms, reinfection or persistent infection rate after two-stage revision were compared between two groups.

RESULTSMSCoN group and MRCoN group were followed up(81.7±38.3) months and(65.9±33.8) months, respectively;23 cases and 27 cases were successfully treated;there was no significant difference between two groups(=0.643). The patients who had surgery history were 4.04 times higher of failure than the patients without a history of surgery[OR=4.04, 95%CI(0.62, 26.5)]. Patients who had sinus were 4.26 times higher of failure than the patients without sinus[OR=4.26, 95%CI(0.7, 25.9)].

CONCLUSIONSTwo-stage revision is an effective procedure in treating patients infected by MSCoN and MRCoN. There is no significant difference of treatment failure rate between MSCoN and MRCoN group by two-stage revision. Surgery history and sinus maybe the risk factors of treatment failure, while methicillin-resistance is not.