Aristolochic acid (AA), extracted from Aristolochiaceae plants, plays an essential role in traditional herbal medicines and is used for different diseases. However, AA has been found to be nephrotoxic and is known to cause aristolochic acid nephropathy (AAN).AA-induced acute kidney injury (AKI) is a syndrome in AAN with a high morbidity that manifests mitochondrial damage as a key part of its pathological progression. Melatonin primarily serves as a mitochondria-targeted antioxidant. However, its mitochondrial protective role in AA-induced AKI is barely reported. In this study, mice were administrated 2.5 mg/kg AA to induce AKI. Melatonin reduced the increase in Upro and Scr and attenuated the necrosis and atrophy of renal proximal tubules in mice exposed to AA. Melatonin suppressed ROS generation, MDA levels and iNOS expression and increased SOD activities in vivo and in vitro. Intriguingly, the in vivo study revealed that melatonin decreased mitochondrial fragmentation in renal proximal tubular cells and increased ATP levels in kidney tissues in response to AA. In vitro, melatonin restored the mitochondrial membrane potential (MMP) in NRK-52E and HK-2 cells and led to an elevation in ATP levels. Confocal immunofluorescence data showed that puncta containing Mito-tracker and GFP-LC3A/B were reduced, thereby impeding the mitophagy of tubular epithelial cells. Furthermore, melatonin decreased LC3A/B-II expression and increased p62 expression. The apoptosis of tubular epithelial cells induced by AA was decreased. Therefore, our findings revealed that melatonin could prevent AA-induced AKI by attenuating mitochondrial damage, which may provide a potential therapeutic method for renal AA toxicity.

Objective:To systematically evaluate the efficacy of different kinds of smoking cessation drugs by network Meta-analysis.Methods:Literature was retrieved from PubMed, Web of Science, Embase, Cochrane Library, CBM, CNKI, VIP, Wan fang database, from the establishment of the database to November 2022, and randomized controlled trials (RCT) about bupropion, varenicline, nicotine replacement therapy (NRT) versus placebo in the treatment of smoking patients were collected. After data extraction from included literature which met inclusion criteria, and quality evaluation with Cochrane 5.1 risk bias evaluation tool, network Meta-analysis was performed by Stata15.1 software.Results:A total of 19 RCTs, involving 6106 patients and three interventions measures (bupropion, varenicline, NRT) and one control measure (placebo) were included. The results of network Meta-analysis showed that in terms of short-term abstinence rate, varenicline [ OR=4.21, 95% CI (2.32, 7.63)], bupropion [ OR=2.81, 95% CI(1.05, 7.54)] were better than placebo ( P<0.05). The surface under the cumulative ranking area (SUCRA): varenicline (90.2%)>bupropion (64.8%)>NRT (41.7%)>placebo (3.2%). In terms of the long-term abstinence rate, varenicline [ OR=3.06, 95% CI (1.59, 5.90)], NRT [ OR=3.39, 95% CI (2.20, 5.21)] were better than placebo ( P<0.05). SUCRA: varenicline (83.8%)>NRT (73.9%)>bupropion (37.2%)>placebo (5.2%). Conclusion:The existing evidence shows that compared with bupropion, NRT, varenicline has the best effect on quitting smoking, but more high-quality randomized trial evidence is needed for verification.

OBJECTIVE： To explore potential mechanism of “Astragalus membranaceus-Draba nemorosa” couplet medicine for heart failure. METHODS： By network pharmacology， based on drug-like and oral bioavailability， the active components of “A. membranaceus-D. nemorosa” for chronic heart failure were screened and the targets of treating chronic heart failure were predicted by using TCMSP，GeneCards database， OMIM database and DRAR-CPI. The active component-chronic heart failure target network was established by Cytoscape 3.6.0 software. The protein-protein interaction network was constructed by utilizing STRING database. Then top 5 targets in the list of connectivity were screened and performed a molecular docking in molecular docking server. Finally， GO bioprocess analysis and KEGG pathway enrichment analysis were performed in DAVID database. RESULTS： The study predicted 28 active components in total， including 20 A. membranaceus and 12 D. nemorosa， such as kaempferol and quercetin， there were four components in common. Totally 92 target gene of active components were obtained， including heat shock protein 90α （HSP90AA1）， tyrosine protein kinase SRC gene， etc. Results of GO bioprocess analysis showed an association with mitochondrial electron transport， mitochondrial intima， cytoplasmic sol， extracellular body， mitochondrial matrix and drug response. KEGG pathway enrichment analysis showed a link with MAPK signal pathway， TGF signal pathway， PI3K signal pathway， cAMP signal pathway， protein kinase B signal pathway， EPK1 signal pathway and NF-κB signal pathway. CONCLUSIONS： “A. membranaceus-D. nemorosa” couplet medicine exerts therapeutic effects on heart failure from multiple targets as HSP90AA1， SRC and mitochondrial electron transport and MAPK signaling pathway. The study can provide reference for further researches on its material basis and mechanism.

Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.
Biomedical Research ; methods ; trends ; Clinical Trials as Topic ; Genetic Predisposition to Disease ; genetics ; Genetic Therapy ; methods ; trends ; Humans ; Mutation ; Retinal Diseases ; genetics ; therapy ; Treatment Outcome

OBJECTIVETo investigate the role of MT-ND1 m.3635G>A mutation in the pathogenesis of Leber's hereditary optic neuropathy (LHON).

METHODSBiochemical characteristics including the activity of complex Ⅰ, ATP production and oxygen consumption rate among lymphoblastoid cell lines derived from 3 carriers, 3 affected matrilineal relatives of the families and 3 controls were compared.

RESULTSComparison of mitochondrial functions in lymphoblastoid cell lines of the carriers, patients and controls showed a 51.0% decrease in the activity of complex Ⅰ in patients compared with controls (P<0.05). The m.3635G>A mutation has resulted in decreased efficiency of ATP synthesis (P<0.05). Comparison of oxygen consumption rate showed that the basal OCR (P<0.05), ATP-linked OCR (P<0.05) and the maximum OCR (P<0.05) have all reduced to some extent compared with the controls.

CONCLUSIONThese results showed that m.3635G>A, as a LHON-associated mutation, can lead to mitochondrial dysfunction.

Adenosine Triphosphate ; genetics ; Asian Continental Ancestry Group ; genetics ; Female ; Humans ; Male ; Mitochondria ; genetics ; Mutation ; genetics ; NADH Dehydrogenase ; genetics ; Optic Atrophy, Hereditary, Leber ; genetics ; Pedigree

Background and purpose:Suppression of apoptotic signaling pathways is an important factor in tumor cell resistance. Research on cell apoptosis will open up a new way of reversing drug resistance and tumor treatment. This study examined the effects of a novel naphthalimide derivative 8c on multidrug resistant colon cancer HCT116/L-OHP cells and explored the molecular mechanisms underlying the apoptosis induction. Methods: The anti-proliferative effects of 8c were detected by CCK-8 assays and the effects on apoptosis induction were examined by lfow cytometry. The mRNA expression levels of p53, Bax and Bcl-2 were measured by real-time PCR;The protein expressions of p-p53, Bax, Bcl-2 and Cyt-c were detected by Western blot. Results:8c (IC50=8.16 μmol/L) seemed to be more potent than amonaifde (IC50=28.37 μmol/L) against HCT116/L-OHP cells. 8c induced apoptosis on HCT116/L-OHP cell lines through intrinsic or mitochondria dependent pathway. The protein expression of phosphorylation of p53 at Ser-15 was increased, but the mRNA level of p53 did not increase in HCT116/L-OHP cells. Bax protein and mRNA levels were signiifcantly increased, and Bcl-2 protein and mRNA levels were decreased, suggesting an increase of Bax/Bcl-2 ratios. Meanwhile, 8c induced a substantial release of cytochrome c from the mitochondria into the cytosol in HCT116/L-OHP cells. Conclusion: 8c induced cell death signal by inducing the activation p53 phosphorylation which subsequently activated related protein expressions of apoptotic pathway, which may be an important mechanism of 8c on inhibiting proliferation of HCT116/L-OHP resistant cells. All the results suggested that 8c was a potent compound to be developed as an anti-tumor and anti-resistance agent for clinic application in the future.

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder associated with mitochondrial DNA (mtDNA) mutations.In the LHON families in different ethnic backgrounds,the mutations of ND1 G3460A,ND4 G11778A and/or ND6 T14484C in the genes encoding subunits of respiratory chain complex Ⅰ account for more than 50％.But,as we know,the phenotypes of mitochondrial diseases are varied,so the same mutational points may generate different clinical phenotypes,and conversely,different mtDNA mutation variants may generate the similar phenotypes.Some states of LHON including the prone to male,incomplete penetrance,and phenotypic variability of vision loss suggest that other modifier factors probably play a synergic role in the development of LHON.Environmental factor,such as chronic cyanide poisoning,smoking,drinking,trauma,nutrition deficiency and mtDNA methylation,affects mitochondrial function.Therefore,there is an inheritance of gene and environment interactions affecting LHON.

Resource of traditional Chinese medicine (TCM) is one of the greatest treasures of China. It made magnif-icent contribution in Chinese lives and breeds. Quality is the foundation of safety, effective and quality control of TCM. With the social development, problem with raising need and falling resource and quality had became more and more serious. It slowed down the speed of TCM modernization and internationalization. This study used Shanghai earthworm, the authentic TCM of Shanghai, as an example. Focus on resource and quality problems, such as species confusion, resource shortage, rough machining, low quality and no standards, this study tried to work out the reason-able and feasible solution. This effort funded a way out of a stalemate of TCM resources and quality. It is important to TCM modernization and internationalization.

Objective To compare the advantages and disadvantages of botulinum toxin A (BTX-A) and phenol block in the treatment of spasticity in children with cerebral palsy. Methods Four hundred and twenty children with spastic cerebral palsy were divided into an experimental group (375 cases) and a control group (45 cases).The children were aged from 1 to 22 years ( average age 6 years).The children in the experimental group were treated with BTX-A block at a dosage of 55 to 350 IU (average 130.5 IU).The children in the control group were treated with a 5％ phenol solution block at a dosage of 0.5 to 4.6 ml ( average 2.2 ml).Children of both groups were given systematic functional rehabilitation training. All the children were evaluated with a physician rating scale (PRS) and the modified Ashworth scale (MAS) before and after the blocking.Effectiveness rates,effectiveness durations and side effects rates were calculated. Results Before treatment there was no significant difference in terms of motor disorder or spasticity between the 2 groups.After treatment,spasticity had been significantly reduced in both groups.The effectiveness rate was 98.4％ in the experimental group and 95.6％ in the control group,a difference which was not significant.The average effectiveness duration was ( 24.9 ± 5.76 ) weeks in the experimental group and ( 69.2 ± 13.76) weeks in the control group,significantly longer.The side effects rate was 5.33 ％ in the experimental group and 15.56％ in the control group,also a significant difference. Conclusion BTX-A could be more widely used because of its safety and credibility.

Objective To investigate the antibacterial activity of combined antimicrobial agents for imipenem-resistant Acinetobacter baumannii in vitro,so as to provide evidence for guiding clinical practice.Methods Twenty-seven isolates of irnipenem resistant Acinetobacter baumannii were collected from March,2007 to February.2008.The minimal inhibitory concentrations(MIC)of the isolates against eleven frequently used antibiotics were determined by E test and agar dilution.Combined drug sensitivity testing was performed by broth checkerboard titration assay.Synergism between minocycline and cefoperazone-sulbaetam was analyzed by time-killing curve.Results The results from checkerboard titration assay and time-kill studies showed that the synergy rates between minocycline and cefperazone-sulbactam,minocycline and amikacin,minocycline and ciprofloxacin were 74.1%,28.0%and 48.1%,respectively.The synergy rates between amikacin and cefoperazone-sulbactam,anaikacin and ciprofloxaein were 23.1%and 37.0%,respectively.The synergy rate between cefoperazone-sulbactam and ciprofloxacin was 7.1%.With combination therapy.both MICs of cefoperazone-sulbactam and MIC of minocyeline decreased to lower than breakpoints.According to time-killing curve,the synergy rate between cefoperazone-sulbactam and minocycline was 100%.Conclusion Minocycline and cefoperazone-sulbaetam can be used for treating infections caused by multidrug resistant Acinetobacter baumannii.