Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority. Our previous research demonstrated the efficacy of artesunate (ART) in alleviating liver fibrosis by eliminating activated hepatic stellate cells (HSCs). However, the underlying mechanism remains unclear despite these findings. Notably, endocytic adaptor protein (NUMB) has significant implications for treating hepatic diseases, but current research primarily focuses on liver regeneration and hepatocellular carcinoma. The precise function of NUMB in liver fibrosis, particularly its ability to regulate HSCs, requires further investigation. This study aims to elucidate the role of NUMB in the anti-hepatic fibrosis action of ART in HSCs. We observed that the expression level of NUMB significantly decreased in activated HSCs compared to quiescent HSCs, exhibiting a negative correlation with the progression of liver fibrosis. Additionally, ART induced senescence in activated HSCs through the NUMB/P53 tumor suppressor (P53) axis. We identified NUMB as a crucial regulator of senescence in activated HSCs and as a mediator of ART in determining cell fate. This research examines the specific target of ART in eliminating activated HSCs, providing both theoretical and experimental evidence for the treatment of liver fibrosis.
Hepatic Stellate Cells/cytology* ; Liver Cirrhosis/genetics* ; Artesunate/pharmacology* ; Cellular Senescence/drug effects* ; Membrane Proteins/genetics* ; Animals ; Humans ; Nerve Tissue Proteins/genetics* ; Tumor Suppressor Protein p53/genetics* ; Male ; Mice

With the accelerated aging society in China, the incidence of biliary surgical diseases in the elderly has increased significantly. The clinical characteristics of these patients indicate that improving treatment outcomes and realizing healthy aging are worthy of attention. How to effectively improve the treatment effect of geriatric biliary surgical diseases has attracted widespread attention. This paper reviews and comments on the hotspots and difficulties of biliary surgery in older patients from six aspects: (1) higher morbidity associated with an aging society, (2) prevention and control of pre-operative risks, (3) extending the indications of laparoscopic surgery, (4) urgent standardization of minimally invasive surgery, (5) precise technological progress in hepatobiliary surgery, and (6) guarantee of peri-operative safety. It is of great significance to fully understand the focus of controversy, actively make use of its favorable factors, and effectively avoid its unfavorable factors, for further improving the therapeutic effects of geriatric biliary surgical diseases, and thus benefits the vast older patients with biliary surgical diseases. Accordingly, a historical record with the highest age of 93 years for laparoscopic transcystic common bile duct exploration has been created by us recently.
Humans ; Aged ; Aged, 80 and over ; Biliary Tract Surgical Procedures ; Gallstones ; Laparoscopy ; Treatment Outcome ; Aging ; Retrospective Studies

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). But little is known about how alanine-serine-cysteine transporter type-2 (ASCT2), a high affinity glutamine transporter, affects HSC senescence and SASP during liver fibrosis. Here, we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers. We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo. The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration. Mechanically, ASCT2 was a direct target of glutaminolysis-dependent proinflammatory SASP, interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82. From a translational perspective, atractylenolide III is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2. The presence of -OH group in atractylenolide III is suggested to be favorable for the inhibition of ASCT2. Importantly, atractylenolide III could be utilized to treat liver fibrosis mice. Taken together, ASCT2 controlled HSC senescence while modifying the proinflammatory SASP. Targeting ASCT2 by atractylenolide III could be a therapeutic candidate for liver fibrosis.

Objective: To investigate the effects and underlying mechanisms of aspirin on endoplasmic reticulum stress in podocytes induced by hyperlipemia. Methods: Cultured podocytes were divided into four groups: control group, aspirin (100 μg/ml) group, oxidized low density lipoprotein (ox-LDL, 100 μg/ml) group, aspirin+ox-LDL group. The expression of protein kinase R-1ike endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor-4 (ATF4) and CAAT/enhancer binding protein homologous protein (CHOP) at 6 h, 12 h, 24 h, 48 h were evaluated by real-time PCR. The related proteins of p-PERK and p-eIF2α at 24 h and ATF4 at 12 h were evaluated by Western blotting, respectively. Results: The expressions of PERK, eIF2α peaked at 24 h, while ATF4 and CHOP peaked at 12 h in ox-LDL group and aspirin+ox-LDL group. Compared with control group, the expressions of PERK, eIF2α, ATF4 and CHOP were significantly higher in ox-LDL group at each times (all P<0.05). Compared with ox-LDL group, the expressions of the above indicators were significantly lower in aspirin+ox-LDL group at each times (all P<0.05). At 24 h, compared with control group, the expressions of p-PERK and p-eIF2α were significantly higher in ox-LDL group (both P<0.05). Compared with ox-LDL group, the expressions of p-PERK and p-eIF2α were significantly lower in aspirin+ox-LDL group (both P<0.05). At 12 h, the expression of ATF4 protein in each group was similar to that of mRNA. There were no significant difference in the expressions of all indicators between aspirin group and control group. Conclusions Hyperlipidemia may cause endoplasmic reticulum stress in podocytes by inducing phosphorylation of PERK and eIF2α, activating ATF4 transcription and inducing high expression of CHOP. Aspirin may partially block the PERK pathway, which may have protective effects for podocytes.

Farnesoid X receptor ( FXR) plays a key role in me-tabolism of substance, such as bile acid, lipid, glucose,( etc) . Newly published credible discoveries have claimed that as a reg-ulatory hub in metabolism, FXR is closely linked with diverse chronic liver diseases, including viral hepatitis, alcoholic fatty liver disease, nonalcoholic fatty liver disease, hepatic fibrosis and hepatocellular carcinoma. This review summarizes the roles and mechanisms of FXR during the courses of chronic liver dis-eases, aiming at providing novel insights and therapeutic target for antifibrotic research and drug development.

MTH1 (MutT Homolog1 )as MutT homologous en-zyme,is a nucleotide pyrophosphatase,mainly involved in DNA damage repair process,especially plays an important role in the process of DNA replication in tumor cells.Recent studies have found that MTH1’s function is responsible for the development of a variety of tumors.Studies have shown that,MTH1 can remove tumor cells’oxidative DNA elements detrimental to the function-al structure,protecting tumor cell division and proliferation, maintaining tumor cell survival,however,normal cells do not need MTH1.Therefore,MTH1 may be only closely associated with abnormal cell growth.This makes MTH1 as therapeutic tar-gets that have been paid much attention.This article reviewed the relationship of MTH1 and tumor,discussed the mechanisms of MTH1 in tumor growth MTH1 and tumor treatment,so as to provide reference for clinical research and treatment of tumor.

Salmonella enterica serovar Choleraesuis strain C500 is a live attenuated vaccine that has been widely used in Chi‐na for over 50 years to prevent piglet paratyphoid .However ,as C500 is obtained by chemical methods ,the genetic background of this strain remained unclear .In this study ,we compared the genomic differences between the virulent reference strain C 78‐2 and C500 by suppression subtractive hybridization combined with the mirror orientation selection method (MOS‐SSH ) .Six genes (asr ,ydgF ,ydgD ,ydgE ,rpoS ,and ptsG) were lost in C500 strain .Using real‐time PCR analysis ,we demonstrated that the genes regulated by rpoS ,a vital transcriptional regulator playing an important role in Salmonella infection ,were downregulated in C500 .Additionally ,the virulence of the rpoS mutant strain C78‐2ΔrpoS was 100 000 times lower than the parental strain in BALB/c mice .So loss of rpoS gene is the major factor leading to the attenuation of C500 strain .

Liver fibrosis occurs as compensatory responses to tis-sue repairing process in a wide range of chronic liver injures.It is characterized by excessive deposition of extracellular matrix (ECM)in liver tissues.The new discovery shows that suppres-sor of cytokine signaling (SOCS-3)is strictly associated with fi-brogenic progression of chronic liver diseases.Recent basic and clinical investigations also demonstrate that liver fibrogenesis is accompanied by SOCS-3,which critically determines the patho-
genesis and prognosis of liver fibrosis.This review summarizes current knowledge on SOCS-3 and the relationships between SOCS-3 and liver fibrosis.On the other hand,it also presents the different strategies that have been used in experimental mod-els to counteract excessive SOCS-3 and the role of SOCS-3 in the prevention and treatment of liver fibrosis.

OBJECTIVETo study the effect and safety of Kudiezi injection on patients with acute ischemic stroke.

METHODSeven hundreds patients were divided into two groups by central randomization system. The study group, 346 cases, was treated with kudiezi injection plus traditional Chinese medicine (TCM) synthesis rehabilitation project, and the control group, 354 cases, was treated with synthetic rehabilitation project. The patients were treated for 10 to 21 days. Before treatment and at the 7th, 14th and 21th day of treatment, the indexes include NIHSS used for evaluating the neurological deficit degree and the motor function score (Fugl-Meyer) for evaluating motor function were observed. The safety index is defined by adverse observation event and laboratory test. The incidence of adverse events and laboratory tests results were observed before and after treatment at the same time.

RESULTApplication of generalized estimating equation model, we found that as the treatment time, NIHSS score and FMI score of the two groups showed a trend of improvement. And at the 14th days and 21th days of treatment, compared to the control group the treatment group showed significant statistical difference on the impact of NIHSS and FMI (P<0.05). No serious adverse events were observed.

CONCLUSIONKudiezi injection plus TCM rehabilitation project of ischemic stroke showed some superiority to western medicine rehabilitation program on improving the neurological deficit and motor function. Kudiezi injection is safe and effective in the treatment of acute ischemic stroke.

Aged ; Brain Ischemia ; drug therapy ; Drug-Related Side Effects and Adverse Reactions ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Female ; Humans ; Injections ; Male ; Medicine, Chinese Traditional ; adverse effects ; Middle Aged ; Product Surveillance, Postmarketing ; Stroke ; drug therapy

OBJECTIVETo verify the efficacy and safety of post-marketed fleabane injection combined with Dengzhan Shengmai capsules in the treatment of ischemic stroke (IS).

METHODA multicentre, prospective, practical, randomized controlled study was carried out to compare the efficacy and safety of Dengzhan group (n = 343) and western medicine group (n = 335), appling "clinical study central stochastic system". The treatment of Dengzhan group is using fleabane injection in acute stage and Dengzhan Shengmai capsules in convalescence. The primary indexes of effect evaluation are the important outcome events in 360 days' follow-up, including mortality, recurrence, disability and quality of life to reflect the effect of clinical study. The indexes of safety evaluation involve laboratory examination results and incidence of adverse events.

RESULTAfter 360 days' follow-up, 4 people died of IS in Dengzhan group, and the mortality rate of which is 1.17%, while 16 died in Western medicine group (WM group), and the mortality rate is 4.78%, suggesting that the mortality rate of Dengzhan group is significantly lower than WM group (P<0.05). Eleven cases recurred in Dengzhan group, and the recurrence rate of which is 3.21%, while 12 recurred in WM group, and the recurrence rate is 3.59%, indicating that the recurrence rate of Dengzhan group is slightly lower than WM group. The disability rate of Dengzhan group is 39.53%, among which the rate of severely disabled cases are 1.49%, while the disability rate of WM group is 40.13%, among which the rate of severely disabled cases are 3.13%, suggesting that the disability rate of Dengzhan group is lower and the severity of disability is also lighter than WM group. In the field of quality of life, the activity ability and the upper limb function store of stroke patients in Dengzhan group improved far much better than WM group (P<0.05). Analysis of safety suggested that, adverse events occurred in 11 cases in Dengzhan group, among which 4 cases is related with the drug treatment, the incidence of adverse events of which is 1.17%, and the main manifestations involve fever and chilling, rash, nausea, dizziness, palpitation, etc. which were all appeared after the treatment of fleabane injection, and disappeared 1 to 2 days after drug withdrawal. 13 cases occurred abnormal liver function and 2 cases abnormal kidney function in Dengzhan group. According to the judgment of clinical physicians, 3 case of ALT abnormality is possibly related to the treatment, the others are all unrelated with the treatment.

CONCLUSIONFleabane injection and Dengzhan Shengmai capsules are all safe and effective TCM in the treatment of ischemic stroke.

Adult ; Aged ; Brain Ischemia ; drug therapy ; Capsules ; Drug-Related Side Effects and Adverse Reactions ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Erigeron ; adverse effects ; Female ; Humans ; Injections ; Male ; Middle Aged ; Product Surveillance, Postmarketing ; Prospective Studies ; Stroke ; drug therapy