ObjectiveTo investigate the effect of Qingrun prescription（QRP）-containing serum on improving insulin resistance in HepG2 cells and its potential mechanisms. MethodsAn insulin resistance model was established in HepG2 cells with 1×10^-6 mol·L^-1 insulin. Branched-chain α-keto acid dehydrogenase （BCKDH） gene silencing was achieved using siRNA， and the cells were divided into 8 groups： normal group， model group （1×10^-6 mol·L^-1 insulin）， metformin group （1 mmol·L^-1 metformin）， high-， medium-， and low-dose QRP groups （20%， 10%， and 5% QRP-containing serum， respectively）， QRP + siRNA-silenced BCKDH （si-BCKDH） group （10% QRP-containing serum + si-BCKDH）， and QRP + si-NC group （10% QRP-containing serum + si-NC）. Glucose levels in the supernatant were measured with a glucose assay kit， while glycogen content was assessed using a glycogen assay kit. Levels of branched-chain amino acids （BCAAs） and branched-chain keto acids （BCKAs） were determined using ultra-high performance liquid chromatography-tandem mass spectrometry （UHPLC-MS/MS）. mRNA transcription and protein expression levels of BCKDH， dishevelled， Egl-10， and pleckstrin （DEP） domain-containing mammalian target of rapamycin （mTOR）-interacting protein （DEPTOR）， mTOR， and ribosomal protein S6 kinase 1 （S6K1） were detected using real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot. ResultsCompared to the normal group， the model group exhibited significantly decreased glucose consumption and glycogen content， increased levels of BCAAs and BCKAs， downregulated expression of BCKDH and DEPTOR， and upregulated mTOR and S6K1 expression （P<0.01）. In comparison to the model group， QRP treatment at all doses significantly enhanced glucose consumption and glycogen content while reducing BCAAs and BCKAs levels （P<0.01）. The high- and medium-dose QRP groups demonstrated significant upregulation of BCKDH mRNA transcription and protein expression， as well as DEPTOR mRNA transcription. Moreover， the DEPTOR protein expression level was significantly increased in high-， medium-， and low-dose QRP groups， while mTOR and S6K1 mRNA and protein expression levels were markedly downregulated （P<0.05， P<0.01）. Compared to the QRP + si-NC group， the QRP + si-BCKDH group exhibited increased BCAAs and BCKAs levels， significantly decreased BCKDH mRNA transcription and protein expression， downregulated DEPTOR mRNA and protein expression， and upregulated mTOR and S6K1 mRNA and protein expression （P<0.05， P<0.01）. ConclusionQRP may improve insulin resistance by reprogramming BCAAs metabolism. This effect involves upregulating BCKDH， reducing BCAAs and BCKAs levels， and suppressing the mTOR pathway activation.

A scoping review was performed to systematically search and summarize the clinical research in the treatment of dysmenorrhea with oral Chinese patent medicines. The oral Chinese patent medicines for treating dysmenorrhea in three major drug lists, guidelines, and textbooks were screened, and the relevant clinical trials were retrieved from eight Chinese and English databases. The key information of the included trials was extracted and visually analyzed. A total of 50 Chinese patent medicines were included, among which oral Chinese patent medicines for the dysmenorrhea patients with the syndrome of Qi stagnation and blood stasis accounted for the highest proportion, and the average daily cost varied greatly among Chinese patent medicines. A total of 150 articles were included, involving 22 Chinese patent medicines, among which Guizhi Fuling Capsules/Pills, Sanjie Zhentong Capsules, and Dan'e Fukang Soft Extract were the most frequently studied. These articles mainly reported randomized controlled trial(RCT), which mainly focused on the comparison of the intervention effect between Chinese patent medicines combined with western medicine and western medicine alone, and the sample size was generally 51-100 cases. The high-frequency outcome indicators belonged to nine domains such as effective rate, adverse reactions, and laboratory examinations. This study showed that oral Chinese patent medicines had advantages in the treatment of dysmenorrhea, and the annual number of related clinical trials showed an overall growing trend. However, there were still problems such as insufficient safety information and vague description of traditional Chinese medicine(TCM) syndromes types in the instructions of Chinese patent medicines. The available clinical research had shortcomings such as uneven distribution of Chinese patent medicines, limited research scale, poor methodological rigor, and insufficient standardization of outcome indicators. In the future, it is necessary to deepen the development of high-quality clinical research and improve the contents of the instructions to ensure the effectiveness and safety of the clinical application of oral Chinese patent medicines in the treatment of dysmenorrhea.
Dysmenorrhea/drug therapy* ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Female ; Administration, Oral ; Nonprescription Drugs/administration & dosage*

This study aims to investigate the mechanism of Qingrun Decoction in alleviating hepatic insulin resistance in type 2 diabetes mellitus(T2DM) rats through the reprogramming of amino acid metabolism. A T2DM rat model was established by inducing insulin resistance through a high-fat diet combined with intraperitoneal injection of streptozotocin. The model rats were randomly divided into five groups: model group, high-, medium-, and low-dose Qingrun Decoction groups, and metformin group. A normal control group was also established. The rats in the normal and model groups received 10 mL·kg~(-1) distilled water daily by gavage. The metformin group received 150 mg·kg~(-1) metformin suspension by gavage, and the Qingrun Decoction groups received 11.2, 5.6, and 2.8 g·kg~(-1) Qingrun Decoction by gavage for 8 weeks. Blood lipid levels were measured in different groups of rats. Pathological damage in rat liver tissue was assessed by hematoxylin-eosin(HE) staining and oil red O staining. Transcriptome sequencing and untargeted metabolomics were performed on rat liver and serum samples, integrated with bioinformatics analyses. Key metabolites(branched-chain amino acids, BCAAs), amino acid transporters, amino acid metabolites, critical enzymes for amino acid metabolism, resistin, adiponectin(ADPN), and mammalian target of rapamycin(mTOR) pathway-related molecules were quantified using quantitative real-time polymerase chain reaction(qRT-PCR), Western blot, and enzyme-linked immunosorbent assay(ELISA). The results showed that compared with the normal group, the model group had significantly increased serum levels of total cholesterol(TC), triglycerides(TG), low-density lipoprotein cholesterol(LDL-C), and resistin and significantly decreased ADPN levels. Hepatocytes in the model group exhibited loose arrangement, significant lipid accumulation, fatty degeneration, and pronounced inflammatory cell infiltration. In liver tissue, the mRNA transcriptional levels of solute carrier family 7 member 2(Slc7a2), solute carrier family 38 member 2(Slc38a2), solute carrier family 38 member 4(Slc38a4), and arginase(ARG) were significantly downregulated, while the mRNA transcriptional levels of solute carrier family 1 member 4(Slc1a4), solute carrier family 16 member 1(Slc16a1), and methionine adenosyltransferase(MAT) were upregulated. Furthermore, the mRNA transcription and protein expression levels of branched-chain α-keto acid dehydrogenase E1α(BCKDHA) and DEP domain-containing mTOR-interacting protein(DEPTOR) were downregulated, while mRNA transcription and protein expression levels of mTOR, as well as ribosomal protein S6 kinase 1(S6K1), were upregulated. The levels of BCAAs and S-adenosyl-L-methionine(SAM) were elevated. The serum level of 6-hydroxymelatonin was significantly reduced, while imidazole-4-one-5-propionic acid and N-(5-phospho-D-ribosyl)anthranilic acid levels were significantly increased. Compared with the model group, Qingrun Decoction significantly reduced blood lipid and resistin levels while increasing ADPN levels. Hepatocytes had improved morphology with reduced inflammatory cells, and fatty degeneration and lipid deposition were alleviated. Differentially expressed genes and differential metabolites were mainly enriched in amino acid metabolic pathways. The expression levels of Slc7a2, Slc38a2, Slc38a4, and ARG in the liver tissue were significantly upregulated, while Slc1a4, Slc16a1, and MAT expression levels were significantly downregulated. BCKDHA and DEPTOR expression levels were upregulated, while mTOR and S6K1 expression levels were downregulated. Additionally, the levels of BCAAs and SAM were significantly decreased. The serum level of 6-hydroxymelatonin was increased, while those of imidazole-4-one-5-propionic acid and N-(5-phospho-D-ribosyl)anthranilic acid were decreased. In summary, Qingrun Decoction may improve amino acid metabolism reprogramming, inhibit mTOR pathway activation, alleviate insulin resistance in the liver, and mitigate pathological damage of liver tissue in T2DM rats by downregulating hepatic BCAAs and SAM and regulating key enzymes involved in amino acid metabolism, such as BCKDHA, ARG, and MAT, as well as amino acid metabolites and transporters.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Rats ; Insulin Resistance ; Diabetes Mellitus, Type 2/genetics* ; Male ; Liver/drug effects* ; Amino Acids/metabolism* ; Rats, Sprague-Dawley ; Humans ; Metabolic Reprogramming

Lymph node metastasis (LNM) is a crucial risk factor influencing an unfavorable prognosis in specific cancers. Fundamental research illuminates our understanding of tumor behavior and identifies valuable therapeutic targets. Nevertheless, the exploration of fundamental theories and the validation of clinical therapies hinge on preclinical experiments. Preclinical models, in this context, serve as the conduit connecting fundamental theories to clinical outcomes. In vivo models established in animals offer a valuable platform for comprehensively observing interactions between tumor cells and organisms. Using various experimental animals, including mice, diverse methods, such as carcinogen-induced tumorigenesis, tumor cell line or human tumor transplantation, genetic engineering, and humanization, have been used effectively to construct numerous models for tumor LNM. Carcinogen-induced models simulate the entire process of tumorigenesis and metastasis. Transplantation models, using human tumor cell lines or patient-derived tumors, offer a research platform closely mirroring the histology and clinical behavior of human tumors. Genetically engineered models have been used to delve into the mechanisms of primary tumorigenesis within an intact microenvironment. Humanized models are used to overcome barriers between human and murine immune systems. Beyond mouse models, various other animal models have unique advantages and limitations, all contributing to exploring LNM. This review summarizes existing in vitro and animal preclinical models, identifies current bottlenecks in preclinical research, and offers an outlook on forthcoming preclinical models.
Animals ; Humans ; Mice ; Lymphatic Metastasis/pathology* ; Disease Models, Animal ; Cell Line, Tumor

Objective:To explore the prognostic value of epidermal growth factor receptor (EGFR) co-mutation status in patients with advanced lung adenocarcinoma.Methods:Clinical data of patients with stage ⅢB-Ⅳ lung adenocarcinoma who were first diagnosed in the Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Hebei North University from January 2019 to December 2022 were collected prospectively. Patients were divided into EGFR mutation group ( n=82) and EGFR co-mutation group ( n=74) according to whether EGFR was combined with other gene mutations. The level of circulating tumor DNA (ctDNA) in peripheral blood was measured by real time fluorescence quantitative PCR. Objective response rate (ORR), disease control rate (DCR), the levels of ctDNA in peripheral blood, and progression-free survival (PFS) were compared between two groups of patients before and after 1 month of treatment. The univariate and multivariate analyses were conducted by Cox proportional hazards regression model. Results:In the EGFR mutation group, there were 45 cases of EGFR19 deletion mutation and 37 cases of EGFR21 mutation. In the EGFR co-mutation group, there were 41 cases of EGFR19 deletion mutation, 33 cases of EGFR21 mutation, 46 cases of TP53 mutation, 16 cases of RB1 mutation, 6 cases of PTEN mutation, 2 cases of MET amplification, 1 case of ERBB2 mutation, 1 case of KRAS mutation, 1 case of RET rearrangement, and 1 case of ALK rearrangement. There were statistically significant differences between the EGFR mutation group and the EGFR co-mutation group in the maximum tumor diameter ( χ2=5.04, P=0.025) and stage ( χ2=3.92, P=0.048). The ORRs of the two groups were 64.63% (53/82) and 37.84% (28/74), respectively, with a statistically significant difference ( χ2=11.19, P<0.001). The DCRs were 96.34% (79/82) and 86.49% (64/74), respectively, with a statistically significant difference ( χ2=4.95, P=0.026). The ctDNA levels in the EGFR mutation group and EGFR co-mutation group after one month of treatment decreased compared to before treatment[2.63 (1.83, 3.30) ng/μl vs. 4.73 (3.92, 5.49) ng/μl, Z=-7.06, P<0.001; 4.26 (2.26, 6.07) ng/μl vs. 5.28 (4.37, 6.09) ng/μl, Z=-5.15, P<0.001], the ctDNA levels in the EGFR co-mutation group were higher than those in the EGFR mutation group before treatment and after 1 month of treatment ( Z=-2.47, P=0.013; Z=-4.29, P<0.001). In the EGFR co-mutation group, the ctDNA levels in peripheral blood of patients who were effectively treated with targeted therapy decreased after 1 month of treatment compared to before treatment [(2.03±0.63) ng/μl vs. (3.92±0.82) ng/μl, t=42.94, P<0.001], the levels of ctDNA in peripheral blood of ineffectively treated patients before and after 1 month of treatment were higher than those of effectively treated patients [(5.84±0.57) ng/μl vs. (3.92±0.82) ng/μl, t=-11.91, P<0.001; (5.87±1.64) ng/μl vs. (2.03±0.63) ng/μl, t=-14.43, P<0.001]. The median PFS of the EGFR mutation group and the EGFR co-mutation group of patients were 10.4 and 8.3 months, respectively, with a statistically significant difference ( χ2=22.28, P<0.001). Univariate analysis suggested that the maximum tumor diameter ( HR=0.10, 95% CI: 0.06-0.16, P<0.001), performance status (PS) score ( HR=0.09, 95% CI: 0.06-0.15, P<0.001), stage ( HR=0.09, 95% CI: 0.05-0.14, P<0.001), pre-treatment ctDNA level ( HR=12.04, 95% CI: 8.21-17.65, P<0.001), ctDNA level after 1 month of treatment ( HR=3.75, 95% CI: 3.10-4.54, P<0.001) and EGFR co-mutations ( HR=2.21, 95% CI: 1.57-3.12, P<0.001) were found to be significant factors affecting the PFS of stage ⅢB-Ⅳ lung adenocarcinoma patients receiving targeted therapy; Multivariate analysis demonstrated that PS score ( HR=0.25, 95% CI: 0.14-0.47, P<0.001), stage ( HR=0.49, 95% CI: 0.24-0.98, P=0.044), pre-treatment ctDNA level ( HR=4.73, 95% CI: 3.08-7.28, P<0.001), ctDNA level after 1 month of treatment ( HR=2.15, 95% CI: 1.65-2.80, P<0.001), and EGFR gene co-mutation ( HR=2.26, 95% CI: 1.40-3.64, P<0.001) were independent risk factors for PFS in stage ⅢB-Ⅳ lung adenocarcinoma patients receiving targeted therapy. Conclusion:Both the EGFR mutation group and EGFR co-mutation group show a decrease in ctDNA levels after targeted therapy for one month compared to before treatment. The median PFS of EGFR co-mutation patients is shorter than that of patients with a single EGFR mutation. PS score, stage, ctDNA levels before and after treatment, and EGFR gene co-mutation are all independent factors affecting PFS in stage ⅢB-Ⅳ lung adenocarcinoma patients after targeted therapy.

Aim To investigate the effects of multi-gly-cosides of Tripterygium wilfordii(GTW)on mitochon-drial dynamics-related proteins and the mechanism of nephroprotective effects in IgA nephrophathy(IgAN)rats.Methods SPF grade male SD rats were random-ly divided into the Control group,modelling group,prednisone group(6.25 mg·kg·d-1)and GTW group(6.25 mg·kg·d-1).The IgAN rat model was established by the method of"bovine serum albumin(BSA)+carbon tetrachloride(CCl4)+lipopolysac-charide(LPS)".The total amount of urinary protein(24 h-UTP)and erythrocyte count in urine were meas-ured in 24 h urine.Blood biochemistry of serum albu-min(ALB),alanine aminotransferase(ALT),urea ni-trogen(BUN),and creatinine(Scr)were measured in abdominal aorta of the rats;immunofluorescence and HE staining were used to observe the histopathology of the kidneys;RT-PCR and Western blotting were used to detect the mRNA and protein expression levels of key proteins regulating mitochondrial division and fu-sion:dynamin-related protein 1(Drp1),mitochondrial fusion protein 1(Mfn1),and mitochondrial fusion pro-tein 2(Mfn2),and PTEN-induced putative kinase 1(Pink1),in the kidney tissue of rats.Results GTW significantly reduced urinary erythrocyte count and 24 h-UTP,decreased serum ALT,BUN and Scr levels,in-creased serum ALB levels,improved renal histopatho-logical status in IgAN rats,increased the protein and mRNA expression levels of Mfn1,Mfn2,and Pink1,and decreased the protein and mRNA expression levels of Drp1 in renal tissues.Conclusions GTW may regu-late mitochondrial structure and maintain the dynamic balance of mitochondrial dynamics by promoting the ex-pression of Mfn1,Mfn2,Pink1 and decreasing Drp1.This may result in a reduction in urinary erythrocyte counts and proteinuria,and an improvement in renal function.

Traumatic supraorbital fissure syndrome (TSOFS) is a symptom complex caused by nerve entrapment in the supraorbital fissure after skull base trauma. If the compressed cranial nerve in the supraorbital fissure is not decompressed surgically, ptosis, diplopia and eye movement disorder may exist for a long time and seriously affect the patients′ quality of life. Since its overall incidence is not high, it is not familiarized with the majority of neurosurgeons and some TSOFS may be complicated with skull base vascular injury. If the supraorbital fissure surgery is performed without treatment of vascular injury, it may cause massive hemorrhage, and disability and even life-threatening in severe cases. At present, there is no consensus or guideline on the diagnosis and treatment of TSOFS that can be referred to both domestically and internationally. To improve the understanding of TSOFS among clinical physicians and establish standardized diagnosis and treatment plans, the Skull Base Trauma Group of the Neurorepair Professional Committee of the Chinese Medical Doctor Association, Neurotrauma Group of the Neurosurgery Branch of the Chinese Medical Association, Neurotrauma Group of the Traumatology Branch of the Chinese Medical Association, and Editorial Committee of Chinese Journal of Trauma organized relevant experts to formulate Chinese expert consensus on the diagnosis and treatment of traumatic supraorbital fissure syndrome ( version 2024) based on evidence of evidence-based medicine and clinical experience of diagnosis and treatment. This consensus puts forward 12 recommendations on the diagnosis, classification, treatment, efficacy evaluation and follow-up of TSOFS, aiming to provide references for neurosurgeons from hospitals of all levels to standardize the diagnosis and treatment of TSOFS.

Objective To observe the clinical effect of ulinastatin (UTI) combined with thymosin alpha 1 (Tαl) in the treatment of septic shock. Methods A retrospective analysis was conducted on the clinical data of 88 patients with septic shock admitted to our hospital from June 2021 to October 2023. The patients were divided into UTI group and UTI+Tα1 group according to different treatment methods, with 44 patients in each group. The treatment effects, clinical indicators, microcirculatory perfusion indicators[central venous oxygen saturation (S_cvO₂), lactate (LAC), capillary refill time (CRT), mean arterial pressure (MAP)], Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, Sequential Organ Failure Assessment (SOFA) score, immune indicators, plasma and serum inflammatory indicators[soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), procalcitonin (PCT), interleukin (IL)-6, tumor necrosis factor-α (TNF-α)], and prognosis were compared between the two groups. Results After 7 days of treatment, the effective rate of treatment in the UTI+Tα1 group was higher than that in the UTI group (P < 0.05). The duration of vasoactive drug use, mechanical ventilation time, ICU stay, and hospital stay were shorter in the UTI+Tα1 group than those in the UTI group (P < 0.05). After 24 and 72 hours of treatment, S_cvO₂ and MAP gradually increased, LAC gradually decreased, and CRT gradually shortened in both groups (P < 0.05). After 24 hours of treatment, S_cvO₂ and MAP were higher, and CRT was shorter in the UTI+Tα1 group than those in the UTI group (P < 0.05). After 72 hours of treatment, CRT was shorter, and MAP was higher in the UTI+Tα1 group than those in the UTI group (P < 0.05). After 7 days of treatment, both APACHE Ⅱ and SOFA scores decreased in both groups compared to treatment before, and their scores were lower in the UTI+Tα1 group than those in the UTI group (P < 0.05). After 7 days of treatment, the levels of CD3 + and CD4⁺ T lymphocytes increased in both groups compared to treatment before, and the levels were higher in the UTI+Tα1 group than those in the UTI group (P < 0.05). After 7 days of treatment, the levels of sTREM-1, PCT, IL-6, and TNF-α decreased in both groups compared to treatment before, and the levels were lower in the UTI+Tα1 group than those in the UTI group (P < 0.05). After a 28-day follow-up, there was no statistically significant difference in mortality between the two groups (P=0.398). Conclusion UTI combined with Tαl can effectively promote the recovery of patients with septic shock, improve microcirculatory perfusion, reduce plasma sTREM-1 and serum PCT levels, inhibit inflammatory responses, and improve prognosis.

Circular RNAs are novel non-coding RNAs with multiple biological functions, which can participate in biological processes such as the occurrence, development, invasion, and metastasis of liver cancer, as well as drug resistance of liver cancer. This article reviews the roles and mechanisms of circR-NAs in chemotherapy resistance, targeted therapy resistance and immunotherapy resistance in liver cancer, in order to provide new ideas for solving liver cancer resistance.

Hypertrophic scar (HS) affects the function and beauty of patients, and brings a heavy psychological burden to patients. However, the specific pathogenesis mechanism of HS in molecular biology level is not yet clear, and this disease is still one of the clinical diseases difficult to prevent and cure. MicroRNA (miR) is a family of single-stranded endogenous noncoding RNAs that can regulate gene expression. The abnormal transcription of miR in hypertrophic scar fibroblasts can affect the transduction and expression of downstream signal pathway or protein, and the exploration of miR and its downstream signal pathway and protein helps deeply understand the occurrence and development mechanism of scar hyperplasia. This article summarized and analyzed how miR and multiple signal pathways involve in the formation and development of HS in recent years, and further outlined the interaction between miR and target genes in HS.
Humans ; MicroRNAs/genetics* ; Cicatrix, Hypertrophic/genetics* ; Fibroblasts ; Hyperplasia