Allergic diseases exhibited the characteristics of latent concealment and dynamic transmutation， which highly align with the pathogenic features of "latency and transformative change" described in the theory of latent pathogens. Based on the "latent pathogens with transformative potential" theory， this paper systematically explored the mechanisms of occurrence， transmission， and outcome of allergic diseases. It proposed that the insufficiency of kidney essence is the root cause enabling pathogens to lurk internally， leading to disease onset due to deficient healthy qi and lurking pathogens； the dysfunction of sanjiao serves as the pathway for pathogen stagnation， driving multi-system transmission； the accumulation of phlegm， stasis， and toxins constitutes the predicament of a protracted course， ultimately resulting in intractable pathological entanglement. Accordingly， a tiered intervention strategy is formulated，i.e. during the latency period， treatment should tonify the kidney and replenish essence to consolidate the foundation and halt the tendency of pathogens to lurk internally； during the transmission period， treatment should regulate sanjiao to intercept disease transmission and curb multi-system proliferation； during the protracted period， treatment should purge phlegm and resolve stasis to eliminate stubborn lesions， and break the vicious cycle of chronic accumulation and damage.

ObjectiveTo investigate the protective effect of Rehmanniae Radix iridoid glycosides （RIG） on the kidney tissue of streptozotocin （STZ）-induced diabetic mice and explore the underlying mechanism. MethodsTwelve of 72 male C57BL/6J mice were randomly selected as the normal group， and the remaining 60 mice were fed with a high-fat diet for six weeks combined with injection of 60 mg·kg^-1 STZ for 4 days to model type 2 diabetes mellitus. The successfully modeled mice were randomized into model， metformin （250 mg·kg^-1）， catalpol （100 mg·kg^-1）， low-dose RIG （RIG-L， 200 mg·kg^-1） and high-dose RIG （RIG-H， 400 mg·kg^-1） groups （n=11）. Mice in each group were administrated with corresponding drugs， while those in the normal group and model group were administrated with the same dose of distilled water by gavage once a day. After 8 weeks of intervention， an oral glucose tolerance test （OGTT） was performed， and the area under the curve （AUC） was calculated. After mice were sacrificed， both kidneys were collected. The body weight， kidney weight， and fasting blood glucose （FBG） were measured. Biochemical assays were performed to measure the serum levels of triglycerides （TG）， total cholesterol （TC）， serum creatinine （SCr）， and blood urea nitrogen （BUN）. Enzyme-linked immunosorbent assay （ELISA） was employed to determine the serum level of fasting insulin （FINS）， and the insulin sensitivity index （ISI） and homeostatic model assessment for insulin resistance （HOMA-IR） were calculated. The pathological changes in kidneys of mice were observed by hematoxylin-eosin staining and Masson staining. The immunohistochemical method （IHC） was employed to assess the expression of interleukin-1 （IL-1）， interleukin-6 （IL-6）， tumor necrosis factor-α（TNF-α）， transforming growth factor-β₁ （TGF-β₁）， and collagen-3 （ColⅢ） in the kidney tissue. The protein levels of TGF-β₁， cell signal transduction molecule 3 （Smad3）， matrix metalloproteinase-9 （MMP-9）， and ColⅢ in kidneys of mice were determined by Western blot. ResultsCompared with the normal group， the model group showcased decreased body weight and ISI （P<0.01）， increased kidney weight， FBG， AUC， FINS， HOMA-IR， TC， TG， SCr， and BUN （P<0.01）， glomerular hypertrophy， capsular space narrowing， and collagen deposition in the kidney， up-regulated protein levels of IL-1， IL-6， TNF-α， TGF-β₁， ColⅢ， and Smad3 （P<0.01）， and down-regulated protein level of MMP-9 （P<0.01） in the kidney tissue. Compared with the model group， the treatment groups had no significant difference in the body weight and decreased kidney weight （P<0.05， P<0.01）. The FBG level declined in the RIG-H group after treatment for 4-8 weeks and in the metformin， catalpol， and RIG-L groups after treatment for 6-8 weeks （P<0.01）. The AUC in the RIG-L， RIG-H， and metformin groups decreased （P<0.05， P<0.01）. The levels of TC， SCr， and BUN in the serum of mice in each treatment group became lowered （P<0.05， P<0.01）. The level of TG declined in the RIG-L， RIG-H， and metformin groups （P<0.05， P<0.01）. The serum level of FINS declined in the catalpol， RIG-L， and metformin groups （P<0.01）. Compared with the model group， the treatment groups showed decreased HOMA-IR （P<0.01）， increased ISI （P<0.01）， alleviated pathological changes in the kidney tissue， and down-regulated expression of IL-1 and TGF-β₁. In addition， the protein levels of IL-6， TNF-α， and ColⅢ in the RIG-H and metformin groups and IL-6 and TNF-α in the RIG-L group were down-regulated （P<0.05， P<0.01）， and the protein levels of IL-6， TNF-α， and ColⅢ in the catalpol group and ColⅢ in the RIG-L group showed a decreasing trend without statistical difference. The protein levels of TGF-β₁， Smad3， and ColⅢ in the RIG-H and metformin groups were down-regulated （P<0.01）. Compared with that in the model group， the protein level of MMP-9 was up-regulated in each treatment group （P<0.01）. ConclusionRIG can improve the renal structure and function of diabetic mice by regulating the TGF-β₁/Smads signaling pathway.

[摘 要] 目的：探讨KH型剪切调节蛋白（KHSRP）靶向调控JAK1/STAT3信号轴对食管胃结合部腺癌（AEG）细胞增殖、迁移和侵袭及移植瘤生长与肺转移的影响。方法：收集2017年1月至2018年12月间在淮河医院确诊的64例AEG组织和癌旁组织标本及临床资料，采用免疫组化法观察AEG组织和癌旁组织中KHSRP的表达水平。qPCR法检测AEG细胞OE-19、TE-7、BIC-1、FLO-1、SK-GT-4、BE-3与正常食管上皮细胞Het-1A中KHSRP的表达差异。通过慢病毒载体对KHSRP进行敲减和过表达处理，分别转染OE-19与TE-7细胞、FLO-1与SK-GT-4细胞，实验分为sh-NC组、sh-KHSRP组和Vector组、KHSRP过表达组（KHSRP组）。采用qPCR法检测敲减或过表达效率，CCK-8法、Transwell小室法分别检测敲减或过表达KHSRP对AEG细胞增殖、迁移和侵袭的影响。构建小鼠异种移植瘤和肺转移模型，观察KHSRP对移植瘤体内生长和转移的作用。WB法验证KHSRP靶向JAK/STAT信号通路。细胞拯救实验验证KHSRP是否通过调节JAK1/STAT3信号通路促进AEG细胞的恶性进程。结果：与癌旁组织相比，AEG组织中KHSRP表达水平显著增高（P < 0.05或P < 0.01）。细胞功能实验分析显示，KHSRP过表达在体外均显著促进AEG细胞增殖、迁移和侵袭（P < 0.05或P < 0.01）。动物实验结果显示，KHSRP在裸鼠体内具有促进AEG细胞移植瘤生长与肺转移的作用（P < 0.05或P < 0.01）。在敲减KHSRP后，JAK/STAT信号通路中JAK1、STAT3磷酸化水平均明显降低，过表达KHSRP后情况则均反之（P < 0.05或P < 0.01）。细胞拯救实验显示，KHSRP可以逆转敲减JAK1/STAT3对细胞增殖、迁移和侵袭的抑制作用（P < 0.05或P < 0.01）。结论：KHSRP通过激活JAK1/STAT3信号通路调控AEG细胞转移的恶性进程，KHSRP有望成为AEG临床治疗的潜在靶点。

OBJECTIVE: To investigate the effectiveness of using 3 hollow compression screws combined with 1 screw off-axis fixation under the guidance of three-dimensional (3D) printed guide plate with mortise-tenon joint structure (mortise-tenon joint plate) for the treatment of Pauwels type Ⅲ femoral neck fractures. METHODS: A clinical data of 78 patients with Pauwels type Ⅲ femoral neck fractures, who were admitted between August 2022 and August 2023 and met the selection criteria, was retrospectively analyzed. The operations were assisted with mortise-tenon joint plates in 26 cases (mortise-tenon joint plate group) and traditional guide plates in 28 cases (traditional plate group), and without guide plates in 24 cases (control group). There was no significant difference in the baseline data of gender, age, body mass index, cause of injury, and fracture side between groups ( P>0.05). The operation time, intraoperative blood loss, frequency of intraoperative fluoroscopy, incision length, incidence of postoperative deep vein thrombosis of lower extremity, pain visual analogue scale (VAS) score at 1 week after operation, and Harris score of hip joint at 3 months after operation were recorded and compared. X-ray re-examination was taken to check the quality of fracture reduction, fracture healing, and the shortening length of the femoral neck at 3 months after operation, and the incidences of internal fixation failure and osteonecrosis of the femoral head during operation. RESULTS: Compared with the control group, the operation time, intraoperative blood loss, and frequency of intraoperative fluoroscopy reduced in the two plate groups, and the quality of fracture reduction was better, but the incision was longer, and the differences were significant ( P<0.05). The operation time and intraoperative blood loss were significantly higher in the traditional plate group than in the mortise-tenon joint plate group ( P<0.05), the incision was significantly longer ( P<0.05); and the difference in fracture reduction quality and the frequency of intraoperative fluoroscopy was not significant between two plate groups ( P>0.05). There was 1 case of deep vein thrombosis of lower extremity in the traditional plate group and 1 case in the control group, while there was no thrombosis in the mortise-tenon joint plate group. There was no significant difference in the incidence between groups ( P>0.05). All patients were followed up 12-15 months (mean, 13 months). There was no significant difference in VAS score at 1 week and Harris score at 3 months between groups ( P>0.05). Compared with the control group, the fracture healing time and the length of femoral neck shortening at 3 months after operation were significantly shorter in the two plate groups ( P<0.05). There was no significant difference between the two plate groups ( P>0.05). There was no significant difference in the incidences of non-union fractures, osteonecrosis of the femoral head, or internal fixation failure between groups ( P>0.05). CONCLUSION For Pauwels type Ⅲ femoral neck fractures, the use of 3D printed guide plate assisted reduction and fixation can shorten the fracture healing time, reduce the incidence of postoperative complications, and be more conducive to the early functional exercise of the affected limb. Compared with the traditional guide plate, the mortise-tenon joint plate can reduce the intraoperative bleeding and shorten the operation time.
Humans ; Femoral Neck Fractures/diagnostic imaging* ; Bone Plates ; Fracture Fixation, Internal/instrumentation* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Bone Screws ; Adult ; Aged ; Treatment Outcome ; Printing, Three-Dimensional ; Operative Time

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS_GSFM and drug efficacy, suggesting that RS_GSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

The research of damp-heat syndrome in modern TCM mainly focuses on inflammatory response, water metabolism, lipid metabolism, hemorheology, intestinal flora and so on. Modern omics techniques such as metabolomics and genomics provide a new perspective for the exploration of the micro-mechanism of damp-heat syndrome. The study found that the abnormal expression of aquaporin is closely related to the formation of "dampness" in damp-heat syndrome, and the release of inflammatory factors reflects the pathological characteristics of "heat". Damp-heat syndrome is often accompanied by dyslipidemia, hemorheological changes and intestinal flora imbalance, showing characteristic changes in urine, blood and saliva metabolomics, and there are differences in gene expression between damp-heat constitution and gentleness constitution. In the future, the pertinence and systematicness of research should be strengthened, the relationship between indicators should be deeply explored, build a biomarker system should be built, the immune-metabolic regulation mechanism should be explored, the multi-target mechanism of heat-clearing and dampness-removing Chinese materia medica should be clarified to further improve the damp-heat syndrome system, and provide theoretical support for clinical treatment.

To investigate the malignant progression and molecular mechanism of KHSRP regulating esophageal squamous cell carcinoma(ESCC) through the JAK1/STAT3 signaling axis.

OBJECTIVE To explore the potential of Aconiti Kusnezoffii Radix in affecting diabetes mellitus type 2(T2DM) and the potential mechanism for T2DM related symptoms based on systematic pharmacology, bioinformatics, molecular docking and in vitro and in vivo experiments. METHODS The database was used to search the related chemical components of Aconiti Kusnezoffii Radix, predict the potential targets and intervene related diseases. The differential genes of T2DM relative healthy people were retrieved from GEO database, mapped with the action target of Aconiti Kusnezoffii Radix, and placed in DAVID database for biological function enrichment. The sensitivity of the target gene to T2DM was analyzed by one-way ANOVA, binary logistic regression analysis and ROC curve. The binding position and interaction force between chemical compounds of Aconiti Kusnezoffii Radix and target proteins were analyzed by molecular docking technology. The effect of Aconiti Kusnezoffii Radix and its chemical compounds on the expression of target protein was verified by T2DM model in vivo and in vitro. RESULTS Through database retrieval and analysis, 304 kinds of target related diseases(P value<0.05, FDR<0.05) were obtained, and T2DM with the highest degree value(Degree=59) was selected and analyzed. The 43 target genes were obtained from the intersection of differential genes in T2DM relatively healthy people and potential action targets of Aconiti Kusnezoffii Radix. A total of 9 genes with significant differences were obtained by one-way ANOVA, 5 meaningful genes were obtained by binary logistic regression analysis, and 3 genes with area under ROC curve AUC>0.5 were obtained. By molecular docking (+)-Isoboldine binds to proteins APEX1, CASP1 and CBFB, Napelline binds to proteins CBX1 and EHMT2 through different forces such as hydrogen bond interaction, ligand interaction, hydrophobic interaction, ionizability and electrostatic interaction, so as to increase the ability of ligands to target proteins. After 2 weeks of treatment with Aconiti Kusnezoffii Radix aqueous extract, Aconiti Kusnezoffii Radix may alleviated the symptoms of T2DM by improving peripheral neuropathy. Moreover, Aconiti Kusnezoffii Radix could affect the protein expression of APEX1, CASP1, CBFB, CBX1 and EHMT2 in rat liver tissue. The effect of (+)-Isoboldine and Napelline chemical compounds in Aconiti Kusnezoffii Radix on the target protein of the model in vitro was consistent with that in vivo. CONCLUSION It is preliminarily revealed that Aconiti Kusnezoffii Radix can be used as a potential therapeutic drug to improve T2DM peripheral neuropathy, which lays a theoretical foundation for the research and development of Chinese Mongolian medicine and the excavation of new target drugs for the treatment of T2DM.

Objective To investigate the clinical effect of transhepatic arterial chemoembolization(TACE)combined with tyrosine kinase inhibitors(TKIs)and programmed death receptors-1(PD-1)inhibitors(TACE+TKIs+PD-1 antibody)in the treatment of moderate advanced unresectable hepatocellular carcinoma(HCC).Methods The clinical data of 65 patients with moderate advanced unresectable hepatocellular carcinoma admitted to the Affiliated Hospital of North Sichuan Medical College from January 2020 to January 2022 were analyzed retrospectively.65 patients were treated with TACE+TKIs+PD-1 antibody.The observation indexes were tumor response,objective response rate(ORR),disease control rate(DCR),total survival time,progression free survival time,conversion operation rate and adverse drug reaction.Results The ORR of 65 p-atients with hepatocellular carcinoma was 49.2％(32/65),and the DCR was 89.2％(58/65).Among them,there were 2 patients with complete remission(CR),30 patients with partial remission(PR),26 patients with stable disease(SD),and 7 patients with progression disease(PD).Among 65 patients with hepatocellular carcinoma,18 patients were transformed into resectable hepatocell-ular carcinoma and underwent RO surgery.The conversion rate was 27.6％(18/65).65 patients were followed up for 3 to 22.4 months,The median follow-up time was 16.5 months.The median overall survival time and median disease progression free survival time of 65 patients were 14.5 months(95％CI:12.3～16.6 months)and 8.8 months(95％CI:6.9～10.6 months),respectively.After treatment,65 patients all had post embolism syndrome(abdominal pain,fever,nausea,vomiting and other symptoms),and some patients had transient abnormal liver function.Adverse drug reactions below grade 3 recovered within a few days.Some patients were associated with multiple adverse drug reactions.1 patient(1.5％)stopped using TACE because of stubborn vomiting,and 5 patients(7.6％)stopped using Lenvatinib because of severe liver function damage during treatment,2 patients(3％)stopped using Camrelizumab because of severe reactive capillary hyperplasia,one patient(1.5％)stopped using Tislelizumab because of severe hypothyroidism,one patient(1.5％)stopped the treatment of Lenvatinib and Sintilimab due to severe gastrointestinal bleeding.The adverse drug reactions of grade 3～4 occurred in other patients were alleviated after drug reduction,symptomatic treatment and hormone treatment.Conclusion TACE+TKIs+PD-1 antibody can obtain reliable clinical efficacy and anti-tumor activity in the treatment of moderate advanced unresectable hepatocellular carcinoma.