ObjectiveTo observe the clinical efficacy of Gandouling decoction combined with neuromuscular electrical stimulation （NMES） in the treatment of dysphagia in Wilson disease （WD） with combined phlegm and stasis. MethodsA total of 80 WD patients with dysphagia due to combined phlegm and stasis treated in the Department of Encephalopathy， the First Affiliated Hospital of Anhui University of Chinese Medicine were randomized into a control group and an observation group， with 40 patients in each group. In addition， 40 healthy volunteers were recruited as the normal group. The control group was treated with basic copper drainage combined with NMES. The observation group was treated with Gandouling Decoction on the basis of the therapy in the control group. Each course of treatment lasted for 8 days， and the patients were treated for a total of 4 courses. All subjects underwent video fluoroscopic swallowing study （VFSS） before and after treatment. During the examination， contrast agents with 4 different characters were used for the swallowing action， and the passing time was recorded. The TCM syndrome score， water swallow test score， standard swallowing assessment （SSA） score， and 24-h urinary copper level before and after treatment were analyzed. ResultsWhen performing VFSS， the passing time of contrast agents of different characters in the oral stage was longer in the WD group than in the normal group （P<0.01）， while it had no significant difference in the pharyngeal stage. After treatment， the passing time in the oral stage shortened in the control and observation groups （P<0.01）， and the observation group outperformed the control group （P<0.01）. After treatment， both the control and observation groups showed declines in TCM syndrome score and SSA score （P<0.01） and an increase in water swallow test score （P<0.01）， and the changes were more obvious in the observation group than in the control group （P<0.01）. In addition， the treatment in the control and observation groups elevated the 24-h urinary copper level （P<0.01）， and the elevation in the observation group was more obvious than that in the control group （P<0.01）. Neither group showed obvious adverse reaction. ConclusionGandouling decoction combined with NMES can significantly ameliorate dysphagia in WD patients with the syndrome of combined phlegm and stasis regarding the TCM syndrome score， water swallow test score， and SSA score， demonstrating definite clinical efficacy and high safety.

ObjectiveTo investigate the correlation with cognitive function based on a new Kayser-Fleischer ring （K-F ring） grading method in Wilson’s disease （WD）. MethodsA total of 136 WD patients who were hospitalized in Encephalopathy Center， The First Affiliated Hospital of Anhui University of Chinese Medicine， from April 2022 to October 2023 were enrolled. All subjects underwent slit lamp examination， and the grade of K-F ring was determined according to the shape and extent of copper deposition in the cornea， whether it formed a ring or not， and whether there was a sunflower-like cloudy change in the lens. The patients were instructed to complete UWDRS， MoCA， and MMSE scale assessments， and these indicators were compared between patients with different K-F ring grades. An analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the least significant difference t-test （homogeneity of variance） or the Dunnett’s T3 test （heterogeneity of variance） was used for further multiple comparisons； the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups； the chi-square test was used for comparison of categorical data between groups. The Spearman correlation analysis was used to investigate the correlation of K-F ring grade with UWDRS， MoCA， and MMSE scores. ResultsAmong the 136 patients with WD， there were 40 patients with grade 4 K-F ring， accounting for the highest proportion of 29.4%， and 14 patients with grade 0 K-F ring， accounting for the lowest proportion of 10.3%， and there were 22 patients with grade 1 K-F ring （16.2%）， 19 with grade 2 K-F ring （14%）， 25 with grade 3 K-F ring （18.4%）， and 16 with grade 5 K-F ring （11.7%）. According to the different grades of K-F ring， there was a significant increase in UWDRS score （F=22.61， P<0.001） and significant reductions in MoCA and MMSE scores （F=16.40 and 13.80， both P<0.001）. The Spearman correlation analysis showed that K-F ring grade was positively correlated with UWDRS score （r=0.67， P<0.01） and was negatively correlated with MoCA and MMSE scores in WD patients （r=-0.59 and -0.57， both P<0.01）. ConclusionThe new K-F ring grading method can determine disease severity in WD patients to a certain degree and partially reflect cognitive function and activities of daily living in such patients.

Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.

The bioactivity-guided isolation of potentially active natural products has been widely utilized in pharmaceutical discovery. In this study, by screening fungal extracts against coxsackievirus B3 (CVB3), three new aspochalasins, templichalasins A‒C (1‒3), along with six known aspochalasins (4‒9) were isolated from an active extract derived from the endophytic fungus Aspergillus templicola LHWf045. Compound 1 features a unique 5/6/5/7/5 pentacyclic ring system, while compounds 2 and 3 possess unusual 5/6/6/7 tetracyclic skeletons. Their structures were characterized through extensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. Additionally, we demonstrated that compound 4 can be readily converted into compounds 1‒3 under mild acidic conditions and proposed a plausible mechanism for this conversion. Bioactivity evaluation of compounds 1‒9 against CVB3 revealed the inhibitory effects of all compounds against the virus. Notably, compound 9 exhibited superior antiviral activity, surpassing the commercial drug ribavirin in selectivity index (SI) value.
Antiviral Agents/isolation & purification* ; Aspergillus/chemistry* ; Molecular Structure ; Enterovirus B, Human/drug effects* ; Endophytes/chemistry* ; Cytochalasins/isolation & purification* ; Drug Discovery ; Humans

Wilson's disease （WD） is a copper metabolism disorder caused by mutations in the ATP7B gene， with diverse phenotypes and complex pathogenesis. It is one of the few rare diseases that can achieve good clinical efficacy through standardized treatment. Since there are few systematic reviews of this disease， we summarize the pathogenesis and treatment methods of WD from traditional Chinese and western medicine by reviewing the literature related to WD. In western medicine， ATP7B gene mutation is considered as the root cause of WD， which affects copper transport and causes copper metabolism disorders. The excessive copper deposited in the body will result in oxidative stress， defects in mitochondrial function， and cell death. Western medicine treatment of WD relies mainly on drugs， and copper antagonists are the first choice in clinical practice， which are often combined with hepatoprotective and antioxidant therapy. Surgery is a common therapy for the patients with end-stage WD， and gene therapy provides an option for WD patients. According to the traditional Chinese medicine （TCM） theory， WD is rooted in constitutional deficiency and copper accumulation and triggered by dampness-heat accumulation or phlegm combined with stasis. The patient syndrome varies in different stages of the disease， and thus the treatment should be based on syndrome differentiation. The TCM treatment method of nourishing the liver and kidneys and warming the spleen and kidneys can address the root cause. The methods of clearing heat and drying dampness， resolving phlegm and dispelling stasis， and soothing liver and regulating qi movement can be adopted to treat symptoms. On the basis of syndrome differentiation， special prescriptions for the treatment of WD have been formulated， such as Gandou decoction， Gandouling， and Gandou Fumu decoction， which have been widely used in clinical practice. TCM and western medicine have their own advantages and shortcomings. The integrated Chinese and western medicine complementing with each other demonstrates great therapeutic potential. This paper summarizes the pathogenesis and treatment of WD with integrated Chinese and western medicine， aiming to provide a reference for the clinical diagnosis and treatment of this disease.

Objective:To investigate the clinicopathological characteristics of early gastric cancer with mixed histological staging, and to analyze the prognostic effect of endoscopic submucosal dissection (ESD) for early gastric cancer.Methods:Clinical data of early gastric cancer patients treated with ESD in Gansu Wuwei Cancer Hospital from January 2011 to March 2020 were collected, and clinicopathological characteristics of patients with mixed-type early gastric cancer were analyzed by descriptive statistical methods. The clinical effects and influencing factors of ESD on early gastric cancer were analyzed by logistic regression. Kaplan-Meier was used to estimate the survival rate, and log-rank test was used to compare the survival rate.Results:A total of 269 patients (280 lesions) were included in this study, including 216 males (80.30%) and 53 females (19.70%), with age of 60.43±8.01 years. There were 25 lesions (8.93%) of mixed early gastric cancer, 248 lesions (88.57%) of differentiated early gastric cancer, and 7 lesions (2.50%) of undifferentiated early gastric cancer. Compared with differentiated and undifferentiated early gastric cancer, the lesion site of mixed early gastric cancer was mainly located in the upper 1/3 of the stomach [64.00% (16/25), 40.73% (101/248) VS 0.00% (0/7), χ2=10.211, P=0.006], the proportion of the lesion size ≤2 cm was relatively small [52.00% (13/25), 80.65% (200/248) VS 85.71% (6/7), χ2=11.173, P=0.004], and the proportion of infiltration depth in the mucosa was lower [52.00% (13/25), 85.48% (212/248) VS 57.14% (4/7), χ2=20.019, P<0.001], the proportion of positive vertical resection margin was relatively high [20.00% (5/25), 2.82% (7/248) VS 0.00% (0/7), χ2=16.657, P<0.001], the proportion of vascular invasion was higher than that of differentiated carcinoma but lower than that of undifferentiated carcinoma [36.00% (9/25), 2.42% (6/248) VS 42.86% (3/7), χ2=58.413, P<0.001], the complete resection rate was lower [76.00% (19/25), 93.15% (231/248) VS 100.00% (7/7), χ2=9.497, P=0.009], the curative resection rate was lower than that of differentiated early gastric cancer, but higher than that of undifferentiated early gastric cancer [48.00% (12/25), 89.52% (222/248) VS 42.86% (3/7), χ2=39.757, P<0.001], and the proportion of eCura grade C2 was higher than that of differentiated cancer, but lower than that of undifferentiated cancer [48.00% (12/25), 5.65% (14/248) VS 57.14% (4/7), χ2=58.766, P<0.001]. The results of multivariate analysis showed that the larger lesions ( P=0.004, OR=0.539, 95% CI: 0.354-0.822) was the risk factor for curative resection. In terms of infiltration depth, mucosal ( P=0.001, OR=51.799, 95% CI: 5.535-84.768) and submucosal 1 ( P<0.001, OR=29.301, 95% CI: 24.694-73.972) were protective factors for curative resection compared with submucosal 2. In terms of differentiation degree, compared with mixed type, differentiated type ( P=0.024, OR=3.947, 95% CI: 1.195-13.032) was the protective factor for curative resection, while undifferentiated type ( P=0.443, OR=0.424, 95% CI: 0.048-3.788) showed no difference between curative resection and mixed type. During the follow-up, 7 patients died. The overall survival time was 114.42±0.97 months, and the 5-year survival rate was 97.10%. There was no significant difference in the survival rate of early gastric cancer patients with different degrees of differentiation ( χ2=0.434, P=0.805). The survival rate of early gastric cancer patients with or without curative resection was significantly different ( χ2=4.081, P=0.043). Conclusion:Mixed early gastric cancer patients show high margin positive rate, vascular infiltration, and less curative resection than differentiated early gastric cancer. Therefore, the process of treating mixed early gastric cancer should be more rigorous. The long-term survival prognosis of early gastric cancer after ESD treatment is promising.

Objective To study the core behavioral symptoms,biological indicators,and pathological changes of a mouse model of breast cancer complicated with depression induced using 4T1 breast cancer cell inoculation combined with chronic restraint stress(CRS).Methods BABL/c mice were randomly divided into Control,Stress,Tumor,and stress combined with tumor(S+T)groups.Mice in the tumor and S+T groups were inoculated under the front legs with breast cancer 4T1 cells.After tumor formation,mice in the stress and S+T groups were subjected to CRS for 21 days.The body weight and food intake of each group were monitored during modeling.After the experiment,the occurrence of depression-like behavior of mice in each group was evaluated by sucrose preference test,open field test,elevated plus-maze test,and forced swimming test.After the mice were decapitated,the weights and volumes of the tumors were measured.Concentrations of serum tumor markers,including carbohydrate antigen(CA199),carcinoembryonic antigen(CEA),and vascular endothelial growth factor(VEGF),and related neurotransmitters,including 5-hydroxytryptamine(5-HT),norepinephrine(NE),and corticosterone(CORT),were determined using ELISA.HE staining was used to observe histopathological changes to the hippocampus and tumor.Results In S+T group mice,body weight and food intake were significantly decreased,tumor weight and volume were significantly increased,serum tumor marker(CA199,CEA,VEGF)levels were significantly increased,enthusiasm and desire to explore a new environment were reduced,stress and despair behaviors were significantly increased,and levels of the serum neurotransmitters 5-HT and NE and levels of CORT were significantly increased.In addition,the cell arrangement in the tumor tissue was loose,the amount of intercellular substance decreased,the pathological nuclear classification phase was increased,the arrangement and morphology of neurons in the CA3 region of the hippocampus were disordered,and there were obvious nuclear vacuolation-like changes.Conclusions A mouse model of breast cancer complicated with depression induced by 4T1 breast cancer cell inoculation combined with CRS showed the typical dual symptoms and biological indicators of breast cancer and depression and can be used as a good reference model for experimental studies of breast cancer complicated with depression.

Pathological mood changes,mainly depression,occurring during the diagnosis and treatment of breast cancer are referred to as breast cancer-related depression(BCRD).Numerous epidemiological and clinical studies have confirmed that BCRD is a complex condition that is difficult to treat and has a poor prognosis.Most existing clinical treatments involve the use of postoperative chemotherapy for breast cancer,and antidepressant drugs,which treat breast cancer and depression as two independent diseases and have various disadvantages such as low efficiency and strong adverse reactions.Traditional Chinese Medicine(TCM)has a unique value in the prevention and treatment of BCRD via its ability to regulate multiple pathways and targets using multiple components at the same time.In this paper,we review the mechanism of BRCD and the therapeutic mechanisms of TCM from the aspects of neurological disorders,inflammatory immune response,and intestinal flora disorders,with a view to providing references for the clinical application and research of TCM in the treatment of BCRD.

Objective:To investigate the efficacy and safety of tenofovir amibufenamide in patients over 65 years old with chronic hepatitis B and liver cirrhosis.Methods:We recruited 45 patients in Linyi People's Hospital with chronic hepatitis B and liver cirrhosis who were treated with TMF antiviral therapy for 48 weeks, compared the virologic response rate and HBV DNA decrease level at 12, 24 and 48 weeks, and the changes in hepatitis B surface antigen, alanine aminotransferase, glomerular filtration rate, creatinine, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum phosphorus and blood lipids, and the changes in ALT normalization rate at 48 weeks. P<0.05 was statistically significant. Results:The age of the enrolled patients was 69.0 (67.0, 72.5) years. At 12, 24, and 48 weeks of treatment, the complete virological response rates were 32.4% (12/37), 70.0% (28/40), and 84.6% (33/39) respectively, and the level of HBV DNA decreased from baseline ( P＜0.05). After 48 weeks of treatment, the level of HBsAg decreased ( P<0.05), and there was no negative HBsAg conversion and seroconversion. After 48 weeks of treatment, the level of ALT decreased ( P<0.05). At 48 weeks of treatment, the rates of ALT reverted to normality were 88.9% (16/18) and 70.4% (19/27), respectively. There was no significant difference in the levels of glomerular filtration rate, creatinine, phosphorus, triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol estimated at baseline before and after treatment ( P＞0.05), and no serious adverse events were observed. Conclusions:For patients over 65 years old with chronic hepatitis B and liver cirrhosis, TMF can significantly inhibit HBV DNA replication, and the ALT normalization rate is high and well tolerated.

Rare diseases, also known as orphan diseases, refer to a category of illnesses characterized by low prevalence, complex disease profiles, and severe symptoms. Rare diseases often manifest early in life, with symptoms frequently appearing in childhood. Among these conditions, changes in bone structure play a crucial role, and many rare diseases of this nature have a genetic basis and lack effective treatment modalities. With advances and breakthroughs in human gene research, the etiology of many rare diseases has been gradually uncovered. This paper reviews recent advances in gene therapy for rare pediatric bone diseases and its application in treating skeletal-related rare conditions. Special attention is directed towards cases such as osteogenesis imperfecta, X-linked hypophosphatemia and achondroplasia, and related gene therapy strategies are introduced. Osteogenesis imperfecta is primarily treated with bone marrow-derived mesenchymal stem cell transplantation and gene editing techniques, with experimental data validating their efficacy and safety; X-linked hypophosphatemic rickets has focused on FGF23 monoclonal antibodies, with clinical trials showing significant improvement in patient symptoms. Achondroplasia is primarily treated with small molecule tyrosine kinase inhibitors and C-type natriuretic peptide analogs, with research indicating these methods significantly improve bone growth. Although gene therapy research is still in its early stages, it provides hope for treating these rare diseases and may become a viable future treatment option for pediatric skeletal-related rare conditions.