BACKGROUND:Intestinal acute graft-versus-host disease is one of the most aggressive complications after allogeneic hematopoietic stem cell transplantation with high lethality.How to improve intestinal inflammation and regulate autophagy by applying traditional Chinese medicine in order to treat intestinal acute graft-versus-host disease is a worthwhile research issue nowadays. OBJECTIVE:To investigate the mechanism of Huangqintang modulating intestinal flora for the treatment of intestinal acute graft-versus-host disease. METHODS:CB6F1 mice were irradiated with 60Co X radiation at a total dose of 8 Gy,and then single nucleated cell suspensions(bone marrow cells+splenocytes)from Balb/c H-2d mice were injected into the tail vein in order to prepare a model of intestinal acute graft-versus-host disease.These samples were randomly divided into the model group and the high-,moderate-,and low-dose Huangqintang groups.After modeling,the model,high-,moderate-,and low-dose groups received different doses of Huangqintang or an equal volume of saline by continuous gavage for 14 days.Clinical acute graft-versus-host disease grading,and survival time was recorded.Small intestinal tissues from each group were stained with hematoxylin and eosin for small intestinal mucosal pathology scoring.The intestinal flora of mice in each group was detected using 16S rDNA sequencing.Autophagy-related markers were detected using immunofluorescence,immunohistochemistry,and PCR. RESULTS AND CONCLUSION:(1)Compared with the model group,the survival time of mice was significantly prolonged(P<0.01);the clinical acute graft-versus-host disease scores were significantly reduced(P<0.01);the pathological grading scores of the small intestinal mucosa were significantly diminished(P<0.01);the levels of the small intestinal tissue inflammatory factors tumor necrosis factor-α,interleukin-1β,and interleukin-6,were significantly decreased(P<0.01);the structural integrity of the small intestinal mucosal epithelium was partially restored in mice after the intervention of moderate and high-dose Huangqintang.(2)The study of intestinal flora found that compared with the model group,the pro-inflammatory strain Enterococcus was significantly reduced(P<0.05),while beneficial bacteria such as Clostridium_innocuum and Rhodococcus,a pro-autophagy bacterium,were significantly elevated(P<0.05)in the moderate-dose Huangqintang group.(3)Compared with the model group,the autophagy markers were significantly elevated in the moderate-dose Huangqintang group(P<0.05);under transmission electron microscopy,the number of autophagic vacuoles of moderate-dose Huangqintang group increased significantly.(4)The results showed that Huangqintang significantly reduced the abundance of conditionally pathogenic bacteria and the level of inflammatory factors in small intestinal tissues,and increased the relative abundance of beneficial bacteria and promoted the expression of autophagy in the small intestinal mucosa,which resulted in a significant improvement of intestinal symptoms in mice with acute graft-versus-host disease.

The Expert Consensus on Clinical Application of Qinbaohong Zhike Oral Liquid in Treatment of Acute Bronchitis and Acute Attack of Chronic Bronchitis （GS/CACM 337-2023） was released by the China Association of Chinese Medicine on December 13^th， 2023. This expert consensus was developed by experts in methodology， pharmacy， and Chinese medicine in strict accordance with the development requirements of the China Association of Chinese Medicine （CACM） and based on the latest medical evidence and the clinical medication experience of well-known experts in the fields of respiratory medicine （pulmonary diseases） and pediatrics. This expert consensus defines the application of Qinbaohong Zhike oral liquid in the treatment of cough and excessive sputum caused by phlegm-heat obstructing lung， acute bronchitis， and acute attack of chronic bronchitis from the aspects of applicable populations， efficacy evaluation， usage， dosage， drug combination， and safety. It is expected to guide the rational drug use in medical and health institutions， give full play to the unique value of Qinbaohong Zhike oral liquid， and vigorously promote the inheritance and innovation of Chinese patent medicines.

Glaucoma is a multifactorial degenerative optic neuropathy, and its irreversible and blinding pathological characteristics mainly come from the damage to the optic nerve, namely glaucomatous optic neuropathy(GON). The difficulty in the treatment of GON lies in the early intervention, and currently there is no optic neuroprotective drug for the treatment of all types of GON. The death of retinal ganglion cells(RGCs)is the core pathological change caused by various pathogenic mechanisms of GON. Recent studies have found that the widespread second messenger cyclic adenosine 3', 5' -monophosphate(cAMP)and its downstream effector protein kinase A(PKA)signal cascade play an important role in the pathogenesis of GON. It can also inhibit the apoptosis of RGCs and play a protective and therapeutic role in glaucoma. Therefore, this article reviews the role of cAMP/PKA pathway in the pathophysiological development of GON, focusing on its effects on glaucoma intraocular pressure regulation, oxidative stress, neuroinflammation and optic nerve degeneration, in order to find a common central regulatory target for the optic nerve damage caused by different pathological mechanisms of GON and promote the further understanding and clinical treatment of this disease.

Background::While type 2 diabetes mellitus (T2DM) is considered a putative causal risk factor for coronary artery disease (CAD), the intrinsic link underlying T2DM and CAD is not fully understood. We aimed to highlight the importance of integrated care targeting both diseases by investigating the phenotypic and genetic relationships between T2DM and CAD.Methods::We evaluated phenotypic associations using data from the United Kingdom Biobank ( N = 472,050). We investigated genetic relationships by leveraging genomic data conducted in European ancestry for T2DM, with and without adjustment for body mass index (BMI) (T2DM: Ncase/ Ncontrol = 74,124/824,006; T2DM adjusted for BMI [T2DM adjBMI]: Ncase/ Ncontrol = 50,409/523,897) and for CAD ( Ncase/ Ncontrol = 181,522/984,168). We performed additional analyses using genomic data conducted in multiancestry individuals for T2DM ( Ncase/ Ncontrol = 180,834/1,159,055). Results::Observational analysis suggested a bidirectional relationship between T2DM and CAD (T2DM→CAD: hazard ratio [HR] = 2.12, 95% confidence interval [CI]: 2.01–2.24; CAD→T2DM: HR = 1.72, 95% CI: 1.63–1.81). A positive overall genetic correlation between T2DM and CAD was observed ( rg = 0.39, P = 1.43 × 10 -75), which was largely independent of BMI (T2DM adjBMI–CAD: rg = 0.31, P = 1.20 × 10 –36). This was corroborated by six local signals, among which 9p21.3 showed the strongest genetic correlation. Cross-trait meta-analysis replicated 101 previously reported loci and discovered six novel pleiotropic loci. Mendelian randomization analysis supported a bidirectional causal relationship (T2DM→CAD: odds ratio [OR] = 1.13, 95% CI: 1.11-1.16; CAD→T2DM: OR = 1.12, 95% CI: 1.07-1.18), which was confirmed in multiancestry individuals (T2DM→CAD: OR = 1.13, 95% CI: 1.10-1.16; CAD→T2DM: OR = 1.08, 95% CI: 1.04-1.13). This bidirectional relationship was significantly mediated by systolic blood pressure and intake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with mediation proportions of 54.1% (95% CI: 24.9-83.4%) and 90.4% (95% CI: 29.3-151.5%), respectively. Conclusion::Our observational and genetic analyses demonstrated an intrinsic bidirectional relationship between T2DM and CAD and clarified the biological mechanisms underlying this relationship.

Background::Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods::Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan–Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. Results::HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF) -β pathway-related genes and Treg signature genes ( CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. Conclusions::HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Background::Pancreatic ductal adenocarcinoma (PDAC) is one of the main types of malignant tumor of the digestive system, and patient prognosis is affected by difficulties in early diagnosis, poor treatment response, and a high postoperative recurrence rate. Carbohydrate antigen 19-9 (CA19-9) has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients. Nevertheless, the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated.Methods::We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC (three CA19-9-positive and three CA19-9-negative PDAC samples) and two paracarcinoma samples. We also downloaded and integrated PDAC samples (each from three CA19-9-positive and CA19-9-negative patients) from an online database. The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence. Moreover, we built an in vitro coculture cellular model to confirm the potential function of CA19-9. Results::Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A, AQP5, and MUC5AC. CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts (apCAFs). Importantly, the proportion of immature ficolin-1 positive (FCN1+) macrophages was high in the CA19-9-negative group, and the proportion of mature M2-like macrophages was high in the CA19-9-positive group. High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis. Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment. Conclusions::Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC. CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.

Enteropathogenic Escherichia coli(EPEC),a zoonotic foodborne pathogen,can induce severe and prolonged di-arrhea,thus substantially affecting global public health safety.To understand the pathogenicity of EPEC and its potential risk to human health,this study investigated the antimicrobial resistance and genome-wide characteristics of EPEC originating from ducks.After identification of EPEC with the plate method and PCR,antimicrobial susceptibility of the isolates was examined with the microbroth dilution method.In addition,analyses of serotype,sequence type(ST),and plasmid incompatibility groups were conducted with whole-genome sequencing(WGS)and bioinformatic methods.Ten EPEC isolates were identified,including serotypes O71∶H40 and O3∶H21.All EPEC strains exhibited multiple drug resistance.The highest proportion of resistance(100％)was observed to ciprofloxacin,streptomycin,tetracycline,and polymyxin B.In contrast,the isolates showed susceptibility to cefoxitin,amikacin,and imipenem.Furthermore,all strains carried the tetracycline resistance gene tet(A)and extended-spectrum β-lactamase(ESBL)resistance genes,including blaOXA-10,blaTEM-1A,and blaTEM-1B.Various virulence genes,associated primarily with the secretory system,were de-tected in the isolates.However,no bf p genes or per ARC genes were identified,thus indicating that the EPEC isolates were atypical EPEC(aEPEC).The results demonstrated the presence of multiple antimicrobial resistance,multiple resistance and viru-lence genes,and various plasmid incompatibility groups,thus in-dicating potential pathogenicity to humans.Strengthened monitoring of duck-derived EPEC is crucial to effectively control the spread of the pathogen and safeguard public health.

In accordance with the One Health concept,this study was aimed at exploring research trends and major topics in global zoonotic diseases,and providing suggestions for the prevention and control of zoonotic diseases in China.Using biblio-metric analysis,we analyzed 289 411 relevant articles in the SCIE database from 2012 to 2022 in the field of zoonotic diseases.We conducted in-depth analysis of publication trends,research themes,and cutting-edge topics in the field of zoonotic diseases.The number of publications in the field of zoonotic diseases has significantly increased since 2019.The United States had the most publications in this field,and was followed by China,which has shown strong growth.Further analysis of co-occurrence clustering of keywords in 7 115 highly cited articles in zoonotic diseases in the past 11 years revealed three major research themes:animal health,human health,and environmental health,according to the One Health concept.Keyword evolution a-nalysis showed that zoonotic disease articles were broadly related to issues such as"food safety"and"microbial resistance"in earlier years,whereas"COVID-19,""COVID-19 variants,"and"COVID-19 vaccine"have become recent research hotspots.Practicing the One Health concept and promoting interdisciplinary,interdepartmental,and interregional collaboration are crucial for enhancing the prevention and control of zoonotic diseases in China,thereby safeguarding national security,public health,and ecological safety.

Schizophrenia is a common chronic mental disorder.Cognitive dysfunction is one of its core symptoms,which severely affects the social functioning of patients.Currently,antipsychotic medication treatments have poor efficacy in improving cognitive functions.Recent studies have found that metformin can improve cognitive dysfunction in patients with schizophrenia.However,the mechanism of action remains unclear.This review summarizes the therapeutic effects of metformin on cognitive dysfunction in schizophrenia patients such as improving insulin resistance,repairing neuronal damage,regulating neuroimmunity,and combating oxidative stress,thereby providing new insights for the treatment of cognitive dysfunction in schizophrenia.

Objective A comparison of different routes for the administration of clodronate disodium liposomes to determine the most effective method of rat endometrial macrophage clearance.Methods Female 8-week-old SD rats were randomly divided into a unilateral control group(injected with 100 μL PBS liposomes into the left uterine cavity),unilateral clearance group(injected with 100 μL clodronate liposomes into the right uterine cavity),bilateral control group(injected with 100 μL PBS liposomes into the bilateral intrauterine),bilateral clearance group(injected with 100 μL clodronate liposomes into the bilateral intrauterine),whole-body control group(injected with 500 μL PBS liposomes into the caudal vein),and whole-body clearance group(injected with 500 μL clodronate liposomes into the caudal vein).Hematoxylin and eosin staining was used to observe the morphology and structures of uterine and ovarian tissues,immunohistochemistry was used to observe the presence of macrophages in uterine and ovarian tissues,and flow cytometry was used to detect changes to macrophage cell counts in uterine and ovarian tissues.Results There were no significant differences in the structures or morphology of the uterus and ovary among the groups.Immunohistochemical staining showed that,compared to the control group,the unilateral and bilateral uterine clearance groups'population of terine macrophages was significantly decreased(P＜0.001),but there was no difference in the accumulation of macrophages in the ovary(P＞0.05).The number of macrophages in both uterine and ovarian tissues decreased in the whole-body clearance group(P＜0.01,P＜0.01).Compared with the unilateral and bilateral clearance groups,the whole-body clearance group had more macrophages in the ovarian tissues(P＜0.05).Flow cytometry showed that,compared with the control group,each clearance group's percentages of macrophages in the uterine tissue were significantly reduced(P＜0.001,P＜0.001,P＜0.05).Compared to the whole-body clearance group,the unilateral and bilateral clearance groups'endometrial macrophages had superior clearance activity(P＜0.05,P＜0.05).In addition,the number of macrophages in ovarian tissue decreased in all clearance groups compared to the control group.The decrease in macrophage number was most pronounced in the whole-body clearance group(P＜0.05),and there was no significant difference in numbers between the unilateral and bilateral clearance groups and the control group(P＞0.05).Conclusions Local injection of clodronate liposomes was more effective than caudal injection for clearing uterine macrophages,and the impact on ovarian macrophages was largely avoided.Thus local clodronate liposome injection is an improved method for establishing a local uterine macrophage clearance model.