Rheumatoid arthritis belongs to arthralgia in the theory of traditional Chinese medicine, with cold dampness obstruction pattern (CDO) and damp heat obstruction pattern (DHO) as the main pattern types. Fine therapeutic effects have been obtained in clinical practice following the differentiation of CDO and DHO. However, suitable animal models are not available currently. For adapting to the clinical diagnosis, as well as carrying out basic research of integrated Chinese and Western medicine and preclinical study on new Chinese medicine in a better way, the “Guidelines for Establishing Animal Models of Rheumatoid Arthritis with Cold Dampness Obstruction Pattern and Damp Heat Obstruction Pattern” (referred to as “Guidelines”) were compiled by our research group in cooperation with renowned experts in clinical, pharmaceutical, zoological, and methodological research fields. According to the theory of disease and syndrome integration, experts standardized the establishment methods for animal models of rheumatoid arthritis with CDO and DHO. The Guidelines were compiled via the nominal group method according to the principle of evidence coming in main place, consensus as the auxiliary, and experience as the references. Contents such as animal species, arthritis induction methods, external stimulation conditions, and assessment indicators were specified in the Guidelines based on the comprehensive evaluation of pathogenesis homology, behavioral phenotypic consistency, and drug therapy predictability between animal models and human diseases. The Guidelines will be applicable to the research on syndromes in rheumatoid arthritis, elucidation of acting mechanism, and development of new medicine, and provide reference for standardizing other types of animal models with the integration of disease and syndrome, to promote the modernization of Chinese medicine research.

Rheumatoid arthritis belongs to arthralgia syndrome in the theory of traditional Chinese medicine， and cold-dampness obstruction syndrome and dampness-heat obstruction syndrome are core syndromes and main syndrome differentiation types of this disease. Fine therapeutic effects have been obtained in the long-term clinical practice of many famous traditional Chinese medicine practitioners following the syndrome differentiation and treatment based on the guiding principles of cold and heat. To adapt to the clinical diagnosis practice of combining disease differentiation and syndrome differentiation， and to better carry out basic research on integrated Chinese and Western medicine and preclinical study on new traditional Chinese medicines， Guidelines for Establishing Animal Models of Rheumatoid Arthritis with Cold-Dampness Obstruction Syndrome and Dampness-Heat Obstruction Syndrome （hereinafter referred to as the Guidelines） were compiled by our research group， in cooperation with the renowned experts in research fields including traditional Chinese medicine， clinical medicine， zoology and evidence-based medicine， which provide a meaningful reference for scientific research， teaching and clinical applications. The compilation process of the Guidelines was guided by the theory of disease and syndrome integration and the principles of "evidence takes the main place， consensus plays an auxiliary role， and experience serves as the reference". Based on the comprehensive evaluation of pathogenesis homology， behavioral phenotypic consistency， and drug treatment predictability compared between animal models and human diseases， by the nominal group method， "recommendations" were formed for recommendations supported by evidence， and "consensus recommendations" were formed for recommendations not supported by evidence. Guidelines were formed involving content such as animal types， arthritis modeling methods， external stimulation conditions， and modeling assessment indicators during the establishment of the animal models of rheumatoid arthritis with cold-dampness obstruction syndrome and dampness-heat obstruction syndrome. The Guidelines are applicable for the disease and syndrome research on rheumatoid arthritis， investigation of therapeutic mechanisms， and development of new traditional Chinese medicine. The Guidelines also provide a reference for the establishment of guidelines on other types of diseases and syndromes combined with animal models to further promote the modernization of traditional Chinese medicine research and its integration with international academic development.

The Guidelines for Establishing Animal Models of Rheumatoid Arthritis with Cold-dampness Obstruction Syndrome and Dampness-heat Obstruction Syndrome （hereinafter referred to as the Guidelines） （No. T/CACM1567-2024） was published by Chinese Association of Chinese Medicine on January 11， 2024. To assist researchers and medical workers in understanding and applying the Guidelines more accurately， and also to provide reference and assistance for the establishment of guidelines on other types of diseases and syndromes combined with animal models， this paper made a declaration of the workflow， technological links， development references， promotion of its application and after-effect evaluation of the Guidelines that has been made according to the requirements of "Draft Group Standard of the Standardization Office of the Chinese Association of Traditional Chinese Medicine".

Yang being solid is an important summary of the normal functional state of yang qi in The Yellow Emperor's Inner Classic.Based on the theory of yang being solid and able to hold on,it is proposed that yang being solid is essential to maintain the state of tightness,thoroughness and quietness for maintaining the health of the human body.Yang losing its solidity is the core patho-genesis of the onset and progression of malignant tumors,which manifests as yang deficiency,yang depression and yang restlessness.If yang is not solid due to its deficiency,yang will lose its warmth and defense and the evil qi will be retained;if yang is not solid due to its depression,yang will lose its warmth and circulation and phlegm and stasis will gather;if yang is not solid due to its restlessness,yang will lose its tranquility,burn yin and consume essence.Aiming at the core pathogenesis of yang losing its solidity,the treatment methods of warming yang and replenishing qi to treat the disease before it occurs,unblocking yang and removing turbidity to disperse the staleness,and clearing and resolving restless yang to fight cancer and detoxify are used in clinical practice.Restoring the solidity of yang is taken as the goal of treating malignant tumors,which provides ideas for the clinical practice of treating malignant tumors with traditional Chinese medicine.

The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an in situ tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL⁺ B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual-conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL⁺ B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of αPD-1 and CAR-T therapies. The application of this in situ tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.

The activation of the sirtuin1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species (ROS) levels. Clinical trials have demonstrated that Zhongfeng Xingnao Liquid (ZFXN) ameliorates post-stroke cognitive impairment (PSCI). However, the underlying mechanism, particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway, remains unclear. This study employed an oxygen-glucose deprivation (OGD) cell model using SH-SY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation (2VO). The effects of ZFXN on learning and memory, neuroprotective activity, mitochondrial function, oxidative stress, and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro. Results indicated that ZFXN significantly increased the B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax) ratio, reduced terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL)⁺ cells, and markedly improved cognition, synaptic plasticity, and neuronal function in the hippocampus and cortex. Furthermore, ZFXN exhibited potent antioxidant activity, evidenced by decreased ROS and malondialdehyde (MDA) content and increased superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels. ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential (MMP), Tom20 fluorescence intensity, adenosine triphosphate (ATP) and energy charge (EC) levels, and mitochondrial complex I and III activity, thereby inhibiting mitochondrial damage. Additionally, ZFXN significantly increased SIRT1 activity and elevated SIRT1, nuclear Nrf2, and HO-1 levels. Notably, these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro. In conclusion, ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.
Sirtuin 1/genetics* ; Animals ; NF-E2-Related Factor 2/genetics* ; Cognitive Dysfunction/genetics* ; Male ; Rats, Sprague-Dawley ; Rats ; Humans ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/administration & dosage* ; Heme Oxygenase-1/genetics* ; Stroke/complications* ; Oxidative Stress/drug effects* ; Apoptosis/drug effects* ; Mitochondria/metabolism* ; Reactive Oxygen Species/metabolism* ; Neuroprotective Agents

Triggering receptor expressed on myeloid cells 2 (TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta (Aβ) clearance in Alzheimer's disease (AD). Energy metabolic reprogramming (EMR) in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD. Jiawei Xionggui Decoction (JWXG) has demonstrated effectiveness in enhancing energy supply, protecting microglia, and mitigating cognitive impairment in APP/PS1 mice. However, the mechanism by which JWXG enhances Aβ phagocytosis through TREM2-mediated EMR in microglia remains unclear. This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR. Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo. The EMR level of microglia was assessed using high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kits. The TREM2/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway was analyzed using Western blotting in BV₂ cells. TREM2^-/- BV₂ cells were utilized for reverse validation experiments. The Aβ burden, neuropathological features, and cognitive ability in APP/PS1 mice were evaluated using ELISA kits, immunohistochemistry (IHC), and the Morris water maze (MWM) test. JWXG enhanced both the phagocytosis of EMR disorder-BV₂ cells (EMRD-BV₂) and increased EMR levels. Notably, these effects were significantly reversed in TREM2^-/- BV₂ cells. JWXG elevated TREM2 expression, adenosine triphosphate (ATP) levels, and microglial phagocytosis in APP/PS1 mice. Additionally, JWXG reduced Aβ-burden, neuropathological lesions, and cognitive deficits in APP/PS1 mice. In conclusion, JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis, thereby reducing Aβ deposition, improving neuropathological lesions, and alleviating cognitive deficits.
Drugs, Chinese Herbal/pharmacology* ; Microglia/drug effects* ; Phagocytosis ; Cognitive Dysfunction/drug therapy* ; Metabolic Reprogramming ; Animals ; Mice ; Cell Line ; Receptors, Immunologic/metabolism* ; Membrane Glycoproteins/metabolism* ; Signal Transduction ; Amyloid beta-Peptides/metabolism* ; Energy Metabolism

OBJECTIVES: This study aims to explore the association between single nucleotide polymorphisms (SNPs) loci near the haplotype region hg19 chr9:100560865-100660865 of the forkhead box E1 (FOXE1) gene and the occurrence of non-syndromic cleft lip with or without cleft palate (NSCL/P) in western Han Chinese population. METHODS: In the first stage, our study recruited 159 NSCL/P patients and performed targeted region sequencing to screen SNPs loci near the haplotype region of the FOXE1 gene associated with NSCL/P. In the second stage, we selected 21 common SNPs and re-enrolled 1 000 non-syndromic cleft lip only (NSCLO) patients, 1 000 non-syndromic cleft palate only (NSCPO) patients, and 1 000 normal controls to verify the association. PLINK software was used to perform Hardy-Weinberg equilibrium (HWE) test. Association analysis for common variants, gene burden analysis for rare mutations, and function prediction of SNPs with non-synonymous mutations were performed using Mutation Taster and other software programs. RESULTS: In the first stage, 126 variants, including 76 single nucleotide variants and 50 insertion-deletions were identified. All the included SNPs confirmed to HWE, and the results of gene burden analysis and prediction of functional harmfulness for rare variants were not statistically significant. Association analysis showed that rs13292899 of the FOXE1 gene was significantly associated with NSCL/P (P=1.85E-27) and was also correlated with NSCLO (P=6.41E-23) and non-syndromic cleft lip with cleft palate (NSCLP) (P=2.36E-15) subtypes. In the validation phase, rs79268293 (P=0.013, P=0.022), rs10983951 (P=0.009 2, P=0.007 6), rs117227387 (P=0.009 2, P=0.007 6), rs3758250 (P=0.009 2, P=0.007 6), and rs116899397 (P=0.009 2, P=0.007 6) were significantly associated with NSCLO and NSCPO; rs13292899 (P=0.008 5), rs74606599 (P=0.008 3), rs143226042 (P=0.008 3), and rs117236550 (P=0.01) were associated with the occurrence of NSCLO; and rs12343182 (P=0.008 7), rs10119760 (P=0.012), rs10113907 (P=0.012), and rs13299924 (P=0.012) were associated with the occurrence of NSCPO. CONCLUSIONS This study found a new susceptible SNP rs13292899 of the FOXE1 gene that is closely associated with NSCL/P and NSCLO subtype and 13 other SNPs associated with NSCLO or NSCPO.
Female ; Humans ; Male ; China ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Forkhead Transcription Factors/genetics* ; Haplotypes ; Polymorphism, Single Nucleotide ; East Asian People/genetics*

Drug addiction is a serious public health problem worldwide,for which there are currently no established therapeutic medications.Since the legalization of cannabis and the approval of cannabidiol(CBD)by the US Food and Drug Administration,its therapeutic potential for the treatment of substance abuse has been widely explored.Numerous studies have shown that CBD can reduce drug reward in animal models of addiction such as self-administration,conditioned positional preference,and intracranial self-stimulation.CBD can also reduce withdrawal symptoms from substances such as amphetamines,opioids,cocaine,marijuana,alcohol,and nicotine.The mechanisms by which CBD modulates drug addiction,however,are complex and understudied.Here we review studies of CBD related to addictive drugs to clarify the regulatory mechanisms of CBD in drug addiction and provide references for related studies on substance abuse.

Objectives:To summarize the characteristics of Fabry′s disease with cardiac involvement.Methods:This was a single-center, cross-sectional, retrospective study. Patients with Fabry disease who were admitted to Zhongda Hospital Affiliated to Southeast University from January 2022 to March 2023 were included. Clinical data, laboratory results, electrocardiogram, echocardiography and cardiac magnetic resonance findings of enrolled patients were collected. Clinical presentations and imaging features of patients with Fabry′s disease with cardiac involvement were summarized and analyzed.Results:A total of 17 patients from 8 families were included, with 9 males and diagnosis age of (44.35±13.72) years. Cardiac involvement and other organ involvement were presented in all patients and the heart was the most vulnerable organ (17/17). 24 h electrocardiogram showed frequent sinus arrhythmia in 3 patients. Echocardiography showed reduced left ventricular ejection fraction in 1 patient, myocardial hypertrophy in 13 patients, and left ventricular wall thickness ≥13 mm in 10 patients. Mitral regurgitation was observed in 11 patients and tricuspid regurgitation in 12 patients. Two patients underwent two-dimensional speckle tracking echocardiography, both revealing reduced regional longitudinal strain of the left ventricle, primarily in the basal segments. Cardiac magnetic resonance showed reduced left ventricular ejection fraction in 2 patients, myocardial hypertrophy in 16 patients, and left ventricular wall thickness≥13 mm in 14 patients. T1 value was reduced in 16 patients, with late gadolinium enhancement observed in 9 patients and “pseudo-normalization” of T1 values in 1 patient. The most susceptible target organ besides the heart was the kidneys (14/17), followed by the central nervous system (9/17). Additional findings inclucling cutaneous angiokeratoma in 4 patients, peripheral neuropathy with burning pain and hypohidrosis or hyperhidrosis in 6 patients, and corneal vortex opacities in 2 patients.Conclusion:The main manifestations of cardiac involvement in Fabry′s disease are decreased cardiac function, left ventricular hypertrophy and myocardial fibrosis. Advanced imaging techniques such as two-dimensional speckle tracking, T1 Mapping, and late gadolinium enhancement are useful in detecting myocardial pathological changes of Fabry′s disease.