Based on the thinking of programmatization and proceduralization， this study integrated traditional Chinese medicine （TCM） classic theories with modern knowledge expression technologies to construct a "formula-symptom" syndrome differentiation thinking model centered on "symptom clustering-main syndrome screening-formula adaptation"， and explored the standardization and intelligentization path of TCM syndrome differentiation and treatment. By establishing the mapping relationship model between formulas and syndromes including quantitative weight analysis of chief， deputy， assistant and envoy medicines， designing the logical hierarchical structure of formula-syndrome decision tree （application of three-level decision tree and fuzzy logic）， and formulating the procedural design of four diagnostic methods （structured collection， correlation model， and dynamic correction mechanism）， the standardization and visualization of the syndrome differentiation process are realized. This model can be transformed into the core data set for artificial intelligence training. Through ternary knowledge graph and machine learning algorithms， it can improve the repeatability of syndrome differentiation and the efficiency of diagnosis and treatment， and implement the strategy of "group model + individual modification" to balance the conflict between quantification and individualization. The core value of this model lies in promoting the objectification and precision development of TCM syndrome differentiation and treatment through the integration of traditional syndrome differentiation thinking and modern system science.

Perimenopause raises the risk and incidence of depression, whereas the underlying molecular mechanism remains unclear. Disturbed glucose regulation has been widely documented in depressive disorders, which renders the brain susceptible to various stresses such as estrogen depletion. However, whether and how glucose dysfunction regulates depression-like behaviors and neuronal damage in perimenopausal transition remains unexplored. Here, a prominent depressive phenotype was found in perimenopausal mice induced by the ovarian toxin 4-vinylcyclohexene diepoxide (VCD). The VCD depression susceptible group (VCD^SS) and the VCD depression resilient group (VCD^RES) were determined using a ROC-based behavioral screening approach. We found that the hippocampus, a crucial region linked to depression, had hyperglycemia and mitochondrial abnormalities. Interestingly, oral administration of the SGLT2 inhibitor empagliflozin (EMPA) and intrahippocampal glucose infusion suggest a close relationship between hyperglycemia in the hippocampus and the susceptibility to depression. We verified that cytochrome c oxidase 7c (COX7C) downregulation is a potential cause of the high glucose-induced neuronal injury using proteomic screening and biochemical validations. High glucose causes COX7C to be ubiquitinated in a S-phase kinase associated protein 1 (SKP1)-dependent manner. According to these results, SKP1/COX7C represents a unique therapeutic target and a novel molecular route for treating perimenopausal depression.

OBJECTIVE To systematically evaluate the clinical efficacy of dapagliflozin in the treatment of heart failure with diabetes mellitus type 2. METHODS The clinical trials of dapagliflozin in the treatment of heart failure with diabetes mellitus type 2 were searched in Embase, PubMed, Web of Science, Cochrane Library, VIP, CNKI and Wanfang databases from the establishment of the database to March 18, 2022. The RevMan 5.3 software was used for meta-analysis, and the TSA 0.9 software was used for sequential analysis. RESULTS The 31 RCT studies meeting the criteria were finally included, involving 2 906 patients. Meta-analysis showed that compared with the control group, the experimental group significantly improved LVEF[MD=4.43, 95% CI(3.35, 5.50), P<0.000 01], total effective rate[MD=4.19, 95%CI(2.52, 6.99), P<0.000 01], and reduced NT-proBNP[MD=–451.84, 95%CI(–608.09, –295.60), P<0.000 01], LVEDD[MD=–2.74, 95%CI(–3.67, –1.82), P<0.000 01, Hb1ac[MD=–0.88, 95%CI(–1.19, –0.57), P<0.000 01], FPG[MD=–1.10, 95%CI(–1.45, –0.75), P<0.000 01], 2hPG[MD=–2.52, 95%CI(–3.37, –1.66), P<0.000 01] and the incidence of adverse reactions[MD=0.63, 95%CI(0.47, 0.83), P=0.001]. Sequential analysis showed that the effect of dapagliflozin on LVEF in patients with heart failure with type 2 diabetes was accurate, and the possibility of excluding false positive was possible. CONCLUSION The treatment of heart failure with diabetes mellitus type 2 with good efficacy and safety is achieved by dapagliflozin, but it still needs to be included in more high-quality RCT studies for further demonstration.

Hand osteoarthritis(HOA)is a disease of hand joint disorders,mainly manifested by hand interphalangeal joint and thumb carpal metacarpal joint pain,swelling,morning stiffness,limited movement,and even deformity,belonging to the category of TCM"bone arthralgia".The authors believe that HOA is more common with Taiyang Shaoyang disease,suitable for simultaneous treatment for Taiyang and Shaoyang,to operate the cardinal,regulate qi,blood,nutritive and defensive levels,dispel wind and cold,remove dampness and arthralgia,using modified Chaihu Guizhi Decoction,with confirmed efficacy.

Lumbar disc herniation is mainly manifested as lower back pain,numbness,weakness,and radiating pain in the lower limbs,which seriously affects the patients'work and quality of life.In clinical practice,it has been found that this disease always belongs to the category of deficiency in healthy qi and excess in pathogenic factors,often accompanied by kidney deficiency and cold dampness.Kidney deficiency is the root cause,while cold dampness is the symptoms.The two factors interact with each other and cause back pain.The treatment is based on dispersing cold and dampness,tonifying the kidneys and strengthening the waist,and the classic ancient formula Shenzhuo Powder is safe and effective.

The aim of this study was to investigate the role of selenoprotein M (SelM) in endoplasmic reticulum stress and apoptosis in nickel-exposed mouse hearts and to explore the detoxifying effects of melatonin. At 21 d after intraperitoneal injection of nickel chloride (NiCl₂) and/or melatonin into male wild-type (WT) and SelM knockout (KO) C57BL/6J mice, NiCl₂ was found to induce changes in the microstructure and ultrastructure of the hearts of both WT and SelM KO mice, which were caused by oxidative stress, endoplasmic reticulum stress, and apoptosis, as evidenced by decreases in malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) activity. Changes in the messenger RNA (mRNA) and protein expression of genes related to endoplasmic reticulum stress (activating transcription factor 4 (ATF4), inositol-requiring protein 1 (IRE1), c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP)) and apoptosis (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Caspase-9, and Caspase-12) were also observed. Notably, the observed damage was worse in SelM KO mice. Furthermore, melatonin alleviated the heart injury caused by NiCl₂ in WT mice but could not exert a good protective effect in the heart of SelM KO mice. Overall, the findings suggested that the antioxidant capacity of SelM, as well as its modulation of endoplasmic reticulum stress and apoptosis, plays important roles in nickel-induced heart injury.
Animals ; Male ; Mice ; Antioxidants/pharmacology* ; Apoptosis ; Endoplasmic Reticulum Stress ; Melatonin/pharmacology* ; Mice, Inbred C57BL ; Nickel/adverse effects* ; Selenoproteins/genetics* ; Heart/drug effects*

Using chemoproteomic techniques, we first identified EIF2AK2, eEF1A1, PRDX3 and VPS4B as direct targets of berberine (BBR) for its synergistically anti-inflammatory effects. Of them, BBR has the strongest affinity with EIF2AK2 via two ionic bonds, and regulates several key inflammatory pathways through EIF2AK2, indicating the dominant role of EIF2AK2. Also, BBR could subtly inhibit the dimerization of EIF2AK2, rather than its enzyme activity, to selectively modulate its downstream pathways including JNK, NF-κB, AKT and NLRP3, with an advantage of good safety profile. In EIF2AK2 gene knockdown mice, the inhibitory IL-1β, IL-6, IL-18 and TNF-α secretion of BBR was obviously attenuated, confirming an EIF2AK2-dependent anti-inflammatory efficacy. The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target, and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammation-related disorders.

OBJECTIVE To optimize th e p rocessing technology of Portulaca oleracea charcoal，and to investigate its improvement effect on the symptom of hemorrhoid model rats. METHODS The effects of roasting temperature ，dosage and roasting time on the processing technology of P. oleracea charcoal were investigated with Box-Behnken response surface methodology using comprehensive score of tannin content ，water-soluble extract content and appearance properties as the index. The optimal process parameters are selected and verified. The hemorrhoid model rats were treated with P. oleracea charcoal（0.8 g/mL）prepared by the optimal processing technology ，once a day ，for 11 days. After last medication ，the perianal pathological score of hemorrhoid model rats were performed ；serum levels of tumor necrosis factor α（TNF-α），interleukin 6（IL-6）and IL- 1β were detected. RESULTS The optimal processing technology of P. oleracea charcoal included roasting temperature of 200 ℃， dosage of 150 g and roasting time of 14 min. Results of validation test showed that the comprehensive score of P. oleracea charcoal was 92.57，and relative error of it with predicted value （96.59）was －4.13％. External use of P. oleracea charcoal 0.8 g/mL prepared by the optimal processing technology could significantly promote the wound healing of hemorrhoid model rats ，reduced the amount of exudate ，and decreased the levels of TNF-α，IL-6 and IL-β in serum. CONCLUSIONS The optimized processing technology of P. oleracea charcoal is feasible. P. oleracea charcoal prepared by the optimized processing technology has good curative effect on the symptom of hemorrhoid model rats.

OBJECTIVE：To optimi ze the ratio of four comp onents of Compound renshen jianti formulation （Panax ginseng ， Dioscorea oppositifolia ，Lycium barbarum fruit，Alpinia oxyphylla ），and to investigate its anti-fatigue activity and acute toxicity. METHODS：The water extract of Compound renshen jianti formulation was prepared by water extraction ，concentration and decompression drying. By single factor tests ，using weight-bearing swimming time as index ，the effects of four factors were investigated，such as the amount of P. ginseng ，D. oppositifolia ，L. barbarum fruit，A. oxyphylla . On the basis of single factor tests，using comprehensive score of weight-bearing swimming time ，serum urea nitrogen content ，liver glycogen content and AUC of blood lactate after exercise as index ，the formulation was optimized by Box-Behnken response surface method. The mice was divided into blank control group （water），positive control group （Renshen hongjingtian capsules ，0.135 g/kg）and compound low-dose，medium-dose and high-dose groups [the optimal ratio of Compound renshen jianti formulation extract （called“optimal compound formulation ”for short ）4.08，8.16，12.24 g/kg，by crude drug] ，intragastric administration of drug or distilled water 20 mL/kg，once a day ，for consecutive 30 d. The weight-bearing swimming time ，the contents of serum urea nitrogen ，liver glycogen and blood lactate AUC after exercise were used to optimize its anti-fatigue activity of optimal compound formulation. The comprehensive score was calculated based on the measured data of mice in the compound formulation middle-dose group ， and the difference between it and the theoretical prediction value was compared. The mice were given optimal compound formulation intragastrically （total dose 16.00 g/kg， by extract）. The general state ， body mass change ， toxic characteristics and death of mice were observed and recorded for 14 days. Median lethal dose （LD50）and maximum tolerated dose （MTD）were measured. RESULTS ：The optimal formulation ratio of Compound renshen jianti formulation included that P. ginseng 1.5 g，D. oppositifolia 10 g，L. barbarum fruit 10 g，A. oxyphylla 3 g. Results of anti-fatigue activity validation test showed that the optimal compound formulation could significantly prolonged weight-bearing swimming time ，reduced serum content of urea nitrogen ，blood lactate content and its AUC （except for low-dose group ），while significantly increased the content of liver glycogen （P＜0.05 or P＜0.01）. Average comprehensive score of medium-dose group was 96.95，which was only 0.06％ different from the theoretical prediction value of 97.01. The results of acute toxicity test showed that there was no death in mice. The oral MTD of the optimal compound formulation was more than 15 g/kg，which was non-toxic. CONCLUSIONS ：The optimal Compound renshen jianti formulation has effective anti-fatigue activity of mice ，and has no significant toxic effect.

OBJECTIVE：To optimi ze the optimal composition proportion of 4 ingredients （Panax ginseng ，Astragalus membranaceus，Polygonatum sibiricum ，Lycium chinensis ）in Compound ginseng immune-enhancing formula （CGIF），and to study immune activity and acute toxicity of the extracts with the optimal ratio. METHODS ：The cell activity test was used to screen the crude drug concentration range of 4 ingredients. After treated with different crude drug concentrations of each medicinal material，using the contents of NO ，IL-6 and TNF-α as indexes，uniform design was used to determine the optimal ratio of each ingredient in CGIF. Totally 240 mice were taken and randomly divided into 4 batches，with 60 mice in each batch. Each batch of mice was randomly divided into blank group （normal saline ），model group （normal saline ），positive drug group [levamisole ，4 mg/（kg·d）]，and optimal proportion extract of CGIF low-dose ，medium-dose and high-dose groups [ 0.952 8，1.905 6，3.811 2 g/（kg·d）]，with 10 mice in each group ；they were given medicine intragastrically ，qd，for consecutive 30 d. Except for blank group，mice in the other groups were intraperitoneally injected with cyclophosphamide [ 40 mg/（kg·d）] on the 24th day after first administration，qd，for consecutive 3 d to induce immunocompromised model. The immune activity of the optimal proportion extract was evaluated by determining visceral coefficients ，spleen lymphocyte transformation capacity ，serum contents of hemolysin，IL-2，IgM，IgG and IgA ，phagocytosis function of peritoneal macrophages. Another 20 mice were collected and given the optimal proportion extract 20 mL/kg intragastrically ，twice；acute toxicity of the formula was investigated with oral maximum tolerated dose （MTD）. RESULTS ：The optimal ratio of CGIF was that crude drug mass ratio of P. ginseng ， membranaceus，P. sibiricum ，L. chinensis was 1 ∶ 2 ∶ 2 ∶ 4. The immunological activity experiment showed that theoptimal proportion extract can significantly improve visceral indexes of mice ， spleen lymphocyte proliferation ability serum contents of hemolysin ，IL-2，IgM，IgG and IgA as well as macrophage phagocy tosis ability （P＜0.05 or P＜ 0.01）. The acute toxicity test indicated that oral MTD was over 15 g/kg，which was non-toxic. CONCLUSIONS ：The optimal proportion extract of CGIF can significantly enhance the immune function of mice and are non-toxic.