Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Pharmacokinetics of traditional Chinese medicine(TCM)is a discipline that adopts pharmacokinetic research methods and techniques under the guidance of TCM theories to elucidate the dynamic changes in the absorption,distribution,metabolism and excretion of active ingredients,active sites,single-flavour Chinese medicinal and compounded formulas of TCM in vivo.However,the sources and components of TCM are complex,and the pharmacodynamic substances and mechanisms of action of the majority of TCM are not yet clear,so the pharmacokinetic study of TCM is later than that of chemical medicines,and is far more complex than that of chemical medicines,and its development also confronts with challenges.The pharmacokinetic study of TCM originated in the 1950s and has experienced more than 70 years of development from the initial in vivo study of a single active ingredient,to the pharmacokinetic and pharmacodynamic study of active ingredients,to the pharmacokinetic study of compound and multi-component of Chinese medicine.In recent years,with the help of advanced extraction,separation and analysis technologies,gene-editing animals and cell models,multi-omics technologies,protein purification and structure analysis technologies,and artificial intelligence,etc.,the pharmacokinetics of TCM has been substantially applied in revealing and elucidating the pharmacodynamic substances and mechanisms of action of Chinese medicines,research and development of new drugs of TCM,scientific and technological upgrading of large varieties of Chinese patent medicines,as well as guiding the rational use of medicines in clinics.Pharmacokinetic studies of TCM have made remarkable breakthroughs and significant development in theory,methodology,technology and application.In this paper,the history of the development of pharmacokinetics of TCM and the progress of cutting-edge research was reviewed,with the aim of providing ideas and references for the pharmacokinetics of TCM and related research.

Objective: To evaluate the secondary attack rates of the SARS-CoV-2 Omicron variant and the associated factors. Methods: A total of 328 primary cases and 40 146 close contacts of the SARS-CoV-2 Omicron variant routinely detected in local areas of Jiangsu Province from February to April 2022 were selected in this study, and those with positive nucleic acid test results during 7 days of centralized isolation medical observation were defined as secondary cases. The demographic information and clinical characteristics were collected, and the secondary attack rate (SAR) and the associated factors were analyzed by using a multivariate logistic regression model. Results: A total of 1 285 secondary cases of close contacts were reported from 328 primary cases, with a SAR of 3.2% (95%CI: 3.0%-3.4%). Among the 328 primary cases, males accounted for 61.9% (203 cases), with the median age (Q₁, Q₃) of 38.5 (27, 51) years old. Among the 1 285 secondary cases, males accounted for 59.1% (759 cases), with the median age (Q₁, Q₃) of 34 (17, 52) years old. The multivariate logistic regression model showed that the higher SAR was observed in the primary male cases (OR=1.632, 95%CI: 1.418-1.877), younger than 20 years old (OR=1.766, 95%CI: 1.506-2.072),≥60 years old (OR=1.869, 95%CI: 1.476-2.365), infected with the BA.2 strain branch (OR=2.906, 95%CI: 2.388-3.537), the confirmed common cases (OR=2.572, 95%CI: 2.036-3.249), and confirmed mild cases (OR=1.717, 95%CI: 1.486-1.985). Meanwhile, the higher SAR was observed in the close contacts younger than 20 years old (OR=2.604, 95%CI: 2.250-3.015),≥60 years old (OR=1.287, 95%CI: 1.052-1.573) and exposure for co-residence (OR=27.854, 95%CI: 23.470-33.057). Conclusion: The sex and age of the primary case of the Omicron variant, the branch of the infected strain, case severity of the primary case, as well as the age and contact mode of close contacts are the associated factors of SAR.
Humans ; Male ; Middle Aged ; Young Adult ; Adult ; COVID-19/epidemiology* ; Incidence ; SARS-CoV-2 ; Logistic Models

Objective: To evaluate the secondary attack rates of the SARS-CoV-2 Omicron variant and the associated factors. Methods: A total of 328 primary cases and 40 146 close contacts of the SARS-CoV-2 Omicron variant routinely detected in local areas of Jiangsu Province from February to April 2022 were selected in this study, and those with positive nucleic acid test results during 7 days of centralized isolation medical observation were defined as secondary cases. The demographic information and clinical characteristics were collected, and the secondary attack rate (SAR) and the associated factors were analyzed by using a multivariate logistic regression model. Results: A total of 1 285 secondary cases of close contacts were reported from 328 primary cases, with a SAR of 3.2% (95%CI: 3.0%-3.4%). Among the 328 primary cases, males accounted for 61.9% (203 cases), with the median age (Q₁, Q₃) of 38.5 (27, 51) years old. Among the 1 285 secondary cases, males accounted for 59.1% (759 cases), with the median age (Q₁, Q₃) of 34 (17, 52) years old. The multivariate logistic regression model showed that the higher SAR was observed in the primary male cases (OR=1.632, 95%CI: 1.418-1.877), younger than 20 years old (OR=1.766, 95%CI: 1.506-2.072),≥60 years old (OR=1.869, 95%CI: 1.476-2.365), infected with the BA.2 strain branch (OR=2.906, 95%CI: 2.388-3.537), the confirmed common cases (OR=2.572, 95%CI: 2.036-3.249), and confirmed mild cases (OR=1.717, 95%CI: 1.486-1.985). Meanwhile, the higher SAR was observed in the close contacts younger than 20 years old (OR=2.604, 95%CI: 2.250-3.015),≥60 years old (OR=1.287, 95%CI: 1.052-1.573) and exposure for co-residence (OR=27.854, 95%CI: 23.470-33.057). Conclusion: The sex and age of the primary case of the Omicron variant, the branch of the infected strain, case severity of the primary case, as well as the age and contact mode of close contacts are the associated factors of SAR.
Humans ; Male ; Middle Aged ; Young Adult ; Adult ; COVID-19/epidemiology* ; Incidence ; SARS-CoV-2 ; Logistic Models

ObjectiveTo investigate the effect of quantitative pulmonary administration of the essential oil from Alpiniae Zerumbet Fructus （EOAZF） on porcine pancreatic elastase （PPE）-induced emphysema in mice and explore its action mechanism. MethodC57BL/6J mice were randomly divided into five group， namely the control group， model group， low- （2 mg·kg^-1） and high-dose （20 mg·kg^-1） EOFAZ groups， and positive control dexamethasone （DEX，1 mg·kg^-1） group. The mice were treated with pulmonary administration of PPE using a microsprayer aerosolizer， once every seven days， for four times in total， for inducing emphysema. During this period， EOFAZ were administered with a quantitative microsprayer aerosolizer once every other day， for 14 times. The lung tissues were then sampled and stained with hematoxylin-eosin （HE） for observing the morphological changes and calculating the pulmonary mean linear intercept （MLI）. The concentrations of tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-6 （IL-6） in the plasma were determined by enzyme-linked immunosorbent assay （ELISA）. The activities of superoxide dismutase （SOD） and catalase （CAT） and the content of malondialdehyde （MDA） in the lung tissues were measured using the biochemical assay kits. The protein expression levels of nuclear factor E₂-related factor 2 （Nrf2）， quinone oxidoreductase1 （NQO1）， B cell lymphoma-2 （Bcl-2）-associated X protein （Bax）， and Bcl-2 in lung tissues were detected by Western blot. ResultThe results of lung morphological observation and MLI detection showed that compared with the control group， the model group showed obvious inflammatory infiltration， alveolar enlargement and fusion， and increased MLI （P<0.05）. Compared with the model group， EOFAZ effectively alleviated the pathological changes such as alveolar dilatation， pulmonary inflammatory cell infiltration， and lung cell apoptosis caused by PPE， and decreased the MLI （P<0.05）. As revealed by ELISA， the inflammatory level of mice in the model group increased significantly （P<0.01）， while the TNF-α， IL-1β， and IL-6 levels in the plasma were decreased after quantitative administration of EOFAZ （P<0.01）. Compared with the control group， the model group exhibited significantly enhanced oxidative stress （P<0.01）. After treatment with EOFAZ by quantitative administration， the activities of SOD and CAT in the lung tissue were increased （P<0.01） and the content of MDA was decreased （P<0.01）. Western blot results demonstrated that the apoptosis-related protein expression in the model group was increased significantly as compared with that in the control group （P<0.01）， whereas the expression levels of antioxidant stress proteins Nrf2 and NQO1 declined （P<0.05）. The relative protein expression of apoptosis-related proteins Bax/Bcl-2 in the EOFAZ groups was lower than that in the model group （P<0.01）， while the expression of antioxidant stress proteins Nrf2 and NQO1 was higher （P<0.05）. ConclusionQuantitative pulmonary administration of EOFAZ effectively alleviates the inflammation and oxidative stress， reduces lung cell apoptosis， and hinders the occurrence and development of emphysema. Its antioxidant mechanism is closely related to the up-regulation of Nrf2 and its downstream NQO1.

Objective: To observe the effect of moxibustion on the expression of N-methyl-D-aspartic acid (NMDA) receptor subtype 2B (NR2B) in the hippocampus of rheumatoid arthritis (RA) rats, and to explore the analgesic mechanisms of moxibustion in RA treatment. Methods: Sixty male Sprague-Dawley rats were randomly divided into a normal group, a model group, a moxibustion group, a moxibustion + NMDA receptor antagonist (AP-5) group, and a moxibustion + NMDA receptor agonist (NMDA) group, with 12 rats in each group. Except for the normal group, rats in the other four groups were treated with complete Freund's adjuvant in a windy, cold, and damp environment to replicate RA models. Rats in the moxibustion group received suspended moxibustion with moxa sticks at Shenshu (BL23) and Zusanli (ST36), and the two points were used alternately. After intraperitoneal injection of AP-5 or NMDA, rats in the moxibustion + AP-5 group and the moxibustion + NMDA group received the same moxibustion intervention as in the moxibustion group, once a day for 15 d. The thermal withdrawal latency (TWL) of rats in each group was detected before and after modeling and after the 15-day intervention. After the 15-day intervention, hematoxylin-eosin staining was performed to observe the pathological changes in knee joints. The real-time fluorescence quantitative polymerase chain reaction method was used to detect the mRNA expression of NR2B in the hippocampus; Western blotting assay was used to detect the protein and the phosphorylated protein expression of hippocampal NR2B. Results: The synovial tissue was proliferated, the synovial lining was significantly thickened, the pannus was formed, and the cartilage and bone tissues were significantly damaged in the model group. After intervention, the pathological morphology of the knee joints in the moxibustion group, the moxibustion + AP-5 group, and the moxibustion + NMDA group was significantly improved, and the improvement in the moxibustion + AP-5 group was more notable than that in the moxibustion + NMDA group. Compared with the normal group, the TWL was significantly decreased (P<0.01), and the mRNA, protein, and phosphorylated protein expression levels of hippocampal NR2B were significantly increased in the model group (P<0.01). Compared with the model group, the TWL of each intervention group was significantly increased (P<0.01 or P<0.05), and the mRNA, protein, and phosphorylated protein expression levels of hippocampal NR2B were significantly decreased (P<0.01). Compared with the moxibustion group, the TWL was significantly increased (P<0.01), and the mRNA, protein, and phosphorylated protein expression levels of hippocampal NR2B were significantly decreased in the moxibustion + AP-5 group (P<0.01); the TWL was significantly decreased (P<0.01), and the mRNA, protein, and phosphorylated protein expression levels of hippocampal NR2B were significantly increased in the moxibustion + NMDA group (P<0.01). Conclusion: Moxibustion reduces hyperalgesia in RA inflammatory rats. The analgesic effect may be related to the decrease in the expression and phosphorylation levels of NR2B in the hippocampus.

Aim To target the key proteins of TLR4 signaling pathway to sereen the compounds of Blumea baisamifera ( L.) DC.in order to explore the anti-in- flammatorv active components and the mechanism of action of key proteins targeting TLR4 signaling pathway in Blumea balsamifera( L.) DC.Methods The effects of ergosterol peroxide ( EP) on cell activity, LPS in¬duced inflammatory factor secretion and NF-kB related protein expression were detected by MTT, EL1SA, Western blot and Subcellular Structural Localization.Results The results showed EP, (3-sitosterol, 16- kaurene, carosterol, luteolin, ergosterol, hyperin and genkwa had more optimal interconnection score.EP (2.3 x 10"5 ~ 9.3 x 10 5 mol • L"1) inhibited the degradation and phosphorylation of inflammatory pro¬tein IkB and phosphorylation of NF-kB p65 down¬stream of TLR4 signaling pathway induced by LPS in BAW264.7 cells,and further inhibit the entrv of NF-kB p65 into the nucleus, thus inhibiting the secretion of cytokines IL-lp and 1L-6.Conclusions The antiin¬flammatory components of Blumea balsamifera ( L.) DC are identified by molecular docking technology and ac-tivity detection technique, and the anti-inflammatory action anrl mechanism of EP as active substances are e- luci dated.

A total of 18 batches of Zhuru Decoction samples were prepared. Chromatographic fingerprints were established for Zhuru Decoction and single decoction pieces, the content of which was then determined. The extraction rate ranges, content, and transfer rate ranges of puerarin, liquiritin, and glycyrrhizic acid, together with the common peaks and the similarity range of the fingerprints, were determined to clarify key quality attributes of Zhuru Decoction. The 18 batches of Zhuru Decoction samples had 25 common peaks and the fingerprint similarity higher than 0.95. Puerariae Lobatae Radix, Glycyrrhizae Radix et Rhizoma, and Zingiberis Rhizoma Recens had 21, 3, and 1 characteristic peaks, respectively. The 18 batches of samples showed the extraction rates within the range of 18.45%-25.29%. Puerarin had the content of 2.20%-3.07% and the transfer rate of 38.5%-45.9%; liquiritin had the content of 0.24%-0.85% and the transfer rate of 15.9%-37.5%; glycyrrhizic acid had the content of 0.39%-1.87% and the transfer rate of 16.2%-32.8%. In this paper, the quality value transmitting of substance benchmarks of Zhuru Decoction was analyzed based on chromatographic fingerprints, extraction rate, and the content of index components. A scientific and stable method was preliminarily established, which provided a scientific basis for the quality control and formulation development of Zhuru Decoction.
Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal/standards* ; Glycyrrhizic Acid/analysis* ; Quality Control ; Rhizome/chemistry*

Objective:To explore the features of free uroflow(FF) curve patterns in female patients with detrusor underactivity(DU) and their clinical significance.Methods:Data of 275 adult female patients with lower urinary tract symptoms(LUTS) underwent urodynamic studies(UDS) at urology center of our hospital from June 2014 to June 2016 were analyzed retrospectively. The uroflow curve patterns of patients with DU were classified and analyzed in the context of parameters of FF, cystometry (CM), and pressure-flow study(PFS). The prevalence of each abnormal uroflow curve pattern in DU patients were calculated and compared with those in non-DU patients.Results:No bell-shaped curve was found in 141 patients with DU. The abnormal curve patterns can be divided into 5 types: Type Ⅰ (bell-shaped curve with saw tooth) in 20 cases (14.2%), Type Ⅱ (box-like curve) in 34 cases (24.1%), Type Ⅲ (triangle curve with decreasing slop) in 62 cases(43.9%), Type Ⅳ (triangle curve with increasing slop) in 4 cases (4.3%), Type Ⅴ (tide-wave curve)in 19 cases (13.5%). Maximum flow rate of free uroflow(Q max.FF) of type Ⅰ [(28.4±9.7) ml/s] was significantly greater than that of type Ⅱ, Ⅲ and Ⅴ[(17.0±4.1), (15.8±5.4) and (12.9±6.4) ml/s, P<0.05]. Flow time of free uroflow(FT.FF) of type Ⅲ and Ⅴ [(43.7±17.2) and (50.1±28.9)s] were significantly longer than that of type Ⅰ and Ⅱ [(18.5±7.3)s and (27.2±9.7)s, P<0.05]. Post voided residual > 50ml was noted in 19 cases (30.6%) of type Ⅲ, 7 cases (36.8%) of type Ⅴ, 1 case (2.9%) of type Ⅱ and no one in type Ⅰ and Ⅳ. Abnormal manifestations in cystometry mainly included bladder hypersensitivity, detrusor overactivity, and stress urinary incontinence. Detrusor pressure at Q max (Pdet.Q max) of type Ⅴ [(7.4±5.0) cmH 2O] was significantly lower than that of type Ⅰ, Ⅱ, Ⅲ [(11.8±6.7), (12.0±5.3), (12.1±5.0) cmH 2O, P<0.05]. Among 134 cases of non-DU, there were type Ⅰ curves in 88 cases (65.7%), type Ⅱ curves in 4 cases (2.9%), type Ⅲ curves in 15 cases (11.2%), type Ⅳ curves in 1 cases (0.7%), type Ⅴ curves in 7 cases (5.2%). And normal bell-shaped curves in 19 cases(14.2%). The prevalence of type Ⅱ, Ⅲ and Ⅴ in DU patients was significantly higher than that in the non DU patients ( P<0.05). Conclusions:This study reveals that the characteristics of reduced detrusor contractility and duration, prolonged bladder emptying or incomplete emptying can be reflected in the patterns of free uroflow curve in female patients with DU. The abnormalities of these free uroflow curve patterns, especially type Ⅱ, Ⅲ and Ⅴ will be helpful in preliminarily screening DU in females.