Psoriasis is an incurable chronic inflammatory disease that requires new interventions. Here, we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis. The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models. Mechanistically, celastrol directly bound to the low-density lipoprotein receptor-related protein 1 (LRP1) β-chain and abolished its binding to the transcription factor c-Jun in the nucleus, which in turn inhibited CCL2 production by skin fibroblasts, blocked fibroblast-macrophage crosstalk, and ameliorated psoriasis progression. Notably, fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation. Taken together, from clinical samples and combined with various mouse models, we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk, and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.

Objective : To explore the risk factors of biliary stricture after liver transplantation and to construct a nomogram prediction model. Methods : The clinical data of 208 liver transplant recipients in hospital were retrospectively analyzed, including 54 cases in the biliary stricture group and 154 cases in the non-biliary stricture group. Multivariate Logistic regression analysis was used to screen out independent predictors, fit the prediction model and construct a visual nomogram to evaluate the prediction model. Survival curves were drawn and multivariate Cox regression analysis was performed. Results : Autoimmune liver diseases(OR=6.610,95%CI: 1.410-30.99), alanine aminotransferase(ALT)(OR=1.007,95%CI: 1.003-1.011), warm ischemia time(OR=1.972,95%CI: 1.399-2.780), cold ischemia time(OR=1.016,95%CI: 1.010-1.022), cytomegalovirus infection(OR=6.037,95%CI: 1.480-24.63) and hepatic vascular stenosis(OR=7.784,95%CI: 2.312-26.20) were independent predictors of biliary stricture after liver transplantation. The area under the curve(AUC) of the nomogram prediction model was 0.921, the cut-off value was 0.238, the sensitivity was 0.889, and the specificity was 0.838. The model showed good discrimination. The Brier score was 0.092, Hosmer-Lemeshow goodness-of-fit testP=0.253, Calibration curve(B=1 000) was in good agreement, and the model showed good calibration. Decision curve analysis(DCA) showed that the application of the model could benefit liver transplant recipients. The postoperative follow-up time was 27-60 months. The cumulative survival rate of the non-biliary stricture group was better than that of the biliary stricture group(P=0.019), but multivariate Cox regression analysis showed that biliary stricture(HR=1.194, 95%CI: 0.624-2.285) was not an independent risk factor for survival after liver transplantation. Conclusion The nomogram model based on autoimmune liver diseases, ALT, warm ischemia time, cold ischemia time, cytomegalovirus infection and hepatic vascular stenosis performs well and can be used to predict the occurrence of biliary stricture after liver transplantation.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons (MNs) with large unmet medical needs. Multiple pathological mechanisms are considered to contribute to the progression of ALS, including neuronal oxidative stress and mitochondrial dysfunction. Honokiol (HNK) has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke, Alzheimer's disease and Parkinson's disease. Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo. Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins (SOD1-G93A cells for short). Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione (GSH) synthesis and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway. Also, honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells. Importantly, honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function. The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice. Overall, honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.

Objective:To explore the risk factors of acute kidney injury(AKI)after liver transplantation(LT), examine its prognostic impact and construct a clinical prediction model.Methods:Clinical data are retrospectively reviewed for 220 LT recipients.They are divided into two groups of AKI(93 cases)and non-AKI(127 cases)according to the occurrence of AKI post-LT.Clinical data of two groups are compared.The variables with statistically significant inter-group differences in univariate analysis are included for multivariate analysis for obtaining the independent risk factors for AKI post-LT.Then the independent risk factors are employed for fitting a prediction model and a visual nomogram is constructed.At the same time, discrimination and calibration of the prediction model are evaluated.Extubation time, length of intensive care unit(ICU)stay, continuous renal replacement therapy(CRRT)rate, length of hospital stay, in-hospital mortality, estimated glomerular filtration rate(eGFR)at discharge, incidence of chronic renal failure(CRF)and readmission times are compared between two groups.Survival analysis is also performed between AKI and non-AKI groups and AKI 0/1 and AKI 2/3 stages.Results:The incidence of AKI post-LT is 42.3%.Age( OR=1.036, 95% CI: 1.001~1.073), preoperative serum creatinine level( OR=1.030, 95% CI: 1.011~1.049), platelet count( OR=0.992, 95% CI: 0.985~0.999), Child-Pugh class C( OR=2.678, 95% CI: 1.031~6.952), postoperative abdominal infection( OR=2.271, 95% CI: 1.120~4.603)and abdominal hemorrhage( OR=3.869, 95% CI: 1.016~14.72)are independent risk factors for AKI post-LT.The AUC/C-index of nomogram prediction model is 0.789 with a Brier score of 0.183, showing decent discrimination and calibration.According to the nomogram score, the recipients with a risk of AKI>50% are included into high-risk group while those with a risk of AKI<50% into low-risk group.Postoperative survival of low-risk group is better than that of high-risk group( P<0.001).Compared with non-AKI group, AKI group had a later extubation time( P=0.003), a longer length of ICU stay( P<0.001)and hospital stay( P=0.001), a higher rate of CRRT usage( P<0.001)and in-hospital mortality( P<0.001), a lower eGFR at discharge( P<0.001)and a higher incidence of CRF( P<0.001).Postoperative survival of non-AKI group was better than that of AKI group( P=0.048).Postoperative survival of patients with AKI 0/1 is better than that of those with AKI 2/3( P=0.002). Conclusions:Advanced age, high preoperative serum creatinine, low preoperative platelet, poor preoperative liver function, postoperative abdominal infection and abdominal hemorrhage may elevate the risks of AKI post-LT.And the nomogram prediction model based upon the above risk factors has a high value of clinical application.

Natural products, and especially the active ingredients found in traditional Chinese medicine (TCM), have a thousand-year-long history of clinical use and a strong theoretical basis in TCM. As such, traditional remedies provide shortcuts for the development of original new drugs in China, and increasing numbers of natural products are showing great therapeutic potential in various diseases. This paper reviews the molecular mechanisms of action of natural products from different sources used in the treatment of inflammatory diseases and cancer, introduces the methods and newly emerging technologies used to identify and validate the targets of natural active ingredients, enumerates the expansive list of TCM used to treat inflammatory diseases and cancer, and summarizes the patterns of action of emerging technologies such as single-cell multiomics, network pharmacology, and artificial intelligence in the pharmacological studies of natural products to provide insights for the development of innovative natural product-based drugs. Our hope is that we can make use of advances in target identification and single-cell multiomics to obtain a deeper understanding of actions of mechanisms of natural products that will allow innovation and revitalization of TCM and its swift industrialization and internationalization.

Objective:To analyze the case characteristics and outcomes of 12 idiopathic giant cell myocarditis(IGCM)cases after heart transplantation(HT).Methods:From June 2004 to May 2022, clinical data were retrospectively reviewed for 12 cases with pathologically confirm IGCM after HT at Fuwai Hospital.General characteristics, clinical manifestations, pathological examinations and postoperative follow-ups are recorded.Results:From June 2004 to May 2022, a total of 1 143 HT operations are performed at Fuwai Hospital and 12 cases of IGCM(1.05%)are confirmed by postoperative pathology.The age is(47.6±7.3)years.There are 5 boys and 7 girls.Initial presenting manifestations are congestive heart failure(7 cases, 58.3%)and arrhythmia(4 cases, 33.3%). Median time from symptom onset to HT is 6 months.All of them are undiagnosed pre-operation.And dilated cardiomyopathy(5 cases, 41.7%)and arrhythmogenic right ventricular cardiomyopathy(3 cases, 25%)are confirmed.The follow-up period is(4~142)months post-HT.One death occurred during perioperative period and another is due to heart failure at 68 months post-HT.Only 1 case of grade 1R transplant heart rejection occurrs at 9 years post-HT and there is no case of recurrence.According to Kaplan-Meier survival analysis, cumulative survival rates of 1/5/10 years post-HT in IGCM patients are 91.7%, 91.7% and 73.3% respectively.No significant difference exist in survival rate for other etiologies post-HT(Log-rank P=0.265). Conclusions:HT is efficacious for end-stage IGCM.Regular and sufficient postoperative immunosuppression is vital for preventing heart transplant rejection and recurrent IGCM.Most IGCM patients have a decent prognosis post-HT.

Objective: To evaluate the sensitivity and specificity of immunohistochemistry (IHC) in the classification of cardiac amyloidosis on endomyocardial biopsy (EMB) and heart allograft. Methods: Twenty cardiac tissues from 19 patients at Fuwai Hospital from January, 1990 to April, 2017 with histopathologic features of amyloidosis and Congo red staining positivity were included. IHC was performed with monoclonal antibodies against AA amyloid and polyclonal antibodies against transthyretin (ATTR), λ-light chain (AL-λ), κ-light chain (AL-κ), ApoAⅠ, ApoAⅡ, ApoA Ⅳ and β₂-microglobin. The extent of interstitial staining was evaluated by light microscopy, and three patterns were recognized; these included diffuse pericellular pattern, discrete pericellular pattern, and nodular pattern. Two patterns of vascular deposition were also noted, including arterial pattern and venous pattern. Endocardial involvement was also assessed and recorded. Results: Nineteen cases were divided into three groups according to the pattern of proteins expression in specimens. The first group (5 cases) only showed single protein expression on EMB. The second group (6 cases) showed more than one protein expression, but one of them was intensely stained or any staining of any protein together with ApoA Ⅳ co-staining. The third group (8 cases) also showed more than one protein expression and all of them had intense staining. Amyloid deposits were successfully subtyped as AL-λ, ATTR, AL-κ and ApoAⅠby IHC in the former two groups with the sensitivity of 11/19. In the third group, amyloid deposits could not be subtyped by immunohistochemistry due to their poor specificity. The pericellular pattern tended to favor AL over ATTR amyloidosis and vascular deposition tended to favor ATTR. Conclusions Amyloid deposits can be reliably subtyped in diagnostic cardiac specimens using IHC. The co-deposition of chaperon proteins, the distribution of amyloid proteins and clinical features are also auxiliary to subtype cardiac amyloidosis.

Objective To construct plasmid vectors of calmodulin(CaM)Mg2+binding site mutants,and to express,purify and identify the mutant proteins. Methods Three kinds of cDNAs coding for the mutated CaM were cloned into pGEX?6P?3 plasmid vectors. These recombinant plasmids were transfected into Escherichia coli BL21 to express GST fusion proteins of CaM mutants. The fusion proteins were purified with Glutathione?Sep?harose 4B beads and PreScission protease. Results Both enzyme digestion analysis and DNA sequence identification proved the successful con?struction of the CaM mutant plasmids. SDS?PAGE results showed the high purity of each CaM mutant protein. The concentrations of three CaM mu?tants were around 1.0 mg/mL. Conclusion Prokayotic expression vectors of CaM Mg2+binding site mutants were successfully developed,and the eli?gible CaM mutant proteins were obtained. This study provided an important basis for further study on CaM’s biological function.

The aging of population and the increasingly morbidity rate of chronic disease had brought great influence on public health and economy.And community whose scientific management model could improve effectivity was a main prevention place for chronic disease.Thus on the basis of domestic and foreign literatures,several types of chronic disease community management models were introduced,and aimed at providing a reference for community chronic disease management.