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.

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ObjectiveTo investigate the role and mechanism of Go-Ichi-Ni-San complex subunit 1 （GINS1） in the progression of hepatocellular carcinoma （HCC） and the development of chemotherapy resistance. MethodsThe tumor database GEPIA2 was used to analyze the differential expression of GINS1 between HCC patients and healthy individuals， and pathological tissue samples were collected from 40 HCC patients who were admitted to The Affiliated Tumor Hospital of Xinjiang Medical University and the First Affiliated Hospital of Xinjiang Medical University from May 2017 to January 2021. Immunohistochemical staining was used to measure the difference in the expression of GINS1 between HCC tissue and corresponding adjacent tissue， and the correlation between the expression level of GINS1 and the clinical TNM stage of HCC was analyzed. Western blot was also used to measure the difference in the expression of GINS1 between HCC Huh7/Hep3B/Li-7/MHCC97H cell lines and normal human QSG7701 hepatocytes. The method of lentivirus transfection was used to establish the MHCC97H cell line with stable GINS1 knockdown and its negative control cell line. CCK-8 assay and colony formation assay were used to measure cell proliferative capacity； scratch assay was used to measure cell migration ability； Transwell assay was used to measure cell invasion ability； cells were treated with oxaliplatin to measure their sensitivity to chemotherapy drugs. Nude mice were used to establish a tumor-bearing model and observe the effect of GINS1 knockdown on the growth of HCC in vivo. Western Blot was used to measure the expression levels of the proteins associated with the Notch pathway and the JAK/STAT pathway. The cells were treated with the Notch receptor agonist Jagged-1 to analyze the association between GINS1 and the Notch/JAK/STAT pathway. The independent-samples t test was used for comparison of continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsThe expression of GINS1 was upregulated in HCC patients， HCC tissue， and HCC cell lines （all P<0.05）， and the expression level of GINS1 was positively correlated with the clinical TNM stage of HCC （r=0.822， P=0.011）. Compared with the negative control cells， the GINS1-knockdown MHCC97H cells showed significant reductions in proliferation， migration， and invasion activities （all P<0.01） and a significantly enhanced sensitivity to oxaliplatin （P<0.01）. Compared with the nude mice in the control group， GINS1 knockdown caused significant inhibition of tumor weight and volume in vivo in nude mice （all P<0.001）. Compared with the negative control cells， the GINS1-knockdown MHCC97H cells showed significant reductions in the expression levels of Notch1， Notch3， p-JAK2， and p-STAT3 （all P<0.05）， while there were no significant differences in the overall expression levels of JAK2 and STAT3 （P>0.05）. After Jagged-1 treatment， the GINS1-knockdown MHCC97H cells showed significant increases in proliferation， migration， and invasion activities and a significant reduction in sensitivity to oxaliplatin， as well as significant increases in the levels of p-JAK2 and p-STAT3 （all P<0.05）. ConclusionGINS1 is upregulated in HCC and can promote HCC progression and chemotherapy resistance through the Notch/JAK2/STAT3 pathway.

Objective:To evaluate the role of nuclear factor erythroid 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in the improvement in postoperative cognitive function by electroacupuncture preconditioning in aged rats.Methods:Eighty clean-grade healthy male Sprague-Dawley rats, aged 24 months, weighing 550-600 g, were divided into 4 groups ( n=20 each) using a random number table method: control group (C group), POCD group, electroacupuncture+ POCD group (EA group), and Nrf2 inhibitor ML385+ electroacupuncture+ POCD group (I group). A rat POCD model was prepared by performing exploratory laparotomy under 3% sevoflurane anesthesia. Nrf2 inhibitor ML385 15 mg/kg was intraperitoneally injected at 30 min before surgery in group I, while the equal volume of normal saline was given instead in the remaining groups. Electroacupuncture stimulation of the Zusanli, Hegu and Neiguan acupoints (disperse-dense waves, current intensity 1 mA, frequency 2/15 Hz, 30 min) was performed at 8: 00 a.m. every day for 5 days prior to model preparation in EA group and I group. An open field test was conducted at 3 days after operation to measure the autonomous motor function, and Morris water maze test was conducted after the end of the open field test at 3-7 days after operation to evaluate the cognitive function. After the Morris water maze test, the rats were sacrificed under anesthesia and hippocampal tissues were taken for determination of the level of reactive oxygen species (ROS, by flow cytometry) and expression of Nrf2 and HO-1 (by Western blot) and for examination of the mitochondrial ultrastructure of hippocampal neurons (with a transmission electron microscope). Results:Compared with group C, the escape latency was significantly prolonged, the number of crossing the original platform quadrant was decreased, the hippocampal ROS levels were increased, the expression of Nrf2 and HO-1 was down-regulated ( P<0.05), and mitochondria were swollen and mitochondrial cristae were broken in the hippocampal CA1 neurons in group POCD. Compared with group POCD, the escape latency was significantly shortened, the number of crossing the original platform quadrant was increased, the hippocampal ROS levels were decreased, the expression of Nrf2 and HO-1 was up-regulated ( P<0.05), and the swelling of mitochondria and rupture of cristae structure were improved in the hippocampal CA1 neurons in group EA. Compared with group EA, the escape latency was significantly prolonged, the number of crossing the original platform quadrant was decreased, the hippocampal ROS levels were increased, the expression of Nrf2 and HO-1 was down-regulated ( P<0.05), and the swelling of mitochondria and rupture of cristae structure were aggravated in the hippocampal CA1 neurons in group I. Conclusions:Activation of the hippocampal Nrf2/HO-1 signaling pathway is involved in improvement in postoperative cognitive function by electroacupuncture preconditioning in aged rats.

Acceleration of tooth movement during orthodontic treatment is challenging,with osteoclast-mediated bone resorption on the compressive side being the rate-limiting step.Recent studies have demonstrated that mechanoreceptors on the surface of monocytes/macrophages,especially adhesion G protein-coupled receptors(aGPCRs),play important roles in force sensing.However,its role in the regulation of osteoclast differentiation remains unclear.Herein,through single-cell analysis,we revealed that CD97,a novel mechanosensitive aGPCR,was expressed in macrophages.Compression upregulated CD97 expression and inhibited osteoclast differentiation;while knockdown of CD97 partially rescued osteoclast differentiation.It suggests that CD97 may be an important mechanosensitive receptor during osteoclast differentiation.RNA sequencing analysis showed that the Rap1a/ERK signalling pathway mediates the effects of CD97 on osteoclast differentiation under compression.Consistently,we clarified that administration of the Rap1a inhibitor GGTI298 increased osteoclast activity,thereby accelerating tooth movement.In conclusion,our results indicate that CD97 suppresses osteoclast differentiation through the Rap1a/ERK signalling pathway under orthodontic compressive force.

As a practical carrier for promoting the tiered diagnosis and treatment model, the medical consor-tium is of great significance for balancing medical resources and boosting medical service efficiency. The construction of medical consortiums not only improves the accessibility of high-quality medical resources for patients, but also enhances the diagnostic and treatment level of member units. Meanwhile, it provides space for the leading hospital to adjust the structure of diseases and improve the level of discipline construction. As the core of medical insurance payment reform, DRG, through indicators such as the case mix index(CMI) and the number of diagnosis related group (DRG), provides objective and quantified data support for case management and disease structure optimization, thus effectively guiding the rational allocation of medical resources and the adjustmentof diseases and surgical types within the medical consortium. Comprehensive use of DRG evaluation indicators can construct a multidimensional medical consortium construction evaluation system, provides a clear direction for medical consortium cooperation, thereby promoting the overall healthy and sustainable development of medical consortiums and achieving a win-win situation for all parties involved. This paper, based on the "1+5+1" medical consortium cooperation model centered around Peking Union Medical College Hospital, utilizes DRG indicators to analyze the benefits for patients, member hospitals, and the leading hospital during the medical consortium construction process, with the hope of providing reference for the construction of a medical consortium evaluation system.

Objective:To evaluate the role of nuclear factor erythroid 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in the improvement in postoperative cognitive function by electroacupuncture preconditioning in aged rats.Methods:Eighty clean-grade healthy male Sprague-Dawley rats, aged 24 months, weighing 550-600 g, were divided into 4 groups ( n=20 each) using a random number table method: control group (C group), POCD group, electroacupuncture+ POCD group (EA group), and Nrf2 inhibitor ML385+ electroacupuncture+ POCD group (I group). A rat POCD model was prepared by performing exploratory laparotomy under 3% sevoflurane anesthesia. Nrf2 inhibitor ML385 15 mg/kg was intraperitoneally injected at 30 min before surgery in group I, while the equal volume of normal saline was given instead in the remaining groups. Electroacupuncture stimulation of the Zusanli, Hegu and Neiguan acupoints (disperse-dense waves, current intensity 1 mA, frequency 2/15 Hz, 30 min) was performed at 8: 00 a.m. every day for 5 days prior to model preparation in EA group and I group. An open field test was conducted at 3 days after operation to measure the autonomous motor function, and Morris water maze test was conducted after the end of the open field test at 3-7 days after operation to evaluate the cognitive function. After the Morris water maze test, the rats were sacrificed under anesthesia and hippocampal tissues were taken for determination of the level of reactive oxygen species (ROS, by flow cytometry) and expression of Nrf2 and HO-1 (by Western blot) and for examination of the mitochondrial ultrastructure of hippocampal neurons (with a transmission electron microscope). Results:Compared with group C, the escape latency was significantly prolonged, the number of crossing the original platform quadrant was decreased, the hippocampal ROS levels were increased, the expression of Nrf2 and HO-1 was down-regulated ( P<0.05), and mitochondria were swollen and mitochondrial cristae were broken in the hippocampal CA1 neurons in group POCD. Compared with group POCD, the escape latency was significantly shortened, the number of crossing the original platform quadrant was increased, the hippocampal ROS levels were decreased, the expression of Nrf2 and HO-1 was up-regulated ( P<0.05), and the swelling of mitochondria and rupture of cristae structure were improved in the hippocampal CA1 neurons in group EA. Compared with group EA, the escape latency was significantly prolonged, the number of crossing the original platform quadrant was decreased, the hippocampal ROS levels were increased, the expression of Nrf2 and HO-1 was down-regulated ( P<0.05), and the swelling of mitochondria and rupture of cristae structure were aggravated in the hippocampal CA1 neurons in group I. Conclusions:Activation of the hippocampal Nrf2/HO-1 signaling pathway is involved in improvement in postoperative cognitive function by electroacupuncture preconditioning in aged rats.

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.

Non-arteritic anterior ischemic optic neuropathy (NAION) is a disease characterized by acute, painless visual acuity loss and visual field impairment, and there is still lack of unified and effective treatment.As new therapeutic strategies, neuroprotection and nerve regeneration have aroused wide public concern, which aim to prevent degeneration and death of neurons or establish a new neural circuit through inhibiting apoptosis pathway and inflammation, promoting axon growth and applying stem cells.Plenty of studies have applied the strategies to NAION patients or NAION animal models, which achieved certain success, but the limitations exist at the same time.For the sake of exploring practical therapies of NAION, researches on the neuroprotection and nerve regeneration strategies of NAION in recent years were reviewed in this article.

【Objective】 To understand the epidemic status of drug-resistant Mycobacteriun tuberculosis in Xi’an in the past three years, and the impact of COVID-19 epidemic during 2020 so as to provide basic information for local multidrug-resistant tuberculosis (MDR-TB) prevention and treatment. 【Methods】 Tuberculosis (TB) detected by sputum culture, the corresponding drug susceptibility tests data, and basic clinical information of TB patients diagnosed in Xi’an from January 2018 to October 2020 were collected from the management system; then the epidemic status and the drug resistance status were analyzed. Multinomial logistic regression was used to analyze the relationship between the patients’ treatment history and the drug resistance of TB strains, and the trend of changes in the drug resistance rate in retreated patients. 【Results】 In the past three years, there was a total drug resistance rate of 25.3% in 5 146 strains of MTB, and 24.8% in treatment initiation and 38.22% in retreatment, respectively. The treatment initiation patients showed a decreased MDR-TB detection rate, and the retreated patients had an increased MDR-TB detection rate. The spectrum of MDR-TB in the retreated patients gradually became more complicated, and the resistance rate of second-line drugs such as Kanamycin and Ofloxacin gradually increased. There were 10 drug-resistant combinations mainly in H+R+S and H+R+S+E. During the year 2020 of COVID-19 epidemic, the number of initial and retreated patients decreased significantly compared with that in 2018 and 2019, but with no difference in the drug-resistance rate. There was an increasing detection rate of PDR and MDR-TB strains in the retreated patients. Multinomial logistic regression results showed that in 2020 the retreated patients had 4.28 times of developing PDR-TB (P=0.001, 95% CI=1.417-12.930), and 5.378 times of developing MDR-TB (P<0.001, 95% CI=2.641-10.952) than patients of treatment initiation. 【Conclusion】 In the past three years, the prevention and control of drug-resistant TB in Xi’an has achieved some progress, but drug resistance in retreated patients is still serious. To avoid and reduce the development of drug-resistant TB, precise and active intervention measures should be taken, and health management of TB patients should be strengthened, especially during the current period of COVID-19 epidemic prevention and control.