Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

OBJECTIVES: To investigate the mechanism of Qihuang Jianpi Zishen Granules (QJZ) for ameliorating renal damage in MRL/lpr mice. METHODS: With 6 female C57BL/6 mice as the normal control group, 30 female MRL/lpr mice were randomized into model group, QJZ treatment groups at low, moderate and high doses, and prednisone treatment group (n=6). After 8 weeks of treatment, the mice were examined for 24-h urine protein, creatinine and albumin levels, serum levels of IgG, complement 3 (C3), C4, anti-dsDNA, interferon γ (IFN‑γ) and interleukin 17 (IL-17). Kidney tissues were sampled for histopathological examination with HE staining and observation of glomerular ultrastructure changes using transmission electron microscopy (TEM). The expressions of MyD88/NF-κB pathway-related molecules in the kidney tissue were detected using RT-qPCR, Western blotting and immunohistochemistry. RESULTS: Compared with those in the model group, the mice treated with QJZ at the 3 doses and prednisone showed significant reductions in the renal injury biomarkers and serum IgG, anti-dsDNA, IFN‑γ and IL-17 levels and elevation of serum C3 and C4 levels. HE staining revealed lessened glomerular endothelial cell proliferation and mesangial thickening in all the treatment groups. TEM observation further demonstrated reduced electron-dense deposits and diminished inflammatory cell infiltration in the glomeruli in the intervention groups. QJZ at the 3 doses and prednisone treatment all significantly lowered renal expression levels of MyD88, NF-κB, p65 and p52 in the mouse models. CONCLUSIONS QJZ can improve renal damage in MRL/lpr mice possibly by inhibiting overactivation of the MyD88/NF-κB pathway.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Female ; Mice, Inbred C57BL ; Mice, Inbred MRL lpr ; Myeloid Differentiation Factor 88/metabolism* ; Mice ; NF-kappa B/metabolism* ; Signal Transduction/drug effects* ; Kidney/metabolism* ; Interleukin-17

OBJECTIVES: To investigate the efficacy of Qihuang Jianpi Zishen Granules (QJZ) for inhibiting renal B cell differentiation in MRL/lpr mice and explore its underlying mechanism. METHODS: Thirty 8-week-old female MRL/lpr mice were randomly divided into model group, QJZ group, prednisone (Pred) group, QJZ+Pred group, and AIM2 inhibitor group (n=6), with 6 8-week-old female C57BL/6 mice as the normal control group. After treatments with normal saline, QJZ, Pred, or AIM2 inhibitor for 8 weeks, the mice were examined for urinary total protein-to-creatinine ratio (TPCR) and albumin-to-creatinine ratio (ACR), serum creatinine (Cr) and blood urea nitrogen (BUN) levels, and renal histopathology (with HE, Masson, and PAS staining) and ultrastructural changes (with electron microscopy). ELISA, immunohistochemistry, immunofluorescence staining and flow cytometry were used to detect blood levels of anti-dsDNA antibodies, cytokines and chemokines, renal deposition of complement components C3 and C4, renal expressions of AIM2, CD19, CD27 and CD138, and changes in splenic B lymphocyte subsets. The effect of QJZ on the AIM2/Blimp-1/Bcl-6 signaling axis was examined using Western blotting. RESULTS: QJZ treatment significantly improved Cr, BUN, TPCR and ACR in MRL/lpr mice, ameliorated renal pathologies, reduced the expressions of ds-DNA, BAFF, IL-21, CXCL12, CXCL13, C3 and C4, and increased IL-10 levels. QJZ significantly downregulated renal expressions of the key B-cell transcription factors Blimp-1 and XBP-1, upregulated Bcl-6 and PAX5 expressions, inhibited B-cell differentiation, and lowered the expressions of AIM2, CD27, CD138 and CD69. Inhibition of AIM2 similarly reduced renal Blimp-1 and XBP-1 expressions, increased Bcl-6 and PAX5 levels, suppressed B-cell differentiation, decreased IgG production, reduced C3 and C4 deposition, and alleviated renal pathology in MRL/lpr mice. CONCLUSIONS QJZ inhibits B cell differentiation and alleviates renal damage in systemic lupus erythematosus possibly by suppressing the AIM2/Blimp-1/Bcl-6 signaling pathway.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Mice, Inbred MRL lpr ; Female ; Mice ; Mice, Inbred C57BL ; Cell Differentiation/drug effects* ; B-Lymphocytes/drug effects* ; Proto-Oncogene Proteins c-bcl-6/metabolism* ; Kidney/drug effects* ; DNA-Binding Proteins/metabolism* ; Signal Transduction ; Lupus Nephritis

ObjectiveTo investigate the clinical efficacy of Qihuang Jianpi Zishen Granules in the treatment of systemic lupus erythematosus （SLE） and its effect on the signal transducer and activator of tranSCription 3/mammalian target of rapamycin （STAT3/mTOR） signaling pathway， and to decipher the possible mechanism. MethodSixty female SLE patients who met the criteria in the First Affiliated Hospital of Anhui University of Chinese Medicine from May 2022 to May 2023 were selected and randomized into a control group and an observation group （30 cases in each group）. The control group was treated with prednisone acetate + hydroxychloroquine sulfate orally， and the observation group was additionally treated with Qihuang Jianpi Zishen granules. The treatment lasted for 8 weeks. The SLE disease activity （SLEDAI）， TCM syndrome score， erythrocyte sedimentation rate （ESR）， hypersensitive C-reactive protein （hs-CRP）， immune indexes ［immunoglobulin G （IgG）， C3， C4， CD4⁺， and CD8⁺］， interleukin （IL）-17， IL-23， interferon （IFN）-γ， 24 h urinary protein （24 h PRO）， serum creatinine （SCr）， and expression of proteins ［STAT3， phosphorylated （p）-STAT3， mTOR protein and STAT3，mTOR mRNA］ in the STAT3/mTOR signaling pathway were determined before and after treatment. In addition， the adverse reactions were recorded. ResultAfter 8 weeks of treatment， the total response rate in the observation group was 93.33% （28/30）， which was higher than that （70.00%， 21/30） in the control group （χ²=4.007， P<0.05）. After treatment， both groups showed declined SLEDAI， TCM syndrome score， ESR， hs-CRP， IgG， CD8⁺， IL-17， IL-23， IFN-γ， 24 h PRO， SCr， and expression of proteins in the STAT3/mTOR pathway （P<0.01） and elevated levels of C3， C4， and CD4⁺ （P<0.01）. Moreover， the observation group had lower SLEDAI， TCM syndrome score， ESR， hs-CRP， IgG， CD8⁺， IL-17， IL-23， IFN-γ， 24 h PRO， SCr， and expression of proteins in the STAT3/mTOR pathway （P<0.05， P<0.01） and higher levels of C3， C4， and CD4⁺ （P<0.05， P<0.01） than the control group after treatment. Neither group showed serious adverse reactions during the treatment period. ConclusionQihuang Jianpi Zishen Granules can ameliorate the inflammatory response， reduce the disease activity， and mitigate the kidney injury in SLE by inhibiting the STAT3/mTOR signaling pathway to regulate the immune function.

Objective·To investigate the pathological and physiological changes underlying noise-induced cochlear nucleus damage and the regulating function of astrocytes on the damage,using a combination of morphological analysis,and molecular biology techniques.Methods·Forty-eight male C57BL/6J mice were randomly divided into two groups and exposed to 110 dB SPL(sound pressure level)broadband noise for 2 hours.Auditory brainstem response(ABR)tests were performed on the mice on days 1,7,14,30,and 90 after the noise exposure.Immunofluorescence staining of cochlear nuclear tissue was conducted to observe cochlear nuclear neurons and auditory synapses,as well as astrocyte activation levels.In addition,the damage to the cochlear nuclear neurons and synapses caused by noise was verified through Western blotting.Results·A significant decrease in cochlear nuclear Bushy cells after noise exposure was observed.The Western blotting results showed that there was severe loss of nerve fibers in cochlear nuclear neurons,indicating that noise caused significant damage to cochlear nucleus neurons.Moreover,a significant loss of auditory synapses labeled with vesicular glutamate transporter 1(Vglutl)was observed,which was the severest on day 14 after noise exposure and slowly recovered on day 90.Interestingly,astrocytes in the cochlear nucleus displayed obvious clustering and activation after noise exposure.By staining with glial fibrillary acidic protein(GFAP),most astrocytes were distributed around the cochlear nucleus,granule cell area,and auditory nerve root before noise exposure,and they had a small size.However,on day 14 after noise exposure,a large number of activated astrocytes aggregated in the ventral cochlear nucleus,and they all showed a pattern of growth around the synapses.Conclusion·Noise exposure leads to significant damage in the cochlear nucleus,and it is possible that astrocytes are involved in its damage and repair processes.These findings will provide a crucial foundation for further understanding the mechanisms of sound signal analysis,integration,and neural plasticity in the cochlear nucleus.

Objective To provide nutritional supportive scheme for patients with radiation injury through the treatment of the one exposed to Nanjing 192Ir source accident.Methods The reasonable nutrition treatment scheme was made on the basis of dietary survey and nutritional index monitoring during clinical stages of the patient,including body weight,body mass index(BMI),biochemical indexes,electrolyte,etc.,as well as metabolic cart determination of resting energy expenditure (REE).Results Patient on admission (days 5 post-irradiated) weighing 42.5 kg,172 days after the first irradiated (the first skin grafting) fell to a minimum of 36 kg,then gradually rise,hen rose back to normal range on days 383 before discharge.Normal admission hemoglobin was 135 g/L,172 d after irradiated to a minimum of 54 g/L,normal discharge;when lymphocytes admission low as 0.5 × 109/L,58 days back to normal after exposure,172 days after irradiated down to 0.4 × 109/L.Serum albumin was normal admission 41.2 g/L,172 days after irradiated down to 25.3 g/L.The normal level of serum prealbumin was 0.22 g/L,248 days to a minimum of 0.04 g/L,the basic return to normal at discharge was 0.17 g/L.Admission normal liver function,bilirubin index slightly higher,the all in one parenteral nutrition after about 2.5 months later,bilirubin and liver function indicators were gradually increased,the adjusted treatment and nutrition liver and gallbladder and other gradually returned to normal after treatment.REE and the body weight were determined by metabolic cart on days 294,308 and 342 for the energy requirements.Conclusions For patient with radiation injury,appropriate nutrition therapy is a key method for the clinical treatment and rehabilitation,which can maintain the nutritional status of patients and improve clinical treatment.

Objective To understand the development of healthcare-associated infection(HAI)management organ-izations in China in the past 30 years.Methods Development of HAI management organizations in 12 provinces (municipalities,autonomous regions)in China was surveyed.Results A total of 166 hospitals were surveyed,96 (57.83%)were tertiary hospitals.Among 164 hospitals which had a history of development of HAI management department,46(28.05%)before 1995,63(38.14%)in 1995-2005,and 55(33.54%)in 2005-2015 set up HAI management departments.HAI management professionals per 1 000 beds in 165 hospitals decreased from 4.80 in 1995 to 4.09 in 2015,occupational categories in HAI management departments in 1995 -2015 were significantly different (χ2 =26.22,P <0.01).The constituent ratios of education background and profession of HAI manage-ment professionals in each province in 1995-2015 were significantly different(χ2 =242.91,47.10,respectively,all P <0.01).In 1995 and 2005,70.81%,53.30% of professionals were with college degree or below;in 2015,the percentage of professionals with bachelor’s degree,doctoral degree,and master’s degree were 53.79%,2.45%, and 22.86% respectively.Most professionals were nursing staff,but the percentage decreased from 58.38% in 1995 to 45.96% in 2015.Conclusion Although HAI management organizations have developed for 30 years and made some achievements,there still remain some problems,the proportion of professionals needs to be enhanced,and personnel structure should be optimized.

Objective To understand the development situation of healthcare-associated infection (HAI)manage-ment departments in the rational antimicrobial application and management in hospitals in China.Methods A total of 166 hospitals from 12 provinces,municipalities,autonomous regions,and military hospitals were selected for survey,the participation of HAI management departments in the rational clinical antimicrobial application and man-agement in different years was compared.Results Of 166 hospitals,68(40.96%)in 2005,119(71.69%)in 2010, and 160(96.39%)in 2015 participated in the establishment of management organizations for rational antimicrobial application (χ2 =121.143,P <0.001).The percentage of HAI management departments participating in antimicro-bial management increased from 10.24%(n=17)in 2005 to 22.29%(n=37)in 2010,and 31.33%(n=52)in 2015 (χ2 =22.172,P < 0.001 ).The percentages of HAI management departments participating in formulating cata-logues for antimicrobial varieties and classification,stipulating permission for antimicrobial use,joining antimicrobi-al management teams,monitoring bacterial resistance,managing antimicrobial prophylaxis in clean incision,super-vising clinical antimicrobial use,conducting clinical consultation,and evaluating prescription were 10.87% -30.72% in 2005,25.90%-65.06% in 2010,and 36.14%-95.18% in 2015 (all P <0.01).Intensity of antimicro-bial use (defined daily dose/100 bed-days,DDD/ 100 bed-days)decreased from 69.16 in 2005 to 41.40 in 2015, antimicrobial usage rate decreased from 46.98% in 2005 to 36.90% in 2015,among patients receiving therapeutic antimicrobial use,specimens sending for pathogenic detection increased from 20.58% in 2005 to 49.39% in 2015. Conclusion Departments of HAI management in China play important role in management of rational antimicrobial application.

Objective To retrospectively study the relationship between several risk factors such as cirrhosis,Child-Pugh classification,tumor size,portal vein tumor thrombus,intraoperative transfusion,hepatic portal occlusion time and the prognosis of hepatic cellular cancer( HCC ) patients after hepatic resection. Methods The clinical data of 123 patients who received hepatic resection for HCC at Tongji Hospital between 2007 and 2009 were retrospectively analyzed. Log-Rank test and Cox proportional hazard model were used in the univariate and multivariate analyses of risk factors. Results 1,2,3,5 year recurrence and survival rates were 54. 17%,66. 67%,81. 40%,87. 50% and 93. 50%,73. 17%,58. 54%,27. 64%,respectively. The mean recurrence time and survival time were 19. 5 months and 42. 9 months. In univariate analysis,presence of cirrhosis(χ2 =11. 159,P=0. 005),Child-Pugh classification(χ2 =7. 715,P=0. 028),tumor size(≥5cm)(χ2 =11. 483,P=0. 004),presence of portal vein invasion(χ2 =22. 271,P=0. 001)were risk factors affecting HCC recurrence. In multivariate analysis,presence of cirrhosis(χ2 =8. 993,P=0. 003),tumor size (≥5cm)(χ2 =4. 022,P=0. 039),presence of portal vein invasion(χ2 =5. 023,P=0. 027)were inde-pendent risk factors affecting HCC recurrence. In univariate analysis,presence of cirrhosis(χ2 =7. 339,P=0. 025),AFP﹥400 ng/ml(χ2 =5. 431,P=0. 042),Child-Pugh classification(χ2 =13. 389,P=0. 002), tumor size(≥5cm)(χ2 =11. 342,P=0. 003),presence of portal vein invasion(χ2 =52. 167,P﹤0. 001), hepatic portal occlusion(χ2 =5. 801,P=0. 037),intraoperative blood transfusion(χ2 =14. 959,P=0. 001) were risk factors affecting a shorter overall survival. In multivariate analysis,presence of cirrhosis(χ2 =9. 133, P=0. 003),Child-Pugh classification(χ2 =4. 799,P=0. 028),tumor size(≥5 cm)(χ2 =9. 101,P=0. 004),presence of portal vein invasion(χ2 =11. 126,P=0. 001),hepatic portal occlusion(χ2 =3. 985, P=0. 046)were independent prognostic factors affecting shorter overall survival. Conclusion Cirrhosis, Child-Pugh classification,tumor size(≥5 cm),presence of portal vein invasion,and hepatic portal occlusion were independent prognostic factors for HCC patients after hepatic resection.

Uncontrolled fibrosis of skin and internal organs is the main characteristic of scleroderma, and collagen is a major extracellular matrix protein that deposits in the fibrotic organs. As the chaperone of collagen, heat shock protein 47 (HSP47) is closely related with the development of fibrosis. To explore the potential function of HSP47 in the pathogenesis of scleroderma, the clinical, in vivo and in vitro studies were performed. In clinical, the increased mRNA level of HSP47 was observed in the skin fibroblasts and PBMC from scleroderma patients, and the enhanced protein level of HSP47 was also detected in the skin biopsy and plasma of the above patients. Unexpectedly, the enhanced levels of HSP47 were positively correlated with the presence of anti-centromere antibody in scleroderma patients. Moreover, a high expression of HSP47 was found in the skin lesion of BLM-induced scleroderma mouse model. Further in vitro studies demonstrated that HSP47 knockdown could block the intracellular and extracellular collagen over-productions induced by exogenous TGF-β. Therefore, the results in this study provide direct evidence that HSP47 is involved in the pathogenesis of scleroderma. The high expression of HSP47 can be detected in the circulatory system of scleroderma patients, indicating that HSP47 may become a pathological marker to assess the progression of scleroderma, and also explain the systemic fibrosis of scleroderma. Meanwhile, collagen over-expression is blocked by HSP47 knockdown, suggesting the possibility that HSP47 can be a potential therapeutic target for scleroderma.
Adolescent ; Adult ; Animals ; Biopsy ; Blotting, Western ; Cells, Cultured ; Collagen ; metabolism ; Female ; Fibroblasts ; drug effects ; metabolism ; Fibrosis ; HSP47 Heat-Shock Proteins ; blood ; genetics ; metabolism ; Humans ; Leukocytes, Mononuclear ; metabolism ; Male ; Mice ; Mice, Inbred C3H ; Middle Aged ; NIH 3T3 Cells ; Protein Binding ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Scleroderma, Systemic ; blood ; genetics ; metabolism ; Skin ; metabolism ; pathology ; Transforming Growth Factor beta ; pharmacology ; Young Adult