Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

The safety and efficacy of PD-1 inhibitors in patients with advanced cancers and HIV/AIDS in China.

Purpose-Immunotherapy has revolutionized cancer therapy, becoming the standard of care for various malignancy treatments. Human immunodeficiency virus (HIV) patients, however, are an underserved group with limited access to clinical trials and cancer therapy. This study was to evaluate the safety and efficacy of programmed cell death 1 (PD - 1) inhibitors in patients with advanced cancer and HIV/acquired immunodeficiency syndrome (AIDS). Methods and Materials-We performed a prospective, open-label, nonrandomized, phase 1 single center study. Patients with advanced cancer and HIV/AIDS received the treatment of PD - 1 inhibitors (camrelizumab, 200 mg, administered intravenously every 3 weeks), along with combination antiretroviral therapy (cART) for HIV. Results-Sixteen participants (12 men and 4 women; median age, 46.5 (29 - 78) years) were enrolled; 1 had non - Hodgkin lymphoma (NHL), and 15 had non - AIDS - defining cancers. Safety was observed over 130 cycles of treatment with camrelizumab. Most treatment-emergent adverse events at least possibly attributed to camrelizumab were grade 1 or 2, including reactive cutaneous capillary endothelial proliferation (RCCEP) (9 participants), hearing loss (1 participant), hypophysitis (1 participant). 3 participants experienced hemorrhage due to poor performance status. HIV was controlled in all participants. Best tumor responses included 3 complete response, 5 partial response, 2 stable disease, and 6 progressive disease. The 2 years progression-free survival (PFS) was 67.0% (95% CI: -0.05, 0.00) and overall survival (OS) was 55.3% (95% CI: -0.05, 0.01) for the 16 patients who had received camrelizumab. Conclusions-This study demonstrates that camrelizumab treatment in patients with advanced cancers and HIV/AIDS was feasible and the clinical outcomes were acceptable.

Attenuated Salmonella carrying siRNA-PD-L1 and radiation combinatorial therapy induces tumor regression on HCC through T cell-mediated immuno-enhancement.

Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance.

To Investigate the Occurrence and Development of Colorectal Cancer Based on the PI3K/AKT/mTOR Signaling Pathway.

Colorectal cancer (CRC) is the most common malignancy of the gastrointestinal, however, the underlying mechanisms of CRC remain largely unknown. New evidence suggests that the PI3K/AKT/mTOR pathway is closely related to CRC. PI3K/AKT/mTOR is a classical signaling pathway that is involved in a variety of biological processes, such as regulating cellular metabolism, autophagy, cell cycle progression, cell proliferation, apoptosis, and metastasis. Therefore, it plays a crucial role in the occurrence and development of CRC. In this review, we focus on the role of the PI3K/AKT/mTOR pathway in CRC, and its application of to the treatment of CRC. We review the importance of the PI3K/AKT/mTOR signaling pathway in tumorigenesis, proliferation and progression, and pre-clinical and clinical experience with several PI3K/AKT/mTOR pathway inhibitors in CRC.

Metagenomic next-generation sequencing versus traditional laboratory methods for the diagnosis of central nervous system opportunistic infections in HIV-infected Chinese adults.

To evaluate clinical value of metagenomic next-generation sequencing (mNGS) in people living with HIV/AIDS (PLWHA) who had CNS disorders. Cerebrospinal fluid (CSF) samples from 48 PLWHA presenting with CNS disorders were sequenced using mNGS and compared with clinical conventional diagnostic methods. In total, 36/48 ss(75%) patients were diagnosed with pathogen(s) infection by mNGS, and the positive detection proportion by mNGS was higher than that by clinical conventional diagnostic methods (75% vs 52.1%, X2 = 5.441, P = 0.020). Thirteen out of 48 patients (27.1%) were detected with 3-7 pathogens by mNGS. Moreover, 77 pathogen strains were detected, of which 94.8% (73/77) by mNGS and 37.0% (30/77) by clinical conventional methods (X2 = 54.206, P < 0.001). The sensitivity and specificity of pathogens detection by mNGS were 63.9% (23/36) and 66.7% (8/12), respectively, which were superior to that by clinical conventional methods (23/36 vs 9/25, X2 = 4.601, P = 0.032; 8/12 vs 5/23, X2 = 5.029, P = 0.009). The application of mNGS was superior for its ability to detect a variety of unknown pathogens and multiple pathogens infection, and relatively higher sensitivity and specificity in diagnosis of CNS disorders in PLWHA.

IDO2-siRNA Carried by Salmonella Combined with Nifuroxazide Attenuates Melanoma Growth.

BACKGROUND: Melanoma, a highly malignant skin cancer, is a hot topic in oncology treatment research. Nowadays, tumor immunotherapy, especially immunotherapy combined with other therapies, has attracted more and more attention. Indoleamine 2,3-dioxygenase 2 (IDO2), a ratelimiting enzyme of the tryptophan metabolism pathway in the urine of dogs with immunosuppression, is highly expressed in melanoma tissue. Additionally, IDO2 significantly inhibits the anti-tumor immunity of the body and has become a novel target of melanoma treatment. Nifuroxazide, as an intestinal antibacterial agent, was found to be able to inhibit Stat3 expression and exert an anti-tumor effect. Therefore, the present study aimed to examine the therapeutic effect of a self-designed IDO2-small interfering RNA (siRNA) delivered by attenuated Salmonella combined with nifuroxazide on melanoma- bearing mice, as well as determine its underlying mechanism. METHODS: The effect of nifuroxazide on melanoma was detected by flow cytometry, CCK-8 and colony- forming ability assays, respectively, in vitro. The plasmid of siRNA-IDO2 was constructed, and the mice-bearing melanoma model was established. After the treatment, the tumor growth and survival rate were monitored, and the morphological changes of tumor tissue were detected by HE staining. The expression of related proteins was detected by Western blotting, and the expression of CD4 and CD8 positive T cells in tumor tissue was detected by IHC and IF, and the proportion of CD4 and CD8 positive T cells in spleen was detected by flow cytometry. RESULTS: The results demonstrated that the combination therapy effectively inhibited the phosphorylation of Stat3 and the expression level of IDO2 in melanoma cells, which effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice. The mechanistic study revealed that, compared with control groups and monotherapy groups, the combination treatment group reduced the atypia of tumor cells, increased the apoptotic rate, enhanced the infiltration of T lymphocytes in tumor tissue and increased the CD4+ and CD8+ T lymphocytes in the spleen, suggesting that the mechanism may be associated with the inhibition of tumor cell proliferation, the increase of apoptosis and the enhancement of the cellular immunity. CONCLUSION: In conclusion, IDO2-siRNA combined with nifuroxazide therapy could serve a significant role in the treatment of melanoma-bearing mice, enhance the tumor immunity and provide an experimental basis for identifying a novel combination method for the treatment of melanoma clinically.

[Corrigendum] METTL3­mediated m6A modification of Bcl­2 mRNA promotes non­small cell lung cancer progression.

Subsequently to the publication of the above paper, the authors have realized, upon reorganizing all their original data, that errors were made during the assembly of the images in Fig. 5 on p. 8. Specifically, in Fig. 5E, the images intended to represent the 'METTL3 sh­METTL3' and 'Bcl­2 sg­METTL3' immuno-histochemistry staining experiments were selected incorrectly. The revised version of Fig. 5, showing the correctly assembled data panels for the 'METTL3 sh­METTL3' and 'Bcl­2 sg­METTL3' experiments in Fig. 5E, is shown on the next page. The authors sincerely apologize for the errors that were inadvertently introduced during the preparation of this Figure, thank the Editor of Oncology Reports for allowing them the opportunity to publish this Corrigendum, and regret any inconvenience that these errors may have caused to the readership. [Oncology Reports 46: 163, 2021; DOI: 10.3892/or.2021.8114].

A novel plasma proteomic-based model for predicting liver fibrosis in HIV/HBV co-infected adults.

To establish a plasma model to predict the risk of liver fibrosis in HIV/HBV co-infected individuals. Quantitative liquid chromatography-tandem mass spectrometry(LC-MS/MS) was used to identify differentially expressed proteins (DEPs) in plasma collected from HIV/HBV co-infected individuals with and without liver fibrosis. In total, 97 DEPs were identified, among which 11 were further validated as potential biomarkers, with immunoglobulin and complement components being the most common proteins. These markedly altered proteins were found to mediate pathophysiological pathways, including humoral immune response, complement and coagulation cascades, and complement activation. A visual logistic model, in which immunoglobulin heavy variable 3-20 (IGHV3-20), immunoglobulin heavy variable 1-24 (IGHV1-24), and macrophage colony-stimulating factor 1 receptor (CSF1R) proteins were included, has been established to predict liver fibrosis in HIV/HBV co-infected individuals. The preliminary conclusion showed that the combination of IGHV3-20, IGFHV1-24, and CSF1R is expected to become a predictive model for liver fibrosis in the context of HIV/HBV co-infection and a further validation should be performed.

SIRT6 Activator UBCS039 Inhibits Thioacetamide-Induced Hepatic Injury In Vitro and In Vivo.

SIRT6 has been reported to have multiple functions in inflammation and metabolism. In the present study, we explored the regulatory effects and mechanisms of SIRT6 in thioacetamide (TAA)-induced mice acute liver failure (ALF) models. The SIRT6 activator UBCS039 was used in this animal and cell experiments. We observed that UBCS039 ameliorated liver damage, including inflammatory responses and oxidative stress. Further study of mechanisms showed that the upregulation of SIRT6 inhibited the inflammation reaction by suppressing the nuclear factor-κB (NF-κB) pathway in the TAA-induced ALF mice model and lipopolysaccharide-stimulated macrophages. In addition, the upregulation of SIRT6 alleviated oxidative stress damage in hepatocytes by regulating the Nrf2/HO-1 pathway. These findings demonstrate that pharmacologic activator of SIRT6 could be a promising target for ALF.

Plasma proteomic analysis reveals altered protein abundances in HIV-infected patients with or without non-Hodgkin lymphoma.

The identification of circulating proteins associated with acquired immunodeficiency syndrome-related non-Hodgkin lymphoma (AIDS-NHL) may help in the development of promising biomarkers for screening, diagnosis, treatment, and prognosis. Here, we used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins (DEPs) in plasma collected from patients with AIDS-NHL and human immunodeficiency virus (HIV)-infected patients without NHL (HIV+ ). Proteins with a log2 (fold change) in abundance >0.26 and p < 0.05 were considered differentially abundant. In total, 84 DEPs were identified, among which 20 were further validated as potential biomarkers, with immunoglobulin and complement components being the most common proteins. Some of the proteins were further verified in a retrospective analysis of the medical records of patients in a larger cohort. These markedly altered proteins were found to mediate pathophysiological pathways that likely contribute to AIDS-NHL pathogenesis, such as the humoral immune response, complement activation, and complement and coagulation cascades. Our findings provide a new molecular understanding of AIDS-NHL pathogenesis and provide new evidence supporting the identification of these proteins as possible biomarkers in AIDS-NHL.

D-MT prompts the anti-tumor effect of oxaliplatin by inhibiting IDO expression in a mouse model of colon cancer.

Colon cancer is one of the most common malignant tumors in the digestive system. Although oxaliplatin, a chemotherapy drug, has been clinically used to treat colon cancer, its therapeutic effect is unsatisfactory. It has been proved that indoleamine dioxygenase 2,3 (IDO) is a tumor immunosuppressive factor for the immune response. Herein, an IDO inhibitor, D-MT (indoximod, 1-Methyl-D-tryptophan), was combined with oxaliplatin to treat colon cancer in mice. T cell infiltration in tumor tissues, the ratios of immune cells in the spleens, and the tumor growth and survival of the mice were detected and recorded. The results showed that the combination of oxaliplatin and D-MT significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice. More importantly, the combination treatment increased the ratios of CD4+ T, CD8+ T and NK cells from the spleen in tumor-bearing mice, and prompted T cell infiltration in tumor tissues. This study provided a new therapeutic strategy for colon cancer treatment in the clinic, especially for patients with oxaliplatin resistance.

Clinical and immunological characteristics in COVID-19 convalescent patients.

The humoral and cellular immunity of convalescent COVID-19 patients is involved in pathogenesis and vaccine immunity. In this study, through CoV-psV neutralization assay and IFN-γ ELISpot testing in 30 cases of COVID-19 patients after 9 months post-SARS-CoV-2 infection, it found that the ratio of memory/naive CD4+ T lymphocytes cells and levels of anti-SARS-CoV-2-IgM and RBD-IgM were slightly but significantly higher in COVID-19 severe convalescent patients than that in non-severe patients. The specific cellular and humoral immunity against SARS-CoV-2 were detectable, regardless of the severity of the disease in the acute phase. This information may help understanding the immune status after SARS-CoV-2 infection.

LOX-1 Deletion Attenuates Myocardial Fibrosis in the Aged Mice, Particularly Those With Hypertension.

Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a transmembrane glycoprotein that mediates uptake of oxidized low-density lipoprotein (ox-LDL) into cells. Previous studies had shown that LOX-1 deletion had a potential to inhibit cardiac fibrosis in mouse models of hypertension and myocardial infarction. Whether LOX-1 deletion also affects cardiac fibrosis associated with aging still remains unknown. The aim of this study was to investigate the effect of LOX-1 deletion on myocardial fibrosis in the aged mice. Methods: C57BL/6 mice and LOX-1 knockout (KO) mice with C57BL/6 background were studied to the age of 60 weeks. Both genotypes of aged mice were exposed to angiotensin II (Ang II) or saline for additional 4 weeks. The mice were then sacrificed, and myocardial fibrosis, reactive oxygen species (ROS) and expression of LOX-1, fibronectin, collagens, p22phox, and gp91phox were measured. Results: LOX-1 deletion markedly reduced Ang II-mediated rise of blood pressure in the aged mice (vs. saline-treated mice). LOX-1 deletion also limited fibrosis and decreased fibronectin and collagen-3 expression in the hearts of aged mice, but not the expression of collagen-1 and collagen-4. LOX-1 deletion also inhibited ROS production and p22phox expression. As the aged mice were exposed to Ang II for 4 weeks (resulting in hypertension), LOX-1 deletion more pronounced inhibiting myocardial fibrosis and ROS production, and decreasing expression of fibronectin, collagen-1, collagen-2, collagen-3, p22phox, and gp91phox. Conclusion: LOX-1 deletion limited fibrosis and ROS production in the hearts of aged mice. This effect was more pronounced in the aged mice with hypertension induced by Ang II infusion.

Favipiravir Versus Arbidol for Clinical Recovery Rate in Moderate and Severe Adult COVID-19 Patients: A Prospective, Multicenter, Open-Label, Randomized Controlled Clinical Trial.

Background: In addition to supportive therapy, antiviral therapy is an effective treatment for coronavirus disease 2019 (COVID-19). Objective: To compare the efficacy and safety of favipiravir and umifenovir (Arbidol) to treat COVID-19 patients. Methods: We conducted a prospective, randomized, controlled, open-label multicenter trial involving adult patients with COVID-19. Enrolled patients with initial symptoms within 12 days were randomly assigned in a 1:1 ratio to receive conventional therapy plus Arbidol (200 mg*3/day) or favipiravir (1600 mg*2/first day followed by 600 mg*2/day) for 7 days. The primary outcome was the clinical recovery rate at day 7 of drug administration (relief for pyrexia and cough, respiratory frequency ≤24 times/min; oxygen saturation ≥98%). Latency to relief for pyrexia and cough and the rate of auxiliary oxygen therapy (AOT) or noninvasive mechanical ventilation (NMV)/mechanical ventilation (MV) were the secondary outcomes. Safety data were collected for 17 days. Results: A total of 240 enrolled COVID-19 patients underwent randomization; 120 patients were assigned to receive favipiravir (116 assessed), and 120 patients were assigned to receive Arbidol (120 assessed). The clinical recovery rate at day 7 of drug administration did not significantly differ between the favipiravir group (71/116) and Arbidol group (62/120) (p = 0.1396, difference in recovery rate: 0.0954; 95% CI: -0.0305∼0.2213). Favipiravir contributed to relief for both pyrexia (difference: 1.70 days, p < 0.0001) and cough (difference: 1.75 days, p < 0.0001). No difference was observed in the AOT or NMV/MV rate (both p > 0.05). The most frequently observed favipiravir-associated adverse event was increased serum uric acid (16/116, OR: 5.52, p = 0.0014). Conclusion: Among patients with COVID-19, favipiravir, compared to Arbidol, did not significantly improve the clinical recovery rate at day 7. Favipiravir significantly improved the latency to relieve pyrexia and cough. Adverse effects caused by favipiravir are mild and manageable.

METTL3­mediated m6A modification of Bcl­2 mRNA promotes non­small cell lung cancer progression.

Methyltransferase­like 3 (METTL3) is an RNA methyltransferase that mediates modification of N6­methyladenosine (m6A), which serves as an oncogene in various types of cancer. The role of m6A modification in the onset and progression of cancer has attracted growing attention. However, the functional and regulatory mechanisms of METTL3 in non­small cell lung cancer (NSCLC) progression are still poorly understood. In the present study, METTL3 expression in NSCLC tissue was analyzed using the Gene Expression Profiling Interactive Analysis database. Western blotting and reverse transcription­quantitative PCR were performed to evaluate the expression of METTL3 in NSCLC tissue and cell lines. Here, knockdown and overexpression of METTL3 notably decreased NSCLC cell viability, apoptosis and migration in vitro and, as well as tumorigenicity in vivo. Expression of METTL3 was upregulated in NSCLC tissue. METTL3 overexpression promoted cell viability and migration in NSCLC, while knockdown of METTL3 yielded the opposite result in vivo and in vitro. METTL3 increased Bcl­2 translation via m6A modification, which increased viability and enhanced migration of NSCLC cells. METTL3 served as an oncogene in NSCLC via METTL3­mediated Bcl­2 mRNA m6A modification, which indicated that targeting METTL3 may be an effective therapeutic strategy for clinical management of NSCLC.

Risk factors for the delayed viral clearance in COVID-19 patients.

Comorbidities are important for the disease outcome of COVID-19, however, which underlying diseases that contribute the most to aggravate the conditions of COVID-19 patients are still unclear. Viral clearance is the most important laboratory test for defining the recovery of COVID-19 infections. To better understand which underlying diseases that are risk factors for delaying the viral clearance, we retrospectively analyzed 161 COVID-19 clinical cases in the Zhongnan Hospital of Wuhan University, Wuhan, China between January 5 and March 13, 2020. The demographic, clinical and laboratory data, as well as patient treatment records were collected. Univariable and multivariable analysis were performed to explore the association between delayed viral clearance and other factors by using logistic regression. Survival analyses by Kaplan-Meier and Cox regression modeling were employed to identify factors negatively influencing the viral clearance negatively. We found that hypertension and intravenous immunoglobulin adversely affected the time of viral RNA shedding. Hypertension was the most important risk factor to delay the SARS-CoV-2 virus clearance, however, the use of Angiotensin-Converting Enzyme Inhibitors(ACEI)/Angiotensin Receptor Blockers(ARB) did not shorten the time for virus clearance in these hypertensive patients' virus clearance. We conclude that patients having hypertension and intravenous immunoglobulin may delay the viral clearance in COVID-19 patients.

Advances in the study of cancer metastasis and calcium signaling as potential therapeutic targets.

Metastasis is still the primary cause of cancer-related mortality. However, the underlying mechanisms of cancer metastasis are not yet fully understood. Currently, the epithelial-mesenchymal transition, metabolic remodeling, cancer cell intercommunication and the tumor microenvironment including diverse stromal cells, are reported to affect the metastatic process of cancer cells. Calcium ions (Ca2+) are ubiquitous second messengers that manipulate cancer metastasis by affecting signaling pathways. Diverse transporter/pump/channel-mediated Ca2+ currents form Ca2+ oscillations that can be decoded by Ca2+-binding proteins, which are promising prognostic biomarkers and therapeutic targets of cancer metastasis. This paper presents a review of the advances in research on the mechanisms underlying cancer metastasis and the roles of Ca2+-related signals in these events.

Clinical characteristics of COVID-19 patients with HIV coinfection in Wuhan, China.

BACKGROUND: Information about the impact of HIV coinfection on clinical characteristics of COVID-19 patients remains limited. METHODS: Maximum body temperatures, fever duration, chest CT and viral shedding, lymphocyte counts, and titer of SARS-CoV-2 antibody were compared between COVID-19 patients with and without HIV infection in Zhongnan Hospital of Wuhan University from January 20th to February 14th, 2020. RESULTS: Compared with 53 COVID-19 patients without HIV infection, the patients with SARS-CoV-2 and HIV coinfection had higher maximum body temperatures (38.7°C vs 37.6°C, P = 0.044), longer duration of fever (8.7 ± 4.5 vs 4.2 ± 2.1 days, P = 0.038), longer time to have improvement of chest CT images (22 vs 15 days from the onset of illness, P = 0.011), lower level of SARS-CoV-2 IgG (5.11 ± 32.33 vs 37.45 ± 15.48 AU/ml, P = 0.042). However, no statistically significant difference of duration of SARS-CoV-2 shedding in the two groups was found (12.3 ± 2.6 vs 13.4 ± 2.4 days, , P = 0.813). CONCLUSION: Lower level of CD4+ T lymphocyte counts caused by HIV infection itself might be one of reasons for relatively weak ability to produce SARS-CoV-2 specific antibodies. The effects of anti-HIV drugs in prevention and treatment of COVID-19 appears to be limited.

Clinical Characteristics of Refractory Coronavirus Disease 2019 in Wuhan, China.

BACKGROUND: Since December 2019, coronavirus disease 2019 (COVID-19), caused by severe adult respiratory syndrome coronavirus 2, occurred in Wuhan, and rapidly spread throughout China. This study aimed to clarify the characteristics of patients with refractory COVID-19. METHODS: In this retrospective single-center study, we included 155 consecutive patients with confirmed COVID-19 in Zhongnan Hospital of Wuhan University from 1 January to 5 February. The cases were divided into general and refractory COVID-19 groups according to the clinical efficacy of treatment after hospitalization, and the differences between groups were compared. RESULTS: Compared with patients with general COVID-19 (45.2%), those with refractory disease were older, were more likely to be male, and had more underlying comorbid conditions, a lower incidence of fever, higher maximum temperatures among patients with fever, higher incidences of shortness of breath and anorexia, more severe disease assessment at admission, higher neutrophil, aspartate aminotransferase, lactate dehydrogenase, and C-reactive protein levels, lower platelet counts and albumin levels, and higher incidences of bilateral pneumonia and pleural effusion (P < .05). Patients with refractory COVID-19 were more likely to receive oxygen, mechanical ventilation, expectorant, and adjunctive treatment, including corticosteroids, antiviral drugs, and immune enhancers (P < .05). Considering the factors of disease severity at admission, mechanical ventilation, and intensive care unit transfer, patients with refractory COVID-19 were also more likely to be male, have manifestations of anorexia on admission, and receive oxygen, expectorant, and adjunctive agents (P < .05). CONCLUSION: In nearly 50% of patients with COVID-19 obvious clinical and radiological remission was not achieved within 10 days after hospitalization. Male, anorexia, and no fever at admission was predictive of poor treatment efficacy.

Liraglutide Attenuates Myocardial Fibrosis via Inhibition of AT1R-Mediated ROS Production in Hypertensive Mice.

BACKGROUND/AIMS: Glucagon-like peptide-1 receptor agonist liraglutide has been reported to exert cardioprotective effects, but its effect on cardiac fibrosis remains controversial. The aim of this study was to investigate the effects of liraglutide on cardiac fibrosis and potential mechanisms. METHODS: C57BL/6 mice (3-month old) were randomly divided into control, hypertension, and hypertension + liraglutide groups. The hypertensive state was created by infusion of Ang II (100 ng/kg·min) for 4 weeks through subcutaneously implanted osmotic pumps. The control mice were infused with saline. Mice were also given vehicle or liraglutide (400 µg/kg·day). Blood pressure (BP), blood sugar, myocardial fibrosis, AT1R expression, and reactive oxygen species (ROS) levels were measured. To further elucidate the mechanisms of fibrosis, mouse cardiac fibroblasts were isolated and treated with liraglutide (300 nM/L) or losartan (10 µM) for 3 hours, followed by Ang II (10-7 M) for additional 12 hours. Reactive oxygen species production and expressions of collagen-1 and -3 were measured. RESULTS: Liraglutide reduced BP and blood sugar but did not affect the body weight of the hypertensive mice. Liraglutide also inhibited collagen accumulation, AT1R expression, and ROS generation in the hearts of the hypertensive mice. In in vitro studies, pretreatment with liraglutide and losartan (as control) markedly inhibited Ang II-induced ROS production and collagen expression in the cultured cardiac fibroblasts. CONCLUSION: Liraglutide reduces myocardial fibrosis in the hypertensive mice, which appears to be dependent on at least in part inhibition of ROS production.