An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.

Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.

Chinese expert consensus on the treatment of modern combat-related spinal injuries.

The battlefield treatments of spinal and spinal cord injury vary from civilian settings. However, there is no unified battlefield treatment guidelines for spine trauma in PLA. An expert consensus is reached, based on spine trauma epidemiology and the concepts of battlefield treatment combined with the existing levels of military medical care in modern warfare. Since the specialized treatment for spine trauma are no significant difference between civilian settings and modern war, the first aid, emergency treatment and early treatment of spine trauma are introduced separately in three levels in this consensus. In Level I facilities, the fast and accurate evaluation of spine trauma followed by fixation and stabilization are recommended during the first-aid stage. Re-evaluation, further treatment for possible hemorrhagic shock, dyspnea and infection are recommended at Level II facilities. At Level III facilities, it is recommended to strengthen the intensive care and the prevention of urinary system and lung infection for the wounded with severe spinal injury, however, spinal surgery is not recommended in a battlefield hospital. The grading standard for evidence evaluation and recommendation was used to reach this expert consensus.

ATRA and Genistein synergistically inhibit the metastatic potential of human lung adenocarcinoma cells.

OBJECTIVE: This study was to investigate the effects of all-trans retinoic acid (ATRA) in combination with Genistein on the proliferation, expression of apoptosis related proteins and adhesion molecules (MUC1 and ICAM-1) and invasiveness of A549 cells, aiming to investigate whether combined therapy of ATRA and Genistein is superior to monotherapy in suppressing metastasis of lung cancer cells. METHODS: ATRA, Genistein and both were used to treat human lung adenocarcinoma cells (A549 cells). Immunohistochemistry was done for MUC1 expression, flow cytometry for ICAM-1 expression, fluorescence quantitative PCR for MUC1 expression and Western blot assay for the expressions of cell cycle related proteins (CDK4, Rb and p-ERK1/2) and apoptosis related proteins (Bax and Bcl-2). Cells were seeded into Matrigel pre-coated Transwell chambers, and the migrating cells were counted. RESULTS: Combined treatment with ATRA and Genistein was able to reduce the expressions of Bcl-2, MUC1 and ICAM-1 and exerted synergistic effects to inhibit the invasion of A549 cells. CONCLUSION: ATRA and Genistein may synergistically inhibit MUC1 and ICAM-1 expressions and affect the expressions of cell cycle related proteins (CDK4, Rb and p-ERK1/2) and apoptosis related proteins (Bax and Bcl-2), inhibit the metastatic potential of lung cancer A549 cells.

Application of the SCCmec element in the molecular typing of methicillin-resistant Staphylococcus aureus.

Acquisition of the staphylococcal chromosome cassette mec (SCCmec) is one of the key reasons for the resistance of methicillin-resistant Staphylococcus aureus (MRSA). SCCmec is composed of a mec gene complex encoding the PBP2a determinant that is responsible for the ß-lactam resistance of MRSA, and a ccr gene complex encoding recombinases that mediate the integration of SCCmec into and its excision from the recipient chromosome, and so-called three junkyard (J) regions of different sizes. The SCCmec elements carried by MRSA from different geographic locations are diverse, and each type contains characteristic DNA fragments in size. These characteristics of SCCmec element may facilitate the usage of SCCmec in the molecular typing of MRSA strains. In this review, we summarize the structure and function of SCCmec elecments, and discuss the application of SCCmec elements in the molecular typing of MRSA.

Decreased SARI expression predicts poor prognosis of Chinese patients with non-small cell lung cancer.

SARI is associated with the risk for several cancers, and loss of SARI expression is frequently found in aggressive and metastatic cancer. Limited evidence shows that SARI is a tumor suppressor gene, but the role of SARI in non-small cell lung cancer (NSCLC) has not been previously reported. This study was to investigate the SARI expression profile in surgically resected lung cancer tissues of Chinese patients by immunohistochemistry and evaluate the relationship between SARI expression and prognosis of lung cancer patients. Furthermore, SARI gene was transfected into lung cancer cells (A549), and the growth curve and cell healing of lung cancer cells were determined, aiming to investigate the influence of SARI on the growth and migration of lung cancer cells in vitro. Results showed that 103 of 195 (52.82%) tissues were positive for SARI. When compared with normal tissues, SARI expression significantly reduced in 50.26% of NSCLC tissues. Patients with negative or reduced SARI expression were more likely to have advanced lung cancer and lymph node metastasis. In squamous carcinoma and adenocarcinoma patients, the SARI expression had no relation with the survival time; However in one-on-one analysis SARI expression in tumor cells and adjacent tissues, patients which tumor cells SARI express reduced than adjacent tissues, survival time was significantly shorter than those without reduction in SARI expression (Log Rank test, p = 0.001). After transfection by SARI gene, the proliferation and migration of A549 cells were obviously inhibited (p < 0.001). These results demonstrate that decreased SARI expression may predict a poor prognosis in NSCLC patients, and SARI may serve as a prognostic biomarker and potential therapeutic target for lung cancer.

Clinical significance of RUNX2 expression in patients with nonsmall cell lung cancer: a 5-year follow-up study.

This study was designed to evaluate expression and prognostic significance of runt-related transcription factor (RUNX)-2 in human nonsmall cell lung cancer (NSCLC). RUNX2 expression was examined at mRNA and protein levels by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot in NSCLC tissues and adjacent normal tissues. In addition, RUNX2 expression was analyzed by immunohistochemistry in 121 clinicopathologically characterized NSCLC cases. The relationship between the expression of RUNX2 and clinicopathological characteristics and prognosis was statistically analyzed. Both qRT-PCR and Western blot demonstrated that RUNX2 mRNA and protein levels were significantly higher in NSCLC tissues compared to the adjacent normal tissues from the same individual. Immunohistochemistry analysis showed that RUNX2 expression was significantly correlated with tumor size, tumor stage, and lymph node metastasis. Higher RUNX2 expression was associated with shorter postoperative survival time of NSCLC patients by Kaplan-Meier method and was found to be an independent risk factor that influences the postoperative survival time of NSCLC patients by Cox regression analysis. In conclusion, these data showed that RUNX2 may play an important role in NSCLC tumorigenesis, and RUNX2 might serve as a novel prognostic marker in NSCLC.

Anti-tumor effects of all-trans retinoic acid are enhanced by genistein.

The effects of all-trans retinoic acid (ATRA) on cancer are complex. ATRA has anti-cancer effects as it promotes cancer cell differentiation. However, ATRA also up-regulates expression of vascular endothelial growth factor (VEGF) in cancer cells, which leads to angiogenesis and can, thus, facilitate cancer growth. Genistein, a crucial non-nutrient component in soybean, exhibits anti-cancer effects by inhibiting protein tyrosine kinase that is involved in up-regulation of VEGF. We hypothesized that genistein, applied simultaneously with ATRA, would counter its undesired angiogenic effects and, thus, enhance the anti-cancer effects of ATRA. The purpose of this study was to document potential synergistic effects of genistein and ATRA in A549 lung adenocarcinoma cells. We further explored the role of genistein on countering the ATRA-induced VEGF expression. We demonstrate that genistein enhances the ATRA-induced growth inhibition of A549 cells by promoting apoptosis. Further, the combined use of ATRA and genistein leads to cancer cell arrest in G0/G1 and G2/M cell cycle phases. Finally, expression of VEGF (both mRNA and protein) was diminished in A549 cells exposed to both ATRA and genistein. In conclusion, our results demonstrate that genistein effectively enhances anti-cancer effects of ATRA, particularly, by countering the ATRA-induced up-regulation of VEGF. Our study provides an experimental basis for combined use of ATRA and genistein in the treatment of lung cancer.

Mitochondrial DNA 4977 BP deletion mutations in lung carcinoma.

BACKGROUND: The most common and also the most often assayed mtDNA deletion mutation, degrees mtDNA 4,977 sub has been demonstrated in various types of human cancer. However, knowledge about degrees mtDNA 4,977 in lung carcinoma is poor. AIM: To study the 4,977 bp deletions of mitochondrial DNA ( degrees mtDNA 4,977) in lung cancer, adjacent histologically normal and normal lung tissue and its potential roles in the development of cancer. MATERIALS AND METHODS: Thirty-seven matched lung cancer/adjacent histologically normal and 20 histologically normal lung tissue samples in subjects without lung cancer were analyzed by PCR technique. RESULTS: degrees mtDNA 4,977 deletions were detected in 54.1% (20/37) of lung cancers, 59.5% (22/37) of adjacent normal and 30.0% (6/20) of normal lung tissue samples. No significant difference was found in the frequency of degrees mtDNA 4,977 deletions between the tumor and adjacent normal lung tissues (P value = 0.815). Moreover, no significant difference was found in the frequency of degrees mtDNA 4,977 deletions between the tumor and histologically normal lung tissues in subjects without lung cancer (P value=0.101). However, the correlation between degrees mtDNA 4,977 deletion and age and smoking factors was present in our data. STATISTICAL ANALYSIS: Fisher's exact test was used to assess the difference in different groups by the Scientific Package for Social Sciences (SPSS), version 10.0, Statistical analysis software. CONCLUSIONS: Mitochondrial DNA 4,977 bp deletion, which is not specific to lung cancer, may reflect the environmental and aging process influences operative during tumor progression.