ABSTRACT
According to the world epidemic report, the mortality of patients with severe coronavirus disease 2019 (COVID-19) is high. Diabetic patients are more susceptible to COVID-19. Since the mortality of COVID-19 patients with diabetes is on the top of list, hyperglycemia is considered an independent risk factor for severe COVID-19. Up to now, there is few effective treatment for severe patients infected with 2019 novel coronavirus (2019-nCoV). Clinical studies observed that cytokine storms existed in patients with severe COVID-19. Sustained high levels of cytokines cause diffuse damage to pulmonary capillary endothelial cells and alveolar epithelial cells, resulting in acute respiratory distress syndrome (ARDS). ARDS is the main cause of death in COVID-19 patients. Host-directed therapy (HDT) is an emerging therapeutic method in the field of anti-infection, which can activate the self-protective immune response, suppress excessive inflammatory response, and be used to assist the treatment of traditional drugs to shorten the course of disease. Metformin has been shown to be effective in HDT and can assist in the treatment of the viral and bacterial infectious disease. This paper discusses the rationality and potential therapeutic mechanism of metformin in the treatment of severe COVID-19. It was speculated that the use of metformin for controlling blood glucose in severe COVID-19 patients with diabetes may prevent or inhibit the occurrence of ARDS, thereby reducing the mortality of COVID-19 patients. The possible mechanism is that metformin could inhibit cytokine storm via suppressing interleukin-6 (IL-6) signaling, prevent the process of lung fibrosis, suppress endocytosis, thereby elevating angiotensin converting enzyme 2 (ACE2) expression.
ABSTRACT
Objective@#To explore the synergistic effect of silibinin combined with crizotinib on anaplastic lymphoma kinase positive (ALK+ ) non-small cell lung cancer (NSCLC) cells and its mechanism.@*Methods@#H2228 and H3122 cells were treated with silibinin, crizotinib alone or in combination. Cell proliferation was measured by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and colony formation assay. Migration or invasion ability was tested by wound healing assay or transwell assay, respectively. Expressions of E-Cadherin and vimentin protein were examined by immunofluorescence staining. The protein expressions of ALK, p-ALK, E-Cadherin and Vimentin were detected by western blotting.The anti-cancer effect of silibinin combined with crizotinib in vivo was determined by subcutaneously injecting 2×106 H2228 cells into immunodeficient nude mice.@*Results@#The result of MTT assay showed that the cell viability of H2228 or H3122 treated with 100 μmol/L silibinin was (88.38±4.10)% or (72.27±3.62)%, respectively, marginally decreased compared with that of the control. The 50% inhibitory concentration (IC50) of H2228 cells treated with crizotinib alone or combined with 100 μmol/L silibinin was (917.10±7.75) nmol/L or (238.73±7.67) nmol/L, respectively. The IC50 of H3122 cells treated with crizotinib alone or combined with 100 μmol/L silibinin was (472.50±15.70) nmol/L or (206.10±12.01) nmol/L, respectively. The IC50s of H2228 and H3122 cells were significantly decreased by combined treatment of crizotinib and silibinin compared to crizotinib treatment alone (P<0.01). When compared with the control group, colony forming ratios of H2228 cells were (83.34±2.72)% in 100 μmol/L silibinin treatment group, (69.42±3.06)% in 400 nmol/L crizotinib treatment group and (27.32±1.42)% in combined treatment group. When compared with the control group, colony forming ratios of H3122 cells were (84.45±5.67)% in 100 μmol/L silibinin treatment group, (45.02±5.83)% in 400 nmol/L crizotinib treatment group and (17.43±3.83)% in combined treatment group. Silibinin combined with crizotinib treatment significantly inhibited the colony formation ability of H2228 and H3122 cells (P<0.01). Migration and invasion results showed that combined treatment of crizotinib and silibinin markedly inhibited the migration and invasion ability of H2228 cells (P<0.01). Western blot results indicated that treated with silibinin alone or in combination of crozitinib for 48 hours, the protein level of E-cadherin in H2228 cells was upregulated, while the expressions of p-ALK and vimentin were downregulated, without obvious alteration of ALK protein expression. In the xenograft model, the mean tumor weight was (9.40±2.58)g in crizotinib treatment group and (4.58±1.07)g in the combined treatment group. The inhibitory effect of tumor growth in vivo of combined treatment was significantly superior to that of crizotinib treatment alone (P<0.05).@*Conclusion@#Silibinin enhances the inhibitory effect of crizotinib on ALK positive NSCLC cells, which may be associated with suppression of ALK activity and mesenchymal-epithelial transition.
ABSTRACT
@#Chronic neck pain is a common chronic musculoskeletal disorder. Research on neck muscle fatigue contributed to the understanding the pathogenesis of chronic neck pain. The influences caused by the neck muscle fatigue, such as the change of cervical proprioception and balance, could easily lead to chronic injury. Changes in morphology and recruitment strategy of cervical muscle could decrease muscle endurance, which bring about further damage. Targeted therapy and training can relieve muscle fatigue, improve muscle function, and reduce the recurrence rate. Surface electromyography has unique advantages in the evaluation of cervical muscle fatigue. The assessment of muscle fatigue could provide for assistance to the treatment and curative effect of chronic neck pain.
ABSTRACT
Chronic neck pain is a common chronic musculoskeletal disorder. Research on neck muscle fatigue contributed to the under-standing the pathogenesis of chronic neck pain. The influences caused by the neck muscle fatigue, such as the change of cervical propriocep-tion and balance, could easily lead to chronic injury. Changes in morphology and recruitment strategy of cervical muscle could decrease muscle endurance, which bring about further damage. Targeted therapy and training can relieve muscle fatigue, improve muscle function, and reduce the recurrence rate. Surface electromyography has unique advantages in the evaluation of cervical muscle fatigue. The assess-ment of muscle fatigue could provide for assistance to the treatment and curative effect of chronic neck pain.
ABSTRACT
@#Chronic neck pain is a common chronic musculoskeletal disorder. Research on neck muscle fatigue contributed to the understanding the pathogenesis of chronic neck pain. The influences caused by the neck muscle fatigue, such as the change of cervical proprioception and balance, could easily lead to chronic injury. Changes in morphology and recruitment strategy of cervical muscle could decrease muscle endurance, which bring about further damage. Targeted therapy and training can relieve muscle fatigue, improve muscle function, and reduce the recurrence rate. Surface electromyography has unique advantages in the evaluation of cervical muscle fatigue. The assessment of muscle fatigue could provide for assistance to the treatment and curative effect of chronic neck pain.