Role of toll-like receptors in the pathogenesis of COVID-19: Current and future perspectives.

The coronavirus disease 2019 (COVID-19) pandemic underlines a persistent threat of respiratory tract infectious diseases and warrants preparedness for a rapid response. At present, COVID-19 has had a serious social impact and imposed a heavy global burden on public health. The exact pathogenesis of COVID-19 has not been fully elucidated. Since the outbreak of COVID-19, a renewed attention has been brought to Toll-like receptors (TLRs). Available data and new findings have demonstrated that the interaction of human TLRs and SARS-CoV-2 is a vital mediator of COVID-19 immunopathogenesis. TLRs such as TLR2, 4, 7 and 8 are potentially important in viral combat and activation of immunity in patients with COVID-19. Therapeutics targeting TLRs are currently considered promising options against the pandemic. A number of TLR-targeting immunotherapeutics are now being investigated in preclinical studies and different phases of clinical trials. In addition, innovative vaccines based on TLRs under development could be a promising approach for building a new generation of vaccines to solve the current challenges. In this review, we summarize recent progress in the role of TLRs in COVID-19, focusing the new candidate drugs targeting TLRs, the current technology and potential paths forward for employing TLR agonists as vaccine adjuvants.

The in vitro and in vivo anti-inflammatory effect of osthole, the major natural coumarin from Cnidium monnieri (L.) Cuss, via the blocking of the activation of the NF-κB and MAPK/p38 pathways.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory condition of the intestines and is difficult to cure once diagnosed. The efficacy of the current clinical treatment for UC is limited. Common anti-inflammatory drugs are prone to adverse effects, while novel biological agents are expensive, although tolerated by patients. Therefore, an urgency exists to find more safe and effective drugs to treat UC. Osthole is an active constituent isolated from the fruit of Cnidium monnieri (L.) Cuss. Osthole has anti-inflammatory activities and offers certain intestinal protection. These characteristics indicate that osthole has the potential to inhibit UC. PURPOSE: The study was conducted to investigate the anti-inflammatory potential of osthole in LPS-induced RAW 264.7 cells and dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. METHODS: In in vitro experiments, mouse monocyte-macrophage RAW 264.7 cells were stimulated by 1 µg/ml LPS to produce inflammatory mediators. Griess reagent was used to determine Nitric Oxide (NO) production, and ELISA kits were used to determine the levels of PGE2, TNF-α, and IL-6. The anti-inflammatory mechanisms of osthole were detected using western blot. In in vivo experiments, UC was induced via the intragastric administration of 3.5% DSS to BALB/C mice for 7 days. During the experiment, clinical signs and body weight were monitored and recorded daily to calculate the DAI score. At the end of the experiment, the colon lengths were measured. The colonic histopathological lesions were evaluated. MPO activity and TNF-α levels were determined using the corresponding kits. The protein expression of TNF-α and NF-κB pathways were analysed using western blot. RESULTS: In an in vitro study, osthole inhibited the production of NO, PGE2, TNF-α, and IL-6 in LPS-induced RAW 264.7 cells. The results of western blot showed that osthole inhibited the expression of iNOS, COX-2, p38 MAPK and IκB α in RAW 264.7 cells. On this basis, in DSS-induced UC mice, it was found that osthole relieved the symptoms of UC by inhibiting weight loss, colon shortening and the DAI score, and simultaneously alleviating colon tissue lesions. It was also found that osthole reduced the levels of TNF-α in serum and colon tissues and effectively inhibited the activity of MPO. The western blot results showed that osthole reduced the expression of NF-κB p65 and p-IκB α and increased the content of IκB α in colon tissues. CONCLUSION: Osthole exerted anti-inflammatory effects by blocking the activation of the NF-κB and MAPK/p38 pathways. Additionally, osthole possesses therapeutic potential in the treatment of UC.

Andrographolide derivative CX-10 ameliorates dextran sulphate sodium-induced ulcerative colitis in mice: Involvement of NF-κB and MAPK signalling pathways.

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), which is characterized by chronic intestinal inflammation and leads to an increased risk of colon cancer. There are many studies using phyto-ingredients as a novel approach for the treatment of UC. The plant Andrographis paniculata (Acanthaceae) is a safe and edible vegetable that has been extensively adopted in traditional Chinese medicine for conditions involving inflammation, and the most active phytochemical agent is andrographolide. The andrographolide derivative 3,14,19-triacetyl andrographolide, which is known as CX-10 (a hemi chemical synthesized from andrographolide), has been found to possess strong anti-inflammatory properties. In the present study, we investigated the therapeutic potential of CX-10 as a complementary and alternative medicine against dextran sulphate sodium (DSS)-induced ulcerative colitis in mice. Our results revealed that CX-10 treatment reduced body weight loss, reduced colon length shortening, decreased colon weight, decreased the spleen index, decreased the disease activity index (DAI), and alleviated histological damage in the colon. The expression of TNF-α and IL-6 and the activity of myeloperoxidase (MPO) in colonic tissues were significantly reduced in CX-10 supplemented mice. It is noteworthy that the efficacy of 200 mg/kg of CX-10 was equivalent to that of the mesalazine positive control (200 mg/kg). Furthermore, western blot analysis revealed that CX-10 treatment reduced the expression of nuclear factor-κB (NF-κB) p65 and p-IκBα, increased the expression of IκBα and down-regulated the phosphorylation of p38 mitogen-activated protein kinase (MAPK), ERK and JNK. In conclusion, CX-10 treatment attenuated DSS-induced UC in mice through inhibiting the activation of NF-κB and MAPK pathways and reducing TNF-α and IL-6 levels, suggesting that CX-10 is a potential therapeutic drug for UC.

Administration of Huperzine A exerts antidepressant-like activity in a rat model of post-stroke depression.

Post-stroke depression (PSD) is the most common mood disorder following a stroke, and is also the main factor limiting recovery and rehabilitation in stroke patients. The present study was aimed to investigate whether Huperzine A (HupA) has antidepressant-like activity in a rat model of PSD, which was developed by middle cerebral artery occlusion followed by an 18-day chronic unpredictable mild stress in conjunction with isolation rearing. The sucrose preference and forced swim tests were used to assess depression-like behavior. Neurological and cognitive functions following ischemia were evaluated by neurological evaluation, the beam-walking test, the forelimb grip force test, and the water maze test. Levels of norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) in the hippocampus and prefrontal cortex were assayed by high performance liquid chromatography. Western blot analysis was used to evaluate hippocampal expression of the 5-hydroxytryptamine 1A receptor (5-HT1AR), cAMP response element binding (CREB), phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF). The results showed that treatment with HupA for 4weeks ameliorated behavioral abnormalities and the impairment of neurological and cognitive functions in PSD rats. This was accompanied by the upregulated hippocampal expression of 5-HT1AR, p-CREB and BDNF, and increased levels of NE, DA, and 5-HT in the hippocampus and prefrontal cortex. These findings suggest that HupA has antidepressant-like effect and can improve neurological and cognitive functions in PSD rats, which suggest its therapeutic potential for depression after stroke.