In vitro effect of Withania somnifera, AYUSH-64, and remdesivir on the activity of CYP-450 enzymes: Implications for possible herb−drug interactions in the management of COVID-19

Ayurvedic medicines Withania somnifera Dunal (ashwagandha) and AYUSH-64 have been used for the prevention and management of COVID-19 in India. The present study explores the effect of Ashwagandha and AYUSH-64 on important human CYP enzymes (CYP3A4, CYP2C8, and CYP2D6) to assess their interaction with remdesivir, a drug used for COVID-19 management during the second wave. The study also implies possible herb−drug interactions as ashwagandha and AYUSH-64 are being used for managing various pathological conditions. Aqueous extracts of ashwagandha and AYUSH-64 were characterized using LC-MS/MS. A total of 11 and 24 phytoconstituents were identified putatively from ashwagandha and AYUSH-64 extracts, respectively. In addition, in silico studies revealed good ADME properties of most of the phytoconstituents of these herbal drugs and suggested that some of these might possess CYP-450 inhibitory activity. In vitro CYP-450 studies with human liver microsomes showed moderate inhibition of CYP3A4, 2C8, and 2D6 by remdesivir, while ashwagandha had no inhibitory effect alone or in combination with remdesivir. AYUSH-64 also exhibited a similar trend; however, a moderate inhibitory effect on CYP2C8 was noticed. Thus, ashwagandha seems to be safe to co-administer with the substrates of CYP3A4, CYP2C8, and CYP2D6. However, caution is warranted in prescribing AYUSH-64 along with CYP2C8 substrate drugs. Furthermore, preclinical and clinical PK studies would be helpful for their effective and safer use in the management of various ailments along with other drugs

Therapeutic Potential of Chrysin in Improving Bone Health

Vitamin D deficiency is endemic worldwide. Although several strategies have been established to enhance vitamin D3 levels, studies specifically focusing on the inhibition of vitamin D metabolism, which may prolong the availability of active vitamin D in pathological conditions, have been less explored. Studies also suggest that higher doses of vitamin D3 fail to achieve optimum vitamin D levels. In this context, we focused on the enzyme CYP3A4, which promotes the inactivation of active vitamin D. The current study aimed to decipher the impact of chrysin, a proven CYP3A4 inhibitor, as an intervention and its effects in combination with low-dose vitamin D3 (40 IU) and bone health in vitamin D deficiency conditions. The in vivo activity of chrysin was evaluated in female Wistar albino rats fed a vitamin-D-deficient diet to attain vitamin D deficiency for 28 days. Chrysin was given alone and in combination with calcium carbonate (CaCO3) and/or vitamin D3. All therapeutic interventions were assessed for serum 25-hydroxyvitamin D3(25-OH-D3) by LC-MS and biochemical, urinary, and bone parameters. Animals treated with chrysin alone and in combination with low-dose vitamin D3 and/or CaCO3 showed an eminent rise in serum 25-OH-D3 levels along with increased serum biochemical parameters. In contrast, a significant decrease in the urinary parameters followed by beneficial effects on bone parameters was noticed in contrast with the vitamin-D-deficient diet group. Our findings revealed that although chrysin alone showed a notable effect on 25-OH-D3 and osseous tissue, comparatively, it showed an intensified therapeutic effect in combination with vitamin D3 and CaCO3, which can be employed as a cost-effective option to improve bone health

Therapeutic Potential of Chrysin in Improving Bone Health

Vitamin D deficiency is endemic worldwide. Although several strategies have been established to enhance vitamin D3 levels, studies specifically focusing on the inhibition of vitamin D metabolism, which may prolong the availability of active vitamin D in pathological conditions, have been less explored. Studies also suggest that higher doses of vitamin D3 fail to achieve optimum vitamin D levels. In this context, we focused on the enzyme CYP3A4, which promotes the inactivation of active vitamin D. The current study aimed to decipher the impact of chrysin, a proven CYP3A4 inhibitor, as an intervention and its effects in combination with low-dose vitamin D3 (40 IU) and bone health in vitamin D deficiency conditions. The in vivo activity of chrysin was evaluated in female Wistar albino rats fed a vitamin-D-deficient diet to attain vitamin D deficiency for 28 days. Chrysin was given alone and in combination with calcium carbonate (CaCO3) and/or vitamin D3. All therapeutic interventions were assessed for serum 25-hydroxyvitamin D3(25-OH-D3) by LC-MS and biochemical, urinary, and bone parameters. Animals treated with chrysin alone and in combination with low-dose vitamin D3 and/or CaCO3 showed an eminent rise in serum 25-OH-D3 levels along with increased serum biochemical parameters. In contrast, a significant decrease in the urinary parameters followed by beneficial effects on bone parameters was noticed in contrast with the vitamin-D-deficient diet group. Our findings revealed that although chrysin alone showed a notable effect on 25-OH-D3 and osseous tissue, comparatively, it showed an intensified therapeutic effect in combination with vitamin D3 and CaCO3, which can be employed as a cost-effective option to improve bone health

Identification of herbal teas and their compounds eliciting antiviral activity against SARS-CoV-2 in vitro

Background: The SARS-CoV-2/COVID-19 pandemic has inflicted medical and socioeconomic havoc, and despite the current availability of vaccines and broad implementation of vaccination programs, more easily accessible and cost-effective acute treatment options preventing morbidity and mortality are urgently needed. Herbal teas have historically and recurrently been applied as self-medication for prophylaxis, therapy, and symptom alleviation in diverse diseases, including those caused by respiratory viruses, and have provided sources of natural products as basis for the development of therapeutic agents. To identify affordable, ubiquitously available, and effective treatments, we tested herbs consumed worldwide as herbal teas regarding their antiviral activity against SARS-CoV-2. Results: Aqueous infusions prepared by boiling leaves of the Lamiaceae perilla and sage elicit potent and sustained antiviral activity against SARS-CoV-2 when applied after infection as well as prior to infection of cells. The herbal infusions exerted in vitro antiviral effects comparable to interferon-β and remdesivir but outperformed convalescent sera and interferon-α2 upon short-term treatment early after infection. Based on protein fractionation analyses, we identified caffeic acid, perilla aldehyde, and perillyl alcohol as antiviral compounds. Global mass spectrometry (MS) analyses performed comparatively in two different cell culture infection models revealed changes of the proteome upon treatment with herbal infusions and provided insights into the mode of action. As inferred by the MS data, induction of heme oxygenase 1 (HMOX-1) was confirmed as effector mechanism by the antiviral activity of the HMOX-1-inducing compounds sulforaphane and fraxetin. Conclusions: In conclusion, herbal teas based on perilla and sage exhibit antiviral activity against SARS-CoV-2 including variants of concern such as Alpha, Beta, Delta, and Omicron, and we identified HMOX-1 as potential therapeutic target. Given that perilla and sage have been suggested as treatment options for various diseases, our dataset may constitute a valuable resource also for future research beyond virology

Therapeutic Potential of Chrysin in Improving Bone Health

Vitamin D deficiency is endemic worldwide. Although several strategies have been established to enhance vitamin D3 levels, studies specifically focusing on the inhibition of vitamin D metabolism, which may prolong the availability of active vitamin D in pathological conditions, have been less explored. Studies also suggest that higher doses of vitamin D3 fail to achieve optimum vitamin D levels. In this context, we focused on the enzyme CYP3A4, which promotes the inactivation of active vitamin D. The current study aimed to decipher the impact of chrysin, a proven CYP3A4 inhibitor, as an intervention and its effects in combination with low-dose vitamin D3 (40 IU) and bone health in vitamin D deficiency conditions. The in vivo activity of chrysin was evaluated in female Wistar albino rats fed a vitamin-D-deficient diet to attain vitamin D deficiency for 28 days. Chrysin was given alone and in combination with calcium carbonate (CaCO3) and/or vitamin D3. All therapeutic interventions were assessed for serum 25-hydroxyvitamin D3(25-OH-D3) by LC-MS and biochemical, urinary, and bone parameters. Animals treated with chrysin alone and in combination with low-dose vitamin D3 and/or CaCO3 showed an eminent rise in serum 25-OH-D3 levels along with increased serum biochemical parameters. In contrast, a significant decrease in the urinary parameters followed by beneficial effects on bone parameters was noticed in contrast with the vitamin-D-deficient diet group. Our findings revealed that although chrysin alone showed a notable effect on 25-OH-D3 and osseous tissue, comparatively, it showed an intensified therapeutic effect in combination with vitamin D3 and CaCO3, which can be employed as a cost-effective option to improve bone health