Plants in Anticancer Drug Discovery: From Molecular Mechanism to Chemoprevention.

Cancer is one of the primary causes of mortality globally, and the discovery of new anticancer drugs is the most important need in recent times. Natural products have been recognized as effective in fight against various diseases including cancer for over 50 years. Plants and microbes are the primary and potential sources of natural compounds to fight against cancer. Moreover, researches in the field of plant-based natural compounds have moved towards advanced and molecular level understandings from the last few decades, leading to the development of potent anticancer agents. Also, plants have been accepted as abundant and prosperous sources for the development of novel therapeutic agents for the management and prevention of different cancer types. The high toxicity of some cancer chemotherapy drugs, as well as their unfavorable side effects and drugs resistance, drives up the demand for natural compounds as new anticancer drugs. In this detailed evidence-based mechanistic review, facts and information about various medicinal plants, their bioactive compounds with their potent anticancer activities against different cancers have been gathered, with further approach to represent the molecular mechanism behind the anticancer activity of these plants. This review will be beneficial for investigators/scientists globally involved in the development of natural, safe, effective, and economical therapeutic agents/drugs against various cancers. This might be an important contribution in the field of drug discovery, where drugs can be used alone or in combination to increase the efficacy of newly synthesized drugs.

Plants-Derived Biomolecules as Potent Antiviral Phytomedicines: New Insights on Ethnobotanical Evidences against Coronaviruses.

SARS-CoV-2 infection (COVID-19) is in focus over all known human diseases, because it is destroying the world economy and social life, with increased mortality rate each day. To date, there is no specific medicine or vaccine available against this pandemic disease. However, the presence of medicinal plants and their bioactive molecules with antiviral properties might also be a successful strategy in order to develop therapeutic agents against SARS-CoV-2 infection. Thus, this review will summarize the available literature and other information/data sources related to antiviral medicinal plants, with possible ethnobotanical evidence in correlation with coronaviruses. The identification of novel antiviral compounds is of critical significance, and medicinal plant based natural compounds are a good source for such discoveries. In depth search and analysis revealed several medicinal plants with excellent efficacy against SARS-CoV-1 and MERS-CoV, which are well-known to act on ACE-2 receptor, 3CLpro and other viral protein targets. In this review, we have consolidated the data of several medicinal plants and their natural bioactive metabolites, which have promising antiviral activities against coronaviruses with detailed modes of action/mechanism. It is concluded that this review will be useful for researchers worldwide and highly recommended for the development of naturally safe and effective therapeutic drugs/agents against SARS-CoV-2 infection, which might be used in therapeutic protocols alone or in combination with chemically synthetized drugs.

Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies.

BACKGROUND & AIMS: Remdesivir is a broad spectrum anti-viral drug that has shown to inhibit SARS-CoV-2, in vitro and in vivo. In absence of any effective treatment for SARS-CoV-2 infection (COVID-19), remdesivir has been tried for a compassionate use in severe COVID-19. Newer randomized controlled studies that have recently become available, showed a mixed result. We aimed to systematically search the literature to understand the pharmacology and clinical effects of remdesivir in patients with COVID-19. METHODS: We systematically searched the PubMed, ClinicalTrial.Org and MedRxiv database up till May 5, 2020 using specific key words such as "Remdesivir" or 'GS-5734″ AND "COVID-19" or "SARS-CoV-2" and retrieved all the article published in English language, that have reported the pharmacology and the clinical outcomes of remdesivir in patients with COVID-19. RESULTS: Initial compassionate use of remdesivir has shown a fairly good result, but difficult to quantify, in the absence of control arm. While the very first double-blind, placebo-controlled, randomized trial conducted in Wuhan, did not find any significant benefit compared to the control, the preliminary result of another similar multi-country trial has shown a significant faster time to recovery but without any difference in mortality. CONCLUSIONS: Remdesivir has shown a mixed result in patients with COVID-19 with an acceptable side effect. However, jury is still out while awaiting the results from the forthcoming trials.

Low Vitamin D Levels in Rheumatoid Arthritis Patient is Associated with Poor Disability Index and Increased Patient Global Disease Assessment Score.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory connective tissue disorder with wide spectrum of presentation from polyarthritis to multisystem involvement. Apart from bones, muscles and other soft tissues, Vitamin D receptors have been found on many immune cells and tissues. The most vital function of Vitamin D is calcium and phosphorus absorption but it can also act as an immune-modulator hormone, which can affects both innate and adaptive immune responses leading to autoimmune diseases. OBJECTIVES: To study the relationship of vitamin D insufficiency with disease activity and functional disability in patients of Rheumatoid Arthritis. MATERIAL AND METHODS: The present study was an observational, cross sectional study done in a tertiary care hospital in New Delhi, India. The inclusion criteria comprised of patients attending the inpatient (IPD) and outpatient department (OPD), age above 18 years and fulfilling 1987 American college of Rheumatology (ACR) criteria for RA. The exclusion criteria was patients suffering from any other connective tissue disorder (CTD) and patients who were taking vitamin D supplements for past 6 months. Thirty patients were enrolled in the study after satisfying inclusion and exclusion criteria and appropriate clinical data and blood sample were collected after informed consent. Joint examination were performed and swollen joint count (SJC), tender joint count (TJC), patient global assessment (PGA) and evaluator global assessment (EGA) scores were recorded. Disease activity using DAS28ESR, DAS28CRP and CDAI were calculated and disability index was assessed using Short Fries Health Assessment Questionnaire. RESULTS: In our study mean vitamin D level was 18.93 ng/ml (S.D. 6.64 ng/ml). Mean DAS28 ESR was 4.57±1.48. Mean Disability Index was 0.52±0.89. All the study population had low Vitamin D level (100%), while 50% patients had vitamin D level in deficiency range (<20ng/ml). On analysis by student t-test, statistically higher PGA (p value 0.024) and Disability Index (p value < 0.001) in vitamin D deficient patients, compared to vitamin D insufficient patient group was observed, however there was no significant difference in disease activity between the groups. CONCLUSION: Low Vitamin D levels are common in Indian rheumatoid arthritis patients. Mean PGA significantly increased, and disability index significantly increased in Vitamin D deficient group compared to insufficient group suggesting vitamin D deficient patients poor wellbeing and more disability.

Effect of high dose vitamin d supplementation on vitamin d nutrition status of pre-pubertal children on anti-epileptic drugs - A randomized controlled trial.

BACKGROUND AND AIMS: Patients on long term anti-epileptic drug therapy are prone for Vitamin D deficiency for a myriad of reasons. The aim of this research was to study the effect of high dose vitamin D supplementation on vitamin D nutrition status of children newly started on anti-epileptic drug therapy. MATERIALS: This randomized controlled trial was conducted in a tertiary care Children's Hospital at New Delhi from November 2011 to March 2013. Eighty three children in the age group 5-10 years newly started on anti-epileptic drugs (AED) were randomized into two groups; group A - the intervention group, to whom 60,000 IU vitamin D3 was given orally/month under direct supervision along with AED for a period of 6 months, and group B- the control group, to whom AED without vitamin D3 was given. Serum 25(OH)D, ionized calcium (iCa), total calcium (tCa), inorganic phosphate (iP), alkaline phosphatase (ALP) and parathyroid hormone (PTH) levels were assayed at baseline and at the end of 6 months and were compared within and between the two groups. RESULTS: The mean 25(OH)D in Group A was maintained at 6 months follow up [ 26 ng/ml, 95% CI 20-34 ng/ml] compared to baseline [25 ng/ml, 95% CI -19 to 33 ng/ml] [ p = 0.83]. In group B, there was a significant decrease in 25(OH)D levels at 6 months [13 ng/ml (95% CI 9 ng/ml-17 ng/ml)] compared to baseline [18 ng/ml (95% CI 13-24 ng/ml)] [p = 0.01]. At 6 months, mean serum 25(OH)D was significantly higher in group A as compared to group B (p = 0.005). CONCLUSION: To conclude, oral administration of 60,000 IU vitamin D3/month is sufficient to maintain serum 25(OH)D level and prevent development of vitamin D deficiency in children newly started on AED over a period of 6 months. Non supplementation leads to the lowering of serum 25(OH)D in these children. TRIAL REGISTRATION NUMBER: CTRI/2017/08/009234.

The study of association of Vitamin B12 deficiency in type 2 diabetes mellitus with and without diabetic nephropathy in North Indian Population.

AIM: Diabetic Mellitus is the chronic metabolic disorder associated with various complications of heart, eyes, nerves, kidney etc. Diabetic Nephropathy is one of the leading causes of death in diabetic patient. We hypothesized that decrease Vitamin B12 levels is associated with Diabetic Nephropathy. Aim of our study is to study the serum Vitamin B12 levels in type 2 diabetes mellitus patients with and without nephropathy. METHODS: Our study population consist of 100 subjects out of which 50 cases of Diabetes Mellitus without Diabetic Nephropathy and 50 cases of Diabetes Mellitus with Diabetic Nephropathy. We measured various routine lab parameters, apart from it, we measured spot urinary albumin to creatinine ratio to assess diabetic nephropathy and in special investigation we measured serum Vitamin B12 by chemiluminesence based immunoassay. RESULT: Serum Vitamin B12 level in the group with nephropathy (181.6±17.6pg/dl) was significantly lower than in the group without nephropathy (286±30.1pg/dl) (p=0.03). CONCLUSION: Our study points towards the decrease levels of serum Vitamin B12 levels associated with the complication of diabetic mellitus such as diabetic nephropathy. So treatment of Vitamin B12 deficiency by supplementing could prevent the development and progression of diabetic nephropathy and improves the overall management of diabetic patient.

Chemomodulatory Potential of Flaxseed Oil Against DMBA/Croton Oil-Induced Skin Carcinogenesis in Mice.

The present study was conducted to evaluate the potential of flaxseed oil to prevent chemically induced skin cancer in mice. Cancer was induced on 2-stage skin carcinogenesis model by single topical application of 7,12 dimethylbenz [a]anthracene (DMBA), as, initiator, and two weeks later it was promoted by croton oil treatment thrice a week on the dorsal surface of mice for 16 weeks. Flaxseed oil (FSO; 100µL/animal/d) was orally administered 1 week before and 1 week after DMBA application (Peri-initiation stage). The animals of the FSO-administered group showed a significant reduction in tumor incidence (76.67%), cumulative number of tumors (37), tumor yield (3.7), and tumor burden (4.81) when compared with the carcinogen-treated control animals. Biochemical parameters in skin and liver tissue such as LPO and phase I enzymes were significantly (P < .01) reduced in the FSO-treated experimental group, whereas the phase II enzymes (GST, DT-diaphorase) and antioxidant parameters (GSH, GPx, SOD, catalase, and vitamin C) exhibited a significant (P < .01) elevation when compared with the animals of the carcinogen-treated control group. Histopathological alterations in the carcinogen-treated control animals were also observed in the form of epidermal hyperplasia, keratinized pearl formation, and acanthosis in skin and tumors, whereas these were found to be reduced after FSO administration. The results of the present study demonstrate that the oral administration of FSO has the potential to modulate the levels of LPO, antioxidants, and detoxification enzymes in the DMBA-croton oil-induced skin carcinogenesis in mice.

A Randomized controlled trial on safety and efficacy of single intramuscular versus staggered oral dose of 600 000IU Vitamin D in treatment of nutritional rickets.

OBJECTIVE: Comparison of efficacy and safety of two different regimens of vitamin D-600 000 IU as a single intramuscular dose, and 60 000IU orally once a week for 10 weeks-in treatment of nutritional rickets. METHODS: Children with nutritional rickets (age: 0.5-5 years, n = 61) were randomized to receive either 60 000IU vitamin D orally once a week for 10 weeks or 600 000IU single intramuscular injection. Serum calcium, phosphate, alkaline phosphatase, urinary calcium/creatinine ratio, serum 25 hydroxy vitamin D and radiological score were compared at 12-week follow-up. RESULTS: No difference was found in efficacy of the two regimens on comparing biochemical and radiological parameters. Serum 25 hydroxy vitamin D >100 ng/ml was found in two children in the oral group and one child in the intramuscular group. No child developed hypercalcemia or hypercalciuria after starting treatment. CONCLUSION: Staggered oral and one-time intramuscular administrations of 600 000IU vitamin D are equally effective and safe in treatment of nutritional rickets.