In this perspective, we propose to leverage reactive oxygen species (ROS) induction as a potential therapeutic measure against viral infections. Our rationale for targeting RNA viral infections by pro-oxidants is routed on the mechanistic hypothesis that ROS based treatment paradigm could impair RNA integrity faster than the other macromolecules. Though antiviral drugs with antioxidant properties confer potential abilities for preventing viral entry, those with pro-oxidant properties could induce the degradation of nascent viral RNA within the host cells, as RNAs are highly prone to ROS mediated degradation than DNA/proteins. We have previously established that Plumbagin is a highly potent ROS inducer, which acts through shifting of the host redox potential. Besides, it has been reported that Plumbagin treatment has the potential for interrupting viral RNA replication within the host cells. Since the on-going Corona Virus Disease - 2019 (COVID-19) global pandemic mediated by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) exhibits high infectivity, the development of appropriate antiviral therapeutic strategies remains to be an urgent unmet race against time. Therefore, additional experimental validation is warranted to determine the appropriateness of repurposable drug candidates, possibly ROS inducers, for fighting the pandemic which could lead to saving many lives from being lost to COVID-19.
Psoriasis is a chronic infl ammatory skin disease that affects 2% to 4% of the population. Infl ammatory arthritis develops in approximately 30% of patients with psoriasis and can have a major effect on activities of daily living and quality of life. Peripheral joint involvement in patients with psoriatic arthritis can be oligo articular or poly articular and can cause joint destruction. Several medications are used to treat psoriatic arthritis, and the choice of agent and the timing of administration in the course of the disease depend on disease manifestations, their severity, and prognostic factors. Therapy typically involves the sequential use of nonsteroidal anti-infl ammatory drugs.
Background Breast cancer is the most common and dreadful form of cancer globally. Inherited mutations in the breast cancer susceptibility gene, BRCA1, increases the cumulative risk of developing breast cancer by 70‐80%. However, hereditary mutations account for only 5‐10% of the breast cancer burden. At the same time, the rest of this menace is attributed to sporadic cases where patients rarely encounter a BRCA1 mutation. Instead, upto 60% of these patients manifest low BRCA1 expression associated with BRCA1 promoter hypermethylation—moreover, many hereditary cases with a mutated BRCA1 allele exhibit promoter hypermethylation in the second allele. Interestingly, most of these cases also develop into a hyper‐aggressive and drug‐resistant form, Triple Negative Breast Cancer (TNBC), where Estrogen Receptors (ER), Progesterone receptors (PR) and Human epidermal growth factor receptors (Her2) are absent or minimally expressed. But the molecular signaling governing this tumorigenesis has remained elusive with an unresolved question of whether promoter hypermethylation is the master controller of the process of tumorigenesis or is a mere consequence of tumor progression. Objective & Methodology To unravel the truth behind this enigma, we induced site‐specific methylations in the CpG island of BRCA1 promoter on wildtype BRCA1 backgrounds using a modified version of CRISPR technology. Results Inducing site‐specific methylation on the BRCA1 promoter effectuated its downregulation via alteration in the balance between its alternate transcripts ‘β’ and ‘α’. Methylation also attenuated the expression of a long noncoding RNA, NBR2 (Neighbor of BRCA1 gene 2), which is transcribed through the BRCA1 promoter in the reverse direction. It, in turn, activates a feedback loop leading to further downregulation of BRCA1 associated with impaired DNA damage repair and a shift in the balance between apoptosis and autophagy evident under glucose starvation conditions. Further, the β subunit of hCG (human chorionic gonadotrophin) hormone, which is often associated with aggressive forms of BRCA1 mutated breast cancers, was significantly overexpressed. With regards to TNBC progression, methylation also led to the downregulation of the hormone receptors except for ER‐ α, which was found to be overexpressed. This ER‐ α surge helps the cells survive the onslaught following DNA Damage under BRCA1 defective condition. Conclusion For the first time, this study elucidates the molecular signaling behind breast tumorigenesis involving BRCA1 hypermethylation. Like BRCA1 mutation screening, our findings open up an outstanding opportunity for screening sporadic breast cancers in females using the combination of NBR2, β‐hCG, and BRCA1 hypermethylation as biomarkers from blood. Moreover, as therapeutic intervention, this study also provides scope for the use of BRCA1 hypermethylation reversing drugs like methotrexate, drugs like biguanides that show better action under NBR2 depleted conditions and development of β‐hCG inhibitors for a better prognosis.
Background: Arthritis and various musculoskeletal disorders are the leading cause of disability in persons between 18 to 65 years of age. Psoriatic arthritis simulates Ayurvedic descriptions of the clinical syndrome - Vatarakta. The study has been designed to evaluate the effectiveness of classical Ashtavaidyan methods of Ayurvedic intervention in the management of psoriatic arthritis and to assess the safety of the therapy. Methodology: Diagnosed cases of psoriatic arthritis (n=30) (20-60 yrs) have undergone the prescribed classical Ashtavaidyan Ayurvedic therapies. The total study period was 57 days which included 21 days each at inpatient and outpatient basis and 15 days of follow up. Initially modified Takradhara was performed along with internal medications for first 14 days; later same internal medication was continued with Sarvanga Abhyanga (therapeutic massage) with Pinda Taila and Vajraka Ghrita in 3:1 ratio externally and Amalaki Thalam for next 7 days. Same internal medicines and oil application were continued for next 21 days as outpatient. Results: The response to treatment was assessed periodically with respective parameters and showed highly significant improvement (P less than 0.001). There was significant reduction in PASI score and also significant changes in functional parameters related to psoriatic arthritis evaluated by using the visual analogue pain scale, DAS score, disability index scores and SF-36 (quality of life Index). The laboratory parameters used to evaluate the liver and renal functions did not show any significant changes that indicate the prescribed treatment is safe. Conclusion: Traditional Ashtavaidyan Ayurveda therapy is effective in reducing the skin lesions and improving functional ability in Vatarakta vis-à-vis psoriatic arthritis over a period of 42 days. Moreover, there was no adverse drug reaction recorded as well no significant change observed in liver and renal function tests.
Women with a family history of mutations in the Breast cancer susceptibility gene, BRCA1 will have an increased risk of developing breast neoplasms. However, majority of the breast cancers are sporadic where BRCA1 mutations are very rare. Instead, 5-65% of sporadic cases manifest BRCA1 promoter hypermethylation and 30-40% of such cases are develop into Triple Negative Breast Cancers. Even then, the molecular mechanism of BRCA1 hypermethylation mediated breast tumorigenesis has remained an enigma till date. Here, we present a novel tumorigenesis pathway for breast cancers that engenders from BRCA1 hypermethylation by using a modified version of CRISPR technology.We report that induction of site-specific methylation on BRCA1 promoter α effectuates a downregulation in BRCA1 expression via alteration in the balance between its alternate transcripts β and α. Induced BRCA1 hypermethylation is also responsible for the attenuation of a long noncoding RNA, NBR2 (Neighbour of BRCA1 gene 2), which is transcribed through the bidirectional BRCA1 promoter α in the reverse direction. Downregulation of NBR2 activates a feedback loop by leading to further downregulation of BRCA1 which is more evident under glucose starvation conditions and is associated with an impaired DNA damage repair pathway. Further, BRCA1 hypermethylation also results in significant overexpression of β-hCG (human chorionic gonadotrophin), which was found to be associated with highly aggressive and drug-resistant forms of BRCA1 mutated breast cancers invitro & in vivo in our previous study. Finally, we report a variation in the hormone receptor levels as the tumor progresses which suggests how BRCA1 deficient cells modulate their expression of ER-α and ER-β to promote their proliferation in early stages of tumor development and at later stages, transform to a basal tumor subtype by shedding down the expression of ER-α & PR.GRAPHICAL ABSTRACT
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