Browsing by Author "Radhakrishnan, Rajan"

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Editorial: The use of plant metabolites to ameliorate sequelae of chemotherapy
(2023) Radhakrishnan, Rajan
Introduction: Cancer continues to be a fatal disease with a high annual mortality rate, globally. Despite medical advancements, cancer treatments are often associated with significant adverse effects, posing a great challenge to chemotherapy.
The Effect of Statins on Male Reproductive Parameters: A Mechanism Involving Dysregulation of Gonadal Hormone Receptors and TRPV1
(2023) Omolaoye, Temidayo S.; Cyril, Asha Caroline; Radhakrishnan, Rajan; Rawat, Surendra Singh; Karuvantevida, Noushad; Du Plessis, Stefan
Abstract: Statins have been shown to cause diverse male reproductive function impairment, and in some cases, orchialgia. Therefore, the current study investigated the possible mechanisms through which statins may alter male reproductive parameters. Thirty adult male Wistar rats (200–250 g) were divided into three groups. The animals were orally administered rosuvastatin (50 mg/kg), simvastatin (50 mg/kg), or 0.5% carboxy methyl cellulose (control), for a 30-day period. Spermatozoa were retrieved from the caudal epididymis for sperm analysis. The testis was used for all biochemical assays and immunofluorescent localization of biomarkers of interest. Rosuvastatin-treated animals presented with a significant decrease in sperm concentration when compared to both the control and simvastatin groups (p < 0.005). While no significant difference was observed between the simvastatin and the control group. The Sertoli cells, Leydig cells and whole testicular tissue homogenate expressed transcripts of solute carrier organic anion transporters (SLCO1B1 and SLCO1B3). There was a significant decrease in the testicular protein expression of the luteinizing hormone receptor, follicle stimulating hormone receptor, and transient receptor potential vanilloid 1 in the rosuvastatin and simvastatin-treated animals compared to the control. The expression of SLCO1B1, SLCO1B2, and SLCO1B3 in the different spermatogenic cells portray that un-bio transformed statin can be transported into the testicular microenvironment, which can subsequently alter the regulation of the gonadal hormone receptors, dysregulate pain-inflammatory biomarkers, and consequently impair sperm concentration.
High-fidelity simulation versus case-based tutorial sessions for teaching pharmacology: Convergent mixed methods research investigating undergraduate medical students' performance and perception
(2024-08) Kaddoura, Rachid; Faraji, Hanan; Otaki, Farah; Radhakrishnan, Rajan; Stanley, Adrian; Jackson, Lisa; Mascarenhas, Sharon; Sudhir, Meghana; Alfroukh, Jalal; Ghelani, Hardik; Azar, Aida Joseph; Khamis, Amar Hassan; Jan, Reem Kais; Al Jayyousi, Reem
Abstract Introduction: Medical educators strive to improve their curricula to enhance the student learning experience. The use of high-fidelity simulation within basic and clinical medical science subjects has been one of these initiatives. However, there is paucity of evidence on using simulation for teaching pharmacology, especially in the Middle East and North Africa region, and the effectiveness of this teaching modality, relative to more traditional ones, have not been sufficiently investigated. Accordingly, this study compares the effects of high-fidelity simulation, which is designed in alignment with adult and experiential learning theories, and traditional case-based tutorial sessions on the performance and perception of undergraduate Year 2 medical students in pharmacology in Dubai, United Arab Emirates. Methods: This study employed a convergent mixed methods approach. Forty-nine medical students were randomly assigned to one of two groups during the 16-week pharmacology course. Each group underwent one session delivered via high-fidelity simulation and another via a case-based tutorial. A short multiple-choice question quiz was administered twice (immediately upon completion of the respective sessions and 5 weeks afterwards) to assess knowledge retention. Furthermore, to explore the students' perceptions regarding the two modes of learning delivery (independently and in relation to each other), an evaluation survey was administered following the delivery of each session. Thereafter, the iterative joint display analysis was used to develop a holistic understanding of the effect of high-fidelity simulation in comparison to traditional case-based tutorial sessions on pharmacology learning in the context of the study. Results: There was no statistically significant difference in students' knowledge retention between high-fidelity simulation and case-based tutorial sessions. Yet, students expressed a greater preference for high-fidelity simulation, describing the corresponding sessions as more varied, better at reinforcing learning, and closer to reality. As such, the meta-inferences led to expansion of the overall understanding around students' satisfaction, to both confirmation and expansion of the systemic viewpoint around students' preferences, and lastly to refinement in relation to the perspective around retained knowledge. Conclusion: High-fidelity simulation was found to be as effective as case-based tutorial sessions in terms of students' retention of knowledge. Nonetheless, students demonstrated a greater preference for high-fidelity simulation. The study advocates caution in adapting high-fidelity simulation, where careful appraisal can lend itself to identifying contexts where it is most effective.
Mechanisms of pain in sickle cell disease
(2020) Takaoka, Kensuke; Cyril, Asha Caroline; Radhakrishnan, Rajan
Objectives: The hallmark of sickle cell disease (SCD) is acute and chronic pain, and the pain dominates the clinical characteristics of SCD patients. Although pharmacological treatments of SCD targeting the disease mechanisms have been improved, many SCD patients suffer from pain. To overcome the pain of the disease, there have been renewed requirements to understand the novel molecular mechanisms of the pain in SCD. Methods: We concisely summarized the molecular mechanisms of SCD-related acute and chronic pain, focusing on potential drug targets to treat pain. Results: Acute pain of SCD is caused by vaso-occulusive crisis (VOC), impaired oxygen supply or infarction-reperfusion tissue injuries. In VOC, inflammatory cytokines include tryptase activate nociceptors and transient receptor potential vanilloid type 1. In tissue injury, the secondary inflammatory response is triggered and causes further tissue injuries. Tissue injury generates cytokines and pain mediators including bradykinin, and they activate nociceptive afferent nerves and trigger pain. The main causes of chronic pain are from extended hyperalgesia after a VOC and central sensitization. Neuropathic pain could be due to central or peripheral nerve injury, and protein kinase C might be associated with the pain. In central sensitization, neuroplasticity in the brain and the activation of glial cells may be related with the pain. Discussion: In this review, we summarized the molecular mechanisms of SCD-related acute and chronic pain. The novel treatments targeting the disease mechanisms would interrupt complications of SCD and reduce the pain of the SCD patients.
Natural compound catechol induces DNA damage, apoptosis, and G1 cell cycle arrest in breast cancer cells
(2020) Radhakrishnan, Rajan
Abstract: Targeting cell cycle and inducing DNA damage by activating cell death pathways are considered as effective therapeutic strategy for combating breast cancer progression. Many of the naturally known small molecules target these signaling pathways and are effective against resistant and/or aggressive types of breast cancers. Here, we investigated the effect of catechol, a naturally occurring plant compound, for its specificity and chemotherapeutic efficacies in breast cancer (MCF-7 and MDA-MB-231) cells. Catechol treatment showed concentration-dependent cytotoxicity and antiproliferative growth in both MCF-7 and MDA-MB-231 cells while sparing minimal effects on noncancerous (F-180 and HK2) cells. Catechol modulated differential DNA damage effects by activating ATM/ATR pathways and showed enhanced γ– H2AX expression, as an indicator for DNA double-stranded breaks. MCF-7 cells showed G1 cell cycle arrest by regulating p21-mediated cyclin E/Cdk2 inhibition. Furthermore, activation of p53 triggered a caspase-mediated cell death mechanism by inhibiting regulatory proteins such as DNMT1, p-BRCA1, MCL-1, and PDCD6 with an increased Bax/Bcl-2 ratio. Overall, our results showed that catechol possesses favorable safety profile for noncancerous cells while specifically targeting multiple signaling cascades to inhibit proliferation in breast cancer cells.
Nigella sativa and its chemical constituents: pre clinical and clinical evidence for their potential anti SARS CoV 2 effects
(2023) Cyril, Asha Caroline; Ali, Najma Mohamed; Parambath, Anagha Nelliyulla; Jan, Reem Kais; Radhakrishnan, Rajan; Karuvantevida, Noushad; Aburamadan, Haneen
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 500 million reported cases of COVID-19 worldwide with relatively high morbidity and mortality. Although global vaccination drive has helped control the pandemic, the newer variant of the virus still holds the world in ransom. Several medicinal herbs with antiviral properties have been reported, and one such promising herb is Nigella sativa (NS). Recent molecular docking, pre-clinical, and clinical studies have shown that NS extracts may have the potential to prevent the entry of coronaviruses into the host cell as well as to treat and manage COVID-19 symptoms. Several active compounds from NS, such as nigelledine, α-hederin, dithymoquinone (DTQ), and thymoquinone (TQ), have been proposed as excellent ligands to target angiotensin-converting enzyme 2 (ACE2 receptors) and other targets on host cells as well as the spike protein (S protein) on SARS-CoV-2. By binding to these target proteins, these ligands could potentially prevent the binding between ACE2 and S protein. Though several articles have been published on the promising therapeutic role of NS and its constituents against SARS-CoV-2 infection, in this review, we consolidate the published information on NS and SARS-CoV-2, focusing on pre-clinical in silico studies as well as clinical trials reported between 2012 and 2023.
Pain in chronic prostatitis and the role of ion channels: a brief overview
(2021) Cyril, Asha Caroline; Jan, Reem Kais; Radhakrishnan, Rajan
Background: Prostatitis is the third most common urologic condition affecting more than half the male population at some point in their lives. There are different categories of prostatitis, of which approximately 90% of cases can be classified under the National Institute of Health (NIH) type III category (chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS)) with no causative agents identified. CP/CPPS is associated with several symptoms, of which the most prominent being chronic pain. Despite its high incidence, pain management in patients with CP/CPPS has been poor, possibly due to the lack of understanding of aetiological factors and mechanisms underlying pain development. Methods: An extensive literature search of published articles on the molecular mechanisms of pain in CP/CPPS was conducted using PubMed and Google Scholar search engines (https://pubmed.ncbi.nlm.nih.gov and https://scholar.google.com). The terms used for the search were: prostatitis, pain mechanism in CP/CPPS, prostatitis pain models, acid-sensing ion channels (ASICs), transient receptor potential vanilloid type 1 (TRPVs), purinergic channels (P2X) in prostatitis pain mechanism and inflammatory mediators in CP/CPPS. The papers were identified based on the title and abstract, and after excluding the articles that did not emphasize the pain mechanism in CP/CPPS. Ninety-five articles (36 review and 59 original research papers) met our criteria and were included in the review. Results: A number of inflammatory mediator molecules and pain channels, including ASICs, transient receptor potential vanilloid channels (TRPVs) and P2Xs have been investigated for their role in prostatitis pain pathology using various animal models. Conclusion: This review summarizes the pain mechanisms in CP/CPPS focusing on the inflammatory mediators, neurotransmitters, pain-transducing ion channels and small animal models developed for studying prostatitis.
Role of flavonoids in thrombotic, cardiovascular, and inflammatory diseases
(2017) Radhakrishnan, Rajan
Abstract: The failure of mechanisms of natural anti-coagulation either due to genetic impairment or due to severe external injuries may result in a condition called thrombosis. This is believed to be the primary cause for a variety of life-threatening conditions such as: heart attack, stroke, pulmonary embolism, thrombophlebitis, and deep venous thrombosis (DVT). The growing number of these incidents requires an alternative anti-coagulant or anti-thrombotic agent that has minimal side effects and improved efficiency. For decades, plant polyphenols, especially flavonoids, were known for their vital role in preventing various diseases such as cancer. Mitigating excessive oxidative stress caused by reactive oxygen species (ROS) with anti-oxidant-rich flavonoids may reduce the risk of hyper-activation of platelets, cardiovascular diseases (CVD), pain, and thrombosis. Furthermore, flavonoids may mitigate endothelial dysfunction (ED), which generally correlates to the development of coronary artery and vascular diseases. Flavonoids also reduce the risk of atherosclerosis and atherothrombotic disease by inhibiting excessive tissue factor (TF) availability in the endothelium. Although the role of flavonoids in CVD is widely discussed, to the best of our knowledge, their role as anti-thrombotic lead has not been discussed. This review aims to focus on the biological uses of dietary flavonoids and their role in the treatment of various coagulation disorders, and may provide some potential lead to the drug discovery process in this area.
Statins and Male Fertility: Is There a Cause for Concern?
(2022) Omolaoye, Temidayo S.; Mubarak, Maitha; Cyril, Asha Caroline; Duvuru, Ruthwik; Radhakrishnan, Rajan; Du Plessis, Stefan
Abstract: The well-known 3-hydroxyl 3-methyl glutaryl-Coenzyme A reductase inhibitors, called statins, have been the main medication used in the treatment of hypercholesterolemia and some cases of cardiovascular diseases. The effectiveness of this drug in controlling cholesterol production is impeccable, however, patients often complain of a variety of side effects, such as myalgia, muscle atrophy, and in some cases, rhabdomyolysis. Not only has the use of statins caused the aforementioned side effects, but they are also shown to cause testicular discomfort, erectile dysfunction, altered semen parameters, and modified steroid hormone production. These reported adverse effects on male fertility are not generally agreed upon, as some have shown the use to be beneficial. Hence, this makes the aftermath effect of statin use on male fertility debatable and controversial. The negative effects have been associated with imbalanced or reduced steroid hormones, which are necessary for proper spermatogenesis and other sexual functions. Meanwhile, the beneficial effects are related to statin’s anti-inflammatory and cardioprotective properties. These contradictory findings are in part due to the different age of users, concentrations of statins, the type and duration of treatment, and the underlying disease and/or comorbidities. Therefore, the current study aims to analyze the literature and gather evidence as to the effects of statin on male sexual health and reproductive parameters, and subsequently give recommendations for the direction of future studies.