Fisetin from Dietary Supplement to a Drug Candidate: An Assessment of Potential

Fisetin is a bioactive compound found in numerous fruits and vegetables, including strawberries, apples, grapes, persimmon, cucumber, onion, etc. The compound is also wellknown for its neurotrophic, anti-inflammatory, anti-carcinogenic, anti-diabetic, and other healthpromoting properties. Although there is increasing agreement that it has therapeutic properties, but its poor water solubility, high lipophilicity, and lower oral bioavailability make it difficult to use clinically. Extensive research has attempted to overcome these restrictions by developing novel and superior delivery systems. Considering the diverse potential, this review is the first to summarise the available data on Fisetin to collate the information related to analytical methods, pharmacological action, their mechanisms, regulatory aspects, and toxicity profile. It also covers the marketed products, related clinical trials, and patent updates of the moiety. In addition, an endeavor has been attempted to discuss and assess the various drug delivery systems employed to increase the biological attributes of Fisetin. The presented manuscript is the first to present a compendium of up-to-date literature on all of the domains considered necessary for this type of natural molecule to carve down its path from being a mere dietary supplement to a promising therapeutic drug candidate. The manuscript is expected to benefit the researchers working on natural and bioactive compounds, industrial scientists, and the general population interested in Fesitin.

Nanotechnology and COVID-19 Convergence: Toward New Planetary Health Interventions Against the Pandemic.

COVID-19 is a systemic disease affecting multiple organ systems and caused by infection with the SARS-CoV-2 virus. Two years into the COVID-19 pandemic and after the introduction of several vaccines, the pandemic continues to evolve in part owing to global inequities in access to preventive and therapeutic measures. We are also witnessing the introduction of antivirals against COVID-19. Against this current background, we review the progress made with nanotechnology-based approaches such as nanoformulations to combat the multiorgan effects of SARS-CoV-2 infection from a systems medicine lens. While nanotechnology has previously been widely utilized in the antiviral research domain, it has not yet received the commensurate interest in the case of COVID-19 pandemic response strategies. Notably, SARS-CoV-2 and nanomaterials are similar in size ranging from 50 to 200 nm. Nanomaterials offer the promise to reduce the side effects of antiviral drugs, codeliver multiple drugs while maintaining stability in the biological milieu, and sustain the release of entrapped drug(s) for a predetermined time period, to name but a few conceivable scenarios, wherein nanotechnology can enable and empower preventive medicine and therapeutic innovations against SARS-CoV-2. We conclude the article by underlining that nanotechnology-based interventions warrant further consideration to enable precision planetary health responses against the COVID-19 pandemic.

Hospital-Based Prevalence, Electroencephalogram (EEG), and Neuroimaging Correlation in Seizures Among Children in Odisha, India.

BACKGROUND: Febrile seizures are very common in pediatric practice. We need to differentiate between febrile seizures and other seizures due to central nervous system (CNS) infection by various means of investigation. Though approximately 30% of patients with febrile seizure have later epilepsy and the risk is around 20% even if electroencephalogram (EEG), and neuro-imagings are normal. But data regarding this is laking in developing countries like India. AIM: The primary objective of this study is to determine the hospital-based prevalence among various types and etiologies of seizures in children admitted to the pediatric department in a teaching hospital of a developing country, India. Besides, the different types of seizures were correlated with the EEG and neuroimaging findings along with the acute onset of seizures among children. METHODS: In this prospective observational study, children from two months to 15 years of age admitted to the Pediatrics Department, KIMS, Bhubaneswar in India between September 2017 and September 2019 were taken. The patients having seizures were included in the study based on the inclusion criteria. Neurological and systemic examinations of the children were recorded and the neuroimaging reports were analyzed. RESULTS: A total of 19,553 patients aged two months to 15 years were admitted during the study period. Of that, 1,192 cases were diagnosed with febrile and unprovoked seizures. It was observed that the hospital-based prevalence of seizures among children in Odisha was 6%. Besides, it is found that generalized seizure disorder was the most common among the children. It was found that abnormal EEG, magnetic resonance imaging (MRI), and computed tomography (CT) brain in 60% (202/340), 49% (113/230), and 47% (136/288) of cases, respectively. MRI is a better modality of investigation in partial seizure cases 22 (64%) to detect CNS abnormality. Also, MRI of the brain is better in evaluating CNS abnormality in complex febrile cases 4 (31%) than CT brain (0%). CONCLUSION: The study concluded that EEG must be the standard modality of test for patients' diagnosis of seizure in children with seizures. CT/MRI scan can give a better supplement to the results but MRI findings are more accurate in cases of complex febrile seizures.

Next-Generation Bioinformatics Approaches and Resources for Coronavirus Vaccine Discovery and Development-A Perspective Review.

COVID-19 is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To fight this pandemic, which has caused a massive death toll around the globe, researchers are putting efforts into developing an effective vaccine against the pathogen. As genome sequencing projects for several coronavirus strains have been completed, a detailed investigation of the functions of the proteins and their 3D structures has gained increasing attention. These high throughput data are a valuable resource for accelerating the emerging field of immuno-informatics, which is primarily aimed toward the identification of potential antigenic epitopes in viral proteins that can be targeted for the development of a vaccine construct eliciting a high immune response. Bioinformatics platforms and various computational tools and databases are also essential for the identification of promising vaccine targets making the best use of genomic resources, for further experimental validation. The present review focuses on the various stages of the vaccine development process and the vaccines available for COVID-19. Additionally, recent advances in genomic platforms and publicly available bioinformatics resources in coronavirus vaccine discovery together with related immunoinformatics databases and advances in technology are discussed.

Recent update of toxicity aspects of nanoparticulate systems for drug delivery.

Potential research outcomes on nanotechnology-based novel drug delivery systems since the past few decades attracted the attention of the researchers to overcome the limitations of conventional deliveries. Apart from possessing enhanced solubility of poorly water-soluble drugs, the targeting potential of the carriers facilitates longer circulation and site-specific delivery of the entrapped therapeutics. The practice of these delivery systems, therefore, helps in maximizing bioavailability, improving pharmacokinetics profile, pharmacodynamics activity and biodistribution of the entrapped drug(s). In addition to focusing on the positive side, evaluation of nanoparticulate systems for toxicity is a crucial parameter for its biomedical applications. Due to the size of nanoparticles, they easily traverse through biological barriers and may be accumulated in the body, where the ingredients incorporated in the formulation development might accumulate and/or produce toxic manifestation, leading to cause severe health hazards. Therefore, the toxic profile of these delivery systems needs to be evaluated at the molecular, cellular, tissue and organ level. This review offers a comprehensive presentation of toxicity aspects of the constituents of nanoparticular based drug delivery systems, which would be beneficial for future researchers to develop nanoparticulate delivery vehicles for the improvement of delivery approaches in a safer way.

Investigating natural antibiofilm components: a new therapeutic perspective against candidal vulvovaginitis.

The rampant emergence of Candida albicans in the vagina and its ability to thrive as a biofilm has outstood the prevalence of candidal vulvovaginitis (CVV), a gender-based fungal infection approximately affecting 75% of the global female population. The biofilm represents a multidimensional microbial population, which often dictates prominent caveats of CVV such as increased fungal virulence, drug resistance and infection relapse/recurrence. Additionally, the conjugated issues of the ineffectiveness of conventional antifungals (azoles), prolonged treatment durations, compromised patient compliance, economic and social burden, exacerbates CVV complications as well. Henceforth, the current hypothesis narrates an investigational proposal for exploration and combination of naturally derived antibiofilm components with luliconazole (imidazole antifungal agent) as a new therapeutic paradigm against CVV. The purported hypothesis unravels a synergistic approach for fabricating Nanostructured Lipid Carriers, NLCs loaded transvaginal gel with dual APIs of natural (antibiofilm) as well as the synthetic (antifungal) origin to target high therapeutic efficacy, delivery, retention, controlled release and bioadhesion in a vaginal milieu. The multipronged effect of antibiofilm and antifungal agents will expectably enhance drug susceptibility thus, maintaining Minimum Inhibitory Concentration (MIC) against cells of C. albicans and targeting its biofilm in planktonic, adherent, and sessile phases. The effective disruption of a biofilm could further lower infection resistance and recurrence as well. In conclusion, the purported hypothesis could speed up the emergence of novel drug combinations and accelerates new product development with solid, synergistic, and complementary activities against C. albicans and its biofilm, making it amenable for generating pre-clinical and clinical results therebycreating a suitableroadmap for commercialization.

Type II diabetes mellitus: a review on recent drug based therapeutics.

Diabetes mellitus (DM) is a metabolic disorder that occurs in the body because of decreased insulin activity and/or insulin secretion. Pathological changes such as nephropathy, retinopathy, and cardiovascular complications inevitably occur in the body with the progression of the disease. DM is mainly categorized into 2 sub-types, type I DM and type II DM. While type I DM is generally treated through insulin replacement therapy, type II DM is treated with oral hypoglycaemics. The major drug therapy for type II DM comprises of insulin secretagogues, biguanides, insulin sensitizers, alpha glucosidase inhibitors, incretin mimetics, amylin antagonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors. Dual drug therapies are often recommended in patients who are unable to achieve therapeutic goals with first line oral hypoglycaemic agents as monotherapy. Inspite of the appreciable therapeutic benefits, the conventional dosage forms depicts differential bioavailability and short half-life, mandating frequent dosage and causing greater side effects leading to therapy ineffectiveness and patient non-compliance. Given the pathological complexity of the said disease, nanotechnology-based approaches are more enticing as it comes with added advantage of site-specific drug delivery with higher bioavailability and reduced dosage regimen. In the present review article, we have made an attempt to explore the pathophysiology of type II DM, the conventional treatment approaches (mono and combination therapy) as well as the nano based drug delivery approaches for the treatment of type II DM.

Menopausal Remediation and Quality of Life (QoL) Improvement: Insights and Perspectives.

Cessation of menstruation, widely known as menopause is a significant transition period in women's life. It leads to the arrest of fertility and creates a depletion of the hormones causing physical, mental, sexual, and social problems which lead to a serious decline in their quality of life. The onset of menopause induces certain sudden changes, while others appear in a phasic manner, henceforth demanding an adequate understanding of its progression, adverse impact on life, and exploration of any remedial measures thereof. Menopause, despite being a natural occurrence, brings in significant changes to women's life, almost sometimes leading to severe debilitation. However, it is still not attended and remains an ignored health issue that warrants the immediate attention of researchers, practitioners, and health policymakers. The present review is an attempt to draw attention towards these women-centric health issues and diligently explores the causes, symptoms and also describes the various procedures for the management of menopausal and postmenopausal syndromes. The review tries to summarise the currently available pharmaceutical interventions and also dwells into herbal and complementary remedies which could ameliorate and provide respite from the etiolating menopausal symptoms.

Formulation and optimization of topotecan nanoparticles: In vitro characterization, cytotoxicity, cellular uptake and pharmacokinetic outcomes.

The study focuses on widening up the therapeutic perspective of anti-cancer therapy by entrapping a hydrophilic anticancer drug, topotecan hydrochloride (TOPO) in biodegradable poly (lactide-co-glycolide) (PLGA) matrix to form topotecan nanoparticles (TOPO NPs) by a double emulsion solvent evaporation technique. Statistical optimization using Box-Behnken design showed that sonication time of primary emulsion for 120 s, drug: polymer ratio of 1:12.65, organic phase: external aqueous phase ratio of 1:2.82 and 0.5% w/v of polyvinyl alcohol in the drug containing phase produced TOPO NPs with a size of 243.2 ±â€¯4 nm and an entrapment efficiency of 60.9 ±â€¯2.2%. TOPO NPs illustrated sustained release of TOPO for a week in phosphate buffer saline (PBS) at simulating physiological (pH 7.4) and acidic tumor microenvironmental (pH 6.5) conditions. A dramatic increase in cellular uptake with a corresponding enhanced cytotoxic potency was also displayed by TOPO NPs against human ovarian cancer cells (SKOV3) over time as compared to native drug, TOPO. These findings were further supported by the enhancement of bioavailability (13.05 fold) conferred by TOPO NPs from the in vivo pharmacokinetic study. The study represents a logistic approach for formulating TOPO NPs which can be used as an effective drug delivery system for the treatment of ovarian cancer.

Revisiting the nanoformulation design approach for effective delivery of topotecan in its stable form: an appraisal of its in vitro Behavior and tumor amelioration potential.

Topotecan (TPT) is indicated against a variety of solid tumors, but has restricted clinical use owing to associated pharmaceutical caveats. This study is focused at formulating a successful TPT PLGA nanosystem which ameliorates the rapid conversion of active lactone form of drug to its inactive carboxylate form and consequently improvises its efficacy. TPT PLGA nanoparticles were formulated by a double emulsion-solvent evaporation technique with sequential optimization to obtain desired particle size, PDI, zeta potential, and entrapment efficiency. Stability of TPT was ensured by maintaining an acidic pH in the drug-containing phase and the system was evaluated for in vitro-in vivo performance including cytotoxic potency. The optimized nanosystem had a particle size of 187.33 ± 7.50 nm, a PDI of 0.179 ± 0.05, and an entrapment efficiency of 56 ± 1.2%. Low pH in the interior of nanoparticles stabilized the drug to remain in its active lactone form and revealed a biphasic release pattern till 15 d. Additionally, an in vitro cytotoxicity testing as well as in vivo antitumor efficacy demonstrated a significant potential of higher proliferation inhibition as compared with neat drug (TPT). Thus, the investigation summarized an innovative simple tool for developing stable TPT NPs for effective delivery for treating solid tumors.

Topotecan-tamoxifen duple PLGA polymeric nanoparticles: investigation of in vitro, in vivo and cellular uptake potential.

The dual drug loaded poly(dl-lactic-co-glycolic acid) (PLGA(1)) nanoparticles (TOP-TAM NPs(2)) concurrently delivering topotecan hydrochloride (TOP(3)) and tamoxifen citrate (TAM(4)) were developed to achieve synergism for the treatment of breast cancer by enhancing the permeation of TOP through the gut and the cells present in the breast. TAM acted as P-glycoprotein (P-gp(5)) inhibitor, reduced the side effects of individual drugs by reducing the dose. The NPs were prepared by double emulsion (w/o/w) method. The optimized TOP-TAM NPs were found to have smooth and spherical morphology by using SEM(6) and TEM(7) technique. Similarly size of nanoparticles was found to be 151.2 ± 1.6 nm with 0.147 ± 0.03 polydispersity index (PDI(8)). The percentage entrapment efficiency of 95.17 ± 3.57 and 57.77 ± 2.2 was found for TAM and TOP respectively. The lyophillized nanoparticles under DSC(9) showed amorphous nature of both TOP and TAM. In an in vitro release study the release of drugs from TOP-TAM NPs was found to follow the Higuchi pattern. The ex vivo gut permeation study revealed that the TAM enhanced the permeation of TOP and increased its bioavailability by 1.9 folds. The permeation and activity of combination of drugs were further confirmed by carrying out cell line studies on MCF-7 cells.