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.

Phytotherapeutic approach for conquering menopausal syndrome and osteoporosis.

Women face a significant change in their reproductive health as menopause sets in. It is marred with numerous physiological changes that negatively impact their quality of life. This universal, transition phase is associated with menopausal and postmenopausal syndrome, which may spread over 2-10 years. This creates a depletion of female hormones causing physical, mental, sexual and social problems and may, later on, manifest as postmenopausal osteoporosis leading to weak bones, causing fractures and ultimately morbidity and mortality. Menopausal hormone therapy generally encompasses the correction of hormone balance through various pharmacological agents, but the associated side effects often lead to cessation of therapy with poor clinical outcomes. However, it has been noticed that phytotherapeutics is trusted by women for the amelioration of symptoms related to menopause and for improving bone health. This could primarily be due to their reduced side effects and lesser costs. This review attempts to bring forth the suitability of phytotherapeutics/herbals for the management of menopausal, postmenopausal syndrome, and menopausal osteoporosis through several published research. It tries to enlist the available botanicals with their key constituents and mechanism of action for mitigating symptoms associated with menopause as well as osteoporosis. It also includes a list of a few herbal commercial products available for these complications. The article also intends to collate the findings of various clinical trials and patents available in this field and provide a window for newer research avenues in this highly important yet ignored health segment.

An Overview of the Dichotomous Role of Microbiota in Cancer Progression and Management.

It is a well-known fact that cancer is considered the second leading cause of mortality across the globe. Although the human oral cavity and intestine are the natural habitat of thousands of microbes, dysbiosis results in malignancies, such as oral squamous cell carcinoma and colorectal cancer. Amongst the intestinal microbes, H. pylori is a deadly carcinogen. Also, causative pathogens for the development of pancreatic and colorectal cancer are found in the oral cavity, such as Fusobacterium nucleatum and Porphyromonas gingivalis. Many periodontopathic micro- organisms, like Streptococcus sp., Peptostreptococcus sp., Prevotella sp., Fusobacterium sp., Porphyromonas gingivalis, and Capnocytophaga gingivalis, strongly have an impact on the development of oral cancers. Three basic mechanisms are involved in pathogen-mediated cancer development, like chronic inflammation-mediated angiogenesis, inhibition of cellular apoptosis, and release of carcinogenic by-products. Microbiota has a dichotomous role to play in cancer, i.e., microbiota can be used for cancer management too. Shreds of evidence are there to support the fact that microbiota enhances the chemotherapeutic drug efficacy. This review presents the possible mechanism of the oncogenic effect of microbiota with emphasis on the oral microbiome and also attempts to explain the intricate role of microbiota in cancer management.

In silico and in vitro assessment of an optimized QbD-guided myoinositol and metformin-loaded mucus-penetrating particle-based gel for the amelioration of PCOS.

Polycystic ovarian syndrome (PCOS) is a multi-factorial endocrine disorder affecting women of reproductive age. However, its high prevalence and the unsuccessful translation of conventional modalities have made PCOS a pharmaco-therapeutic challenge. In the present study, we explored bi-formulations (comprising metformin-loaded mucus-penetrating nanoparticles, MTF-MPPs, and myoinositol-loaded mucus-penetrating particles, MI-MPPs) incorporated in a carbomer gel tailored for intravaginal administration. For the development and optimization of the MPPs-gel, a QbD (quality by design) approach was employed, including the initial and final risk assessment, central composite design of experts, and method validation. The optimized MTF-MPPs and MI-MPPs possessed an optimum nanometric particle size (195.0 nm and 178.8 nm, respectively) and a PDI of 0.150 and 0.123, respectively, together with a negligible negative zeta potential (-5.19 mV and -6.19 mV, respectively) through the vaginal mucus. It was observed that the MPPs are small and monodisperse with a neutral surface charge. It was observed that the MPPs-gel formulations released approximately 69.86 ± 4.65% of MTF and 67.14 ± 5.74% of MI within 120 h (5 days), which was observed to be sustained unlike MFT-MI-gel with approximately 94.89 ± 4.17% of MTF and 90.91 ± 15% of MI drugs released within 12 h. The confocal microscopy study of rhodamine-loaded MPPs indicated that they possessed a high fluorescence intensity at a depth of 15 µm, while as the penetration trajectory in the vaginal tissue increased to 35 µm, their intensity was reduced, appearing to be more prominent in the blood vessels. The analyzed data of MPPs-gel suggest that the optimized MPPs-gel formulation has potential to reach the targeted area via the uterovaginal mucosa, which has a wide network of blood vessels. Subsequently, in vivo studies were conducted and the results revealed that the proposed MPPs-gel formulation could regulate the estrous cycle of the reproductive system compared to the conventional formulation. Moreover, the formulation significantly reduced the weight of the ovaries compared to the control and conventional vaginal gel. Biochemical estimation showed improved insulin and sex hormone levels. Thus, the obtained data revealed that the deep penetration and deposition of MTF and MI on the targeted area through intravaginal delivery resulted in better therapeutic effects than the conventional vaginal gel. The obtained results confirmed the amelioration of PCOS upon treatment using the prepared MPPs-gel formulation. According to the relevant evaluation studies, it was concluded that MPPs-gel was retained in the vaginal cavity for systemic effects. Also, the sustained and non-irritating therapeutic effect meets the safety aspects. This work serves as a promising strategy for intravaginal drug delivery.

Potential of Lipid-Based Nanocarriers against Two Major Barriers to Drug Delivery-Skin and Blood-Brain Barrier.

Over the past few years, pharmaceutical and biomedical areas have made the most astounding accomplishments in the field of medicine, diagnostics and drug delivery. Nanotechnology-based tools have played a major role in this. The implementation of this multifaceted nanotechnology concept encourages the advancement of innovative strategies and materials for improving patient compliance. The plausible usage of nanotechnology in drug delivery prompts an extension of lipid-based nanocarriers with a special reference to barriers such as the skin and blood-brain barrier (BBB) that have been discussed in the given manuscript. The limited permeability of these two intriguing biological barriers restricts the penetration of active moieties through the skin and brain, resulting in futile outcomes in several related ailments. Lipid-based nanocarriers provide a possible solution to this problem by facilitating the penetration of drugs across these obstacles, which leads to improvements in their effectiveness. A special emphasis in this review is placed on the composition, mechanism of penetration and recent applications of these carriers. It also includes recent research and the latest findings in the form of patents and clinical trials in this field. The presented data demonstrate the capability of these carriers as potential drug delivery systems across the skin (referred to as topical, dermal and transdermal delivery) as well as to the brain, which can be exploited further for the development of safe and efficacious products.

Quality by Design Assisted Optimization and Risk Assessment of Black Cohosh Loaded Ethosomal Gel for Menopause: Investigating Different Formulation and Process Variables.

Black cohosh (Cimicifuga racemosa) (CR) is a popular herb and is medically lauded for ameliorating myriad symptoms associated with menopause. However, its pharmaceutical limitations and non-availability of a patient-compliant drug delivery approach have precluded its prevalent use. Henceforth, the current research premise is aimed at developing an ethosomal gel incorporating triterpene enriched fraction (TEF) obtained from CR and evaluating its effectiveness through the transdermal application. TEF-loaded ethosomes were formulated using solvent injection, optimized and characterised. The optimized ethosomes were then dispersed into a polymeric gel base to form ethosomal gel which was further compared with the conventional gel by in-vitro and ex-vivo experiments. Here, the quality by design (QbD) approach was exploited for the optimization and development of ethosomal gel. The elements of QbD comprising initial risk assessment, design of experimentation (DoE), and model validation for the development of formulation have all been described in detail. The optimized ethosomes (F03) showed a nanometric size range, negative zeta potential and good entrapment. The in vitro release profile of gel revealed a burst release pattern following the Korsmeyer Peppas model having Fickian diffusion. The transdermal flux of ethosomal gel was observed to be more than that of conventional gel. Texture analysis and rheological characterization of the gel, revealed good strength showing shear thinning and pseudoplastic behaviour. The confocal microscope investigation revealed the deeper skin permeation of ethosomal gel than conventional gel. This result was further strengthened by DSC, IR and histological assessment of the animal skin (Wistar rat), treated with the optimized formulation. Conclusively, the implementation of QbD in the formulation resulted in a better understanding of the process and the product. It aids in the reduction of product variability and defects, hence improving product development efficiencies. Additionally, the ethosomal gel was found to be a more effective and successful carrier for TEF than the conventional gel through the transdermal route. Moreover, this demands an appropriate animal study, which is underway, for a stronger outcome.

Amalgamation of Nanotechnology for Delivery of Bioactive Constituents in Solid Tumors.

Solid tumor is one of the highly prevalent cancers among humans and the treatment is often restricted by drug resistance to chemotherapeutics. One of the main reasons might be attributed to the limited penetration ability of drugs through tumor tissues due to heterogeneity within the tumor microenvironment. Over the recent years, so much research has been carried out for developing phytochemicals as cancer therapeutic agents. These are well-established as potential candidates for preventing and treating cancer, especially solid tumors, but have limited clinical applications due to their large molecular size, low bioavailability, stability, and target specificity, along with other side effects when used at high concentrations. There has been a widely proposed nano delivery system of bioactive constituents to overcome these obstacles. This nanostructured system might be able to potentiate the action of plant constituents, by reducing the side effects at a lesser dose with improved efficacy. Indeed, nanosystems can deliver the bioactive constituents at a specific site in the desired concentration and avoid undesired drug exposure to normal tissues. Furthermore, these nanoparticles demonstrate high differential absorption efficiency in the target cells over normal cells by preventing them from interacting prematurely with the biological environment, enhancing the cellular uptake and retention effect in disease tissues, while decreasing the toxicity. This review discusses various treatment stratagems used for the management of solid tumors with special emphasis on nanocarrier systems as a potential treatment strategy for herbal drugs. This also covers a wide list of plants that are used for the treatment of solid tumors and cancers along with their mechanisms of action and enlists various nanocarrier systems used for different phytoconstituents. This review gives a brief idea about different plants and their constituents exploited for their anticancer/antitumor potential along with several nanocarrier systems employed for the same and gives future directions to stress the nanotechnology platform as a valuable approach for the prevention and treatment of solid tumors.

COVID 19 pandemic challenges and their management: A review of medicines, vaccines, patents and clinical trials with emphasis on psychological health issues.

The SARS-CoV-2 (COVID 19) paroxysm is a dominant health exigency that caused significant distress, affecting physical and mental health. Increased mortality, a stressed healthcare system, financial crisis, isolation, and new living and working styles enhanced societal commiseration leading to poor health outcomes. Though people try to maintain good physical health but unfortunately the mental affliction is still ignored. Poor psychological health has emerged as a burgeoning social issue and demands attention. Henceforth, the fundamental objective of this review article is to collate information about COVID-linked physical and psychological agony in diverse population groups with related symptoms and accessible diagnosis techniques. Recent studies have unraveled the fragile mental states of people who have either contracted COVID 19 or had near and dear ones falling prey to it. The impact of the epidemic on the human mind both in short and long-term, with possible risk and preventive factors together with suggested solutions for maintaining good health have also been discussed here. It also enlists the available medications, vaccines and investigational research in the form of patents and clinical trials. This article can be taken as an updated information sheet for COVID 19, accompanied by its management techniques with special emphasis on coping strategies for mental health. Further, it may also assist the policymakers to devise approaches that could enable the public to overcome the pandemic-driven adversity not only in the given situation but also futuristically.

A Novel Approach of Targeting Linezolid Nanoemulsion for the Management of Lymph Node Tuberculosis.

Tuberculosis (TB) represents a major public health problem, globally affecting children and adults. Lymphatic TB is the most common type of extrapulmonary tuberculosis, which affects the peripheral lymph nodes. This burgeoning disease requires a long-term treatment of multiple antibiotics to kill Mycobacterium tuberculosis, resulting in an increased rate of multidrug-resistant tuberculosis. To overcome drug resistance with the first-line antibiotics, linezolid W/O nanoemulsion was developed in this current work. W/O nanoemulsion was prepared by oil phase titration technique using sunflower oil, span 80 and tween 80, and optimized by pseudophase ternary diagrams. The particle size, polydispersity index, zeta potential, viscosity, and refractive index for the optimized formulation were found to be 92.32 nm, 0.066, -21.9 mV, 32.623 cP, and 1.453, respectively. Drug release from the developed nanoemulsion followed the zero-order kinetic. The antimicrobial efficacy study confirms the antibacterial potential of the developed nanoemulsion. In vivo studies conducted on Wistar rats confirms the lymphatic targeting with a high amount of drug at the target organ just after 8 h of dosing. As a result of the foregoing promising results, it may be inferred that the suggested nanoemulsion could be a viable therapy option for lymph node tuberculosis.

Benefits of Black Cohosh (Cimicifuga racemosa) for Women Health: An Up-Close and In-Depth Review.

Women's health is an imminent concern worldwide, but it remains an ignored segment of research in most developing countries, and is yet to take the center stage in even developed nations. Some exclusive female health concerns revolve around both pathological and physiological aspects. These gender-specific maladies include breast, cervical, and ovarian cancers, and physiological concerns such as menopause and osteoporosis, which are often coexistent. Recently, women's health issues, including postmenopausal syndrome, have attracted the attention of researchers and practitioners alike, opening newer pharmaceutical research and clinical avenues. Although not counted as a disease, postmenopausal syndrome (PMS) is a female health phenomenon underpinned by hormonal depletion. Enhanced life expectancy in women has added to their suffering, and pharmacological interventions are needed. Amongst the available treatment modalities, the use of numerous botanicals has emerged as an efficient health management tool for women. Cimicifuga racemosa (CR or Black Cohosh) is a plant/herb which has been traditionally exploited and extensively used by women. This review is an attempt to compile and provide a summary of the importance of CR in complementary and alternative therapies for the improvement of various disorders related to women, such as menopausal syndrome, mammary cancer, and osteoporosis. It aims to systematically highlight the bioactive constituents, pharmacology, pharmacokinetics, therapeutic potentials, quality control processes, chromatographic techniques, and possible mechanisms of action of clinically effective phytomedicine for women's health. Various clinical trials and patents relating to CR and women's health have been collated. Furthermore, the plant and its related products have been considered from a regulatory perspective to reveal its commercial feasibility. The present review summarizes the existing data on CR focusing on women's health, which can help to introduce this traditional phytomedicine to the world and provide some reference for future drug development.

Nanotechnology in Cosmetics and Cosmeceuticals-A Review of Latest Advancements.

Nanotechnology has the potential to generate advancements and innovations in formulations and delivery systems. This fast-developing technology has been widely exploited for diagnostic and therapeutic purposes. Today, cosmetic formulations incorporating nanotechnology are a relatively new yet very promising and highly researched area. The application of nanotechnology in cosmetics has been shown to overcome the drawbacks associated with traditional cosmetics and also to add more useful features to a formulation. Nanocosmetics and nanocosmeceuticals have been extensively explored for skin, hair, nails, lips, and teeth, and the inclusion of nanomaterials has been found to improve product efficacy and consumer satisfaction. This is leading to the replacement of many traditional cosmeceuticals with nanocosmeceuticals. However, nanotoxicological studies on nanocosmeceuticals have raised concerns in terms of health hazards due to their potential skin penetration, resulting in toxic effects. This review summarizes various nanotechnology-based approaches being utilized in the delivery of cosmetics as well as cosmeceutical products, along with relevant patents. It outlines their benefits, as well as potential health and environmental risks. Further, it highlights the regulatory status of cosmeceuticals and analyzes the different regulatory guidelines in India, Europe, and the USA and discusses the different guidelines and recommendations issued by various regulatory authorities. Finally, this article seeks to provide an overview of nanocosmetics and nanocosmeceuticals and their applications in cosmetic industries, which may help consumers and regulators to gain awareness about the benefits as well as the toxicity related to the continuous and long-term uses of these products, thus encouraging their judicious use.

Raw Materials, Technology, Healthcare Applications, Patent Repository and Clinical Trials on 4D Printing Technology: An Updated Review.

After the successful commercial exploitation of 3D printing technology, the advanced version of additive manufacturing, i.e., 4D printing, has been a new buzz in the technology-driven industries since 2013. It is a judicious combination of 3D printing technologies and smart materials (stimuli responsive), where time is the fourth dimension. Materials such as liquid crystal elastomer (LCE), shape memory polymers, alloys and composites exhibiting properties such as self-assembling and self-healing are used in the development/manufacturing of these products, which respond to external stimuli such as solvent, temperature, light, etc. The technologies being used are direct ink writing (DIW), fused filament fabrication (FFF), etc. It offers several advantages over 3D printing and has been exploited in different sectors such as healthcare, textiles, etc. Some remarkable applications of 4D printing technology in healthcare are self-adjusting stents, artificial muscle and drug delivery applications. Potential of applications call for further research into more responsive materials and technologies in this field. The given review is an attempt to collate all the information pertaining to techniques employed, raw materials, applications, clinical trials, recent patents and publications specific to healthcare products. The technology has also been evaluated in terms of regulatory perspectives. The data garnered is expected to make a strong contribution to the field of technology for human welfare and healthcare.

Biomedical Application, Patent Repository, Clinical Trial and Regulatory Updates on Hydrogel: An Extensive Review.

Hydrogels are known for their leading role in biomaterial systems involving pharmaceuticals that fascinate material scientists to work on the wide variety of biomedical applications. The physical and mechanical properties of hydrogels, along with their biodegradability and biocompatibility characteristics, have made them an attractive and flexible tool with various applications such as imaging, diagnosis and treatment. The water-cherishing nature of hydrogels and their capacity to swell-contingent upon a few ecological signals or the simple presence of water-is alluring for drug conveyance applications. Currently, there are several problems relating to drug delivery, to which hydrogel may provide a possible solution. Hence, it is pertinent to collate updates on hydrogels pertaining to biomedical applications. The primary objective of this review article is to garner information regarding classification, properties, methods of preparations, and of the polymers used with particular emphasis on injectable hydrogels. This review also covers the regulatory and other commerce specific information. Further, it enlists several patents and clinical trials of hydrogels with related indications and offers a consolidated resource for all facets associated with the biomedical hydrogels.

In Silico Drug Screening Based Development of Novel Formulations for Onychomycosis Management.

Onychomycosis is a prominent fungal infection that causes discoloration, thickening, and mutilation leading to the separation of the nail from the nail bed. Treatment modalities for onychomycosis may include oral, topical, or combination therapy with antifungals and at times may require chemical or surgical intervention. The burden of side effects of antifungals is enormous, and therefore using molecular docking-based drug selection in context with the target keratin protein would ensure better disease management. Ciclopirox, Amorolfine HCl, Efinaconazole, Tioconazole, and Tavaborole were submitted for assessment, revealing that Amorolfine HCl is the best fit. Consequently, two formulations (Nail lacquer and nanoemulgel) were developed from Amorolfine HCl to validate the in silico screening outcomes. The formulations were further fortified with over-the-counter ingredients vis-a-vis with vitamin E in nail lacquer and undecylenic acid in nanoemulgel for their prominent roles in improving nail health. Both the formulations were systematically designed, optimized, and characterized. Amorolfine HCl containing nanoemulgel (NEG) was developed using undecylenic acid as an oil phase and thioglycolic acid as a penetration enhancer. The quality parameters evaluated were particle size, the zeta potential for nanoemulsion (NE) (78.04 ± 4.724 nm and -0.7mV, respectively), in vitro cumulative drug release (96.74% for NE and 88.54% for NEG), and transungual permeation (about 73.49% for NEG and 54.81% for NE). Nail lacquer was evaluated for the drying time, non-volatile content, and blush test. In vitro cumulative drug release of the developed nail lacquer and comparator marketed formulations were around 81.5% and 75%, respectively. Similarly, the transungual drug permeation was 6.32 µg/cm2 and 5.89 µg/cm2, respectively, in 24 h. The in silico guided preparation of both formulations containing Amorolfine HCl and over the counter ingredients is amenable for therapeutic use against onychomycosis and will be evaluated in the in vivo model.

Nutritional constituents of mulberry and their potential applications in food and pharmaceuticals: A review.

Mulberry is a fast growing deciduous plant found in wide variety of climatic, topographical and soil conditions, and is widely distributed from temperate to subtropical regions. Due to presence of valuable phytochemical constituents, mulberry as a whole plant has been utilized as a functional food since long time. Mulberry fruits are difficult to preserve as they have relatively high water content. Therefore for proper utilization, different value-added products like syrups, squashes, teas, pestil sand köme, pekmez (turkuish by-products), yogurts, jams, jellies, wines, vinegar, breads, biscuits, parathas, and many more are made. In overseas, these value-added products are commercially sold and easily available, though in India, this versatile medicinal plant is still missing its identity at commercial and industrial scale. Leaves of mulberry are economically viable due to their important role in the sericulture industry since ancient times. Mulberries or its extracts exhibit excellent anti-microbial, anti-hyperglycaemic, anti-hyperlipidemic, anti-inflammatory, anti-cancer effects and is used to combat different acute and chronic diseases. Different parts of Morus species like fruits, leaves, twigs, and bark exhibit strong anti-tyrosinase inhibition activity that makes it a suitable candidate in cosmetic industries as a whitening agent. The current review provides a comprehensive discussion concerning the phytochemical constituents, functionality and nutraceutical potential of mulberry and as a common ingredient in various cosmetic products.

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.

Design and development of a commercially viable in situ nanoemulgel for the treatment of postmenopausal osteoporosis.

Aim: To investigate the potential of a thermosensitive intranasal formulation of raloxifene hydrochloride (RH) for systemic delivery with the possibility of enhanced bioavailability and anti-osteoporotic efficacy. Methods: In this work, a commercially scalable nanoemulsion in thermosensitive gel, aligned with better clinical acceptability, has been developed and evaluated. Results: A significant 7.4-fold improvement in bioavailability of RH was recorded when compared with marketed tablets. Likewise, in vivo pharmacodynamics studies suggested 162% enhanced bone density and significantly improved biochemical markers compared with per-oral marketed tablet. Conclusion: The formulation, being safe and patient compliant, successfully tuned anti-osteoporotic effects with improved therapeutic performance. Further, the work provided an exceptional lead to carry out the study in clinical settings.