Nano-nutraceuticals to Combat Oxidative Stress: Unlocking Newer Paradigms in Adjuvant Therapy.

Nutraceuticals are products that provide both nutritional and therapeutic benefits. These compounds can slow the aging process and provide physiological effects shielding individuals from acute and chronic diseases. People's interests have shifted from allopathic to Ayurvedic to nutraceuticals in recent years. These are often common dietary supplements that have drawn customers worldwide because of their high nutritional safety and lack of adverse effects when used for a long time. Although conventional dosage forms, including pills, tablets, and semi-solids, are still available, they nevertheless have poorer bioavailability, less stability, and less effectiveness for targeted delivery of bioactives. The use of effective nanocomplex systems as nano-antioxidants using nanotechnology has become a promising field. Among its many uses, nanotechnology is mostly used to create foods and nutraceuticals that are more bioavailable, less toxic, and more sustainable. Additionally, it has been emphasized how precisely nano-pharmaceuticals for oxidative stress produce the desired effects. These improvements show improved antioxidant delivery to the target region, reduced leakage, and increased targeting precision. The outcomes demonstrated that oxidative stress-related illnesses can be effectively treated by lowering ROS levels with the use of nanonutraceuticals. The major ideas and uses of nano-nutraceuticals for health are outlined in this review, with an emphasis on reducing oxidative stress.

Unlocking InhA: Novel approaches to inhibit Mycobacterium tuberculosis.

Multidrug-resistant tuberculosis continues to pose a health security risk and remains a public health emergency. Antimicrobial resistance result from treatment regimens that are both insufficient and incomplete leading to the emergence of multidrug-resistant tuberculosis, extensively drug-resistant tuberculosis and totally drug-resistant tuberculosis. The impact of tuberculosis on the people suffering from HIV (Human immunodeficiency virus infection) have resulted in the increased research efforts in designing and discovery of novel antitubercular drugs that may result in decreasing treatment duration, minimising the need for multiple drug intake, minimising cytotoxicity and enhancing the mechanism of action of drug. While many drugs are available to treat tuberculosis, a precise and timely cure is still absent. Consequently, further investigation is needed to identify more recent molecular equivalents that have the potential to swiftly remove this disease. Isoniazid (INH), a treatment for tuberculosis (TB), targets the enzyme InhA (mycobacterium enoyl acyl carrier protein reductase), the Mycobacterium tuberculosis enoyl-acyl carrier protein (ACP) reductase, most common INH resistance is circumvented by InhA inhibitors that do not require KatG (catalase-peroxidase) activation, as a result, researchers are trying to work in the area of development of InhA inhibitors which could help in eradicating the era of tuberculosis from the world.

An insight into recent updates on analytical techniques for bioactive alkaloids.

INTRODUCTION: Alkaloids represent a wide class of naturally existing nitrogen-containing organic compounds having diverse biological activities. They are primary bioactive substances extracted from diverse plant parts. Due to their diverse biological activities, they are frequently used as medicines. The alkaloids have diverse pharmacological impacts on the human body; alkaloids are used for prevention, treatment, and reduction of discomfort associated with chronic illnesses. As most alkaloids exist in plants in complex form, combined with numerous other natural plant components, it is essential to recognize and characterize these molecules using different analytical techniques. OBJECTIVES: We aimed to review the literature on the methods and protocols for the analysis of naturally occurring alkaloids. METHODS: We carried out a literature survey using the PubMed, Scopus, and Google Scholar databases and other relevant published materials. The keywords used in the searches were "alkaloids," "analytical methods," "HPLC method," "GC method," "electrochemical methods," and "bioanalytical methods," in various combinations. RESULTS: In this article, several classes of alkaloids are presented, along with their biological activities. Moreover, it includes a thorough explanation of chromatographic techniques, hyphenated techniques, electrochemical techniques, and current trending analytical methods utilized for the isolation, identification, and comprehensive characterization of alkaloids. CONCLUSIONS: The various analytical techniques play an important role in the identification as well as the characterization of various alkaloids from plants, plasma samples, and urine samples. The hyphenation of various chromatographic techniques with mass spectrometry and NMR spectroscopy plays a crucial role in the characterization of unknown compounds.

Journey of Teplizumab: A Promising Drug in the Treatment of Type 1 Diabetes Mellitus.

Type 1 diabetes (T1D) is a chronic autoimmune disease caused by CD4+ and CD8+ that are activated via CD3+ cells and finally lead to the macrophages destroying the beta cells in the pancreas thereby causing diabetes. The anti-CD3 humanized monoclonal antibody was approved on 17th November 2022 by the United States Food Drug Administration (USFDA) with the name teplizumab and the brand name TZIELD. This is the only approved drug that treats type 1 diabetes (T1D) by delaying the onset of stage 3 in type 1 diabetes (T1D). This review outlines essential features of teplizumab including its brief introduction to its mechanism and other therapies for the treatment and various risks as well as the pharmacokinetics and pharmacodynamics of this disease and the clinical trial reports for the completed and ongoing therapies.

Paradigms and Success Stories of Natural Products in Drug Discovery Against Neurodegenerative Disorders (NDDs).

Neurodegenerative disorders (NDDs) are multifaceted complex disorders that have put a great health and economic burden around the globe nowadays. The multi-factorial nature of NDDs has presented a great challenge in drug discovery and continuous efforts are in progress in search of suitable therapeutic candidates. Nature has a great wealth of active principles in its lap that has cured the human population since ancient times. Natural products have revealed several benefits over conventional synthetic medications and scientists have shifted their vision towards exploring the therapeutic potentials of natural products in the past few years. The structural mimicking of natural compounds to endogenous ligands has presented them as a potential therapeutic candidate to prevent the development of NDDs. In the presented review, authors have summarized demographical facts about various NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and various types of sclerosis in the brain. The significant findings of new active principles of natural origin along with their therapeutic potentials on NDDs have been included. Also, a description of clinical trials and patents on natural products has been enlisted in this compilation. Although natural products have shown promising success in drug discovery against NDDs, still their use is associated with several ethical issues which need to be solved in the upcoming time.

Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects adults, characterized by muscle weakness resulting from the specific death of motor neurons in the spinal cord and brain. The pathogenesis of ALS is associated with the accumulation of mutant superoxide dismutase 1 (SOD1) proteins and neurofilaments in motor neurons, highlighting the critical need for disease-modifying treatments. Current therapies, such as riluzole and edaravone, provide only symptomatic relief. Recently, tofersen gained approval from the US FDA under the brand name Qalsody as the first and only gene therapy for ALS, addressing a significant pathological aspect of the disease. METHODS: We carried out a literature survey using PubMed, Scopus, National Institutes of Health, and Biogen for articles published in the English language concerned with "amyotrophic lateral sclerosis", pathophysiology, current treatment, treatment under clinical trial, and the newly approved drug "tofersen" and its detailed summary. RESULTS: A comprehensive review of the literature on the pathophysiology, available treatment, and newly approved drug for this condition revealed convincing evidence that we are now able to better monitor and treat ALS. CONCLUSIONS: Although treatment of ALS is difficult, the newly approved drug tofersen has emerged as a potential therapy to slow down the progression of ALS by targeting SOD1 mRNA, representing a significant advancement in the treatment of ALS.

Alkaloids as Additional Weapons in the Fight against Breast Cancer: A review.

Breast carcinoma is among the most frequent cancerous tumour in females around the globe. The major modalities now employed in the therapeutic management of breast cancer include surgeries, chemotherapy, and specialized medicines. Despite their potential to help individuals' problems, they are also associated with many negative impacts. As a result, natural products are increasingly regarded to be a preferable alternative. Alkaloids are essential biochemical substances that can be used to develop new drugs. Numerous alkaloids that originate from natural plants have been shown in vitro and in vivo to have anti-proliferation and anti-metastasis actions on different kinds of carcinoma. According to the data collected in this study, the utilization of alkaloids as anti-tumor medicines appears to be extremely potent; nevertheless, extensive studies and clinical trials are required before utilizing individual alkaloids. In this overview, we provide a detailed and vital exploration of pre-existing alkaloids possessing anti-tumor activities due to bioactive compounds. This study also includes an overview of synthesized analogues and pharmacological characteristics that will be beneficial to scientists working on alkaloids for medicinal purposes. In a recent survey of the literature, alkaloids are an important component of plant-derived antitumor medicines that hold great potential for the future development of cancer therapy and preventive therapies. We have also discussed structural analysis relationship (SAR) studies. Moreover, it covers clinical trial medications and FDA-approved medicines from the last five years that will be useful in further research.

Neuroprotective Effect of Natural Indole and ß-carboline Alkaloids against Parkinson's Disease: An Overview.

Parkinson's disease (PD) is a devastating neurodegenerative condition that mostly damages dopaminergic neurons in the substantia nigra and impairs human motor function. Males are more likely than females to have PD. There are two main pathways associated with PD: one involves the misfolding of α-synuclein, which causes neurodegeneration, and the other is the catalytic oxidation of dopamine via MAO-B, which produces hydrogen peroxide that can cause mitochondrial damage. Parkin (PRKN), α-synuclein (SNCA), heat shock protein (HSP), and leucine-rich repeat kinase-2 (LRRK2) are some of the target areas for genetic alterations that cause neurodegeneration in Parkinson's disease (PD). Under the impact of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is also important in Parkinson's disease (PD), inhibition of mitochondrial complex 1 results in enhanced ROS generation in neuronal cells. Natural products are still a superior option in the age of synthetic pharmaceuticals because of their lower toxicity and moderate side effects. A promising treatment for PD has been discovered using beta-carboline (also known as " ß-carboline") and indole alkaloids. However, there are not many studies done on this particular topic. In the herbs containing ß-carbolines and indoles, the secondary metabolites and alkaloids, ß-carbolines and indoles, have shown neuroprotective and cognitive-enhancing properties. In this review, we have presented results from 18 years of research on the effects of indole and ß-carboline alkaloids against oxidative stress and MAO inhibition, two key targets in PD. In the SAR analysis, the activity has been correlated with their unique structural characteristics. This study will undoubtedly aid researchers in looking for new PD treatment options.

Recent advances in nitrogen-containing heterocyclic compounds as receptor tyrosine kinase inhibitors for the treatment of cancer: Biological activity and structural activity relationship.

Erratic cell proliferation is the initial symptom of cancer, which can eventually metastasize to other organs. Before cancer becomes metastatic, its spread is triggered by pro-angiogenic factors including vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), Platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and Platelet Factor (PF4), all of which are part of receptor tyrosine kinase (RTK) family. Receptor tyrosine kinases (RTKs) are cell-surface proteins and aresignaling enzymes that transfer ATP-phosphate to tyrosine residue substrates. Important biological processes like proliferation, differentiation, motility, and cell-cycle regulation are all possessedby these proteins. Unusual RTK expression is typically associated with cell growth abnormalities, which is linked to tumor acquisition, angiogenesis, and cancer progression. In addition to the already available medications, numerous other heterocyclic are being studied for their potential action against a variety of cancers. In the fight against cancer, in particular, these heterocycles have been used for their dynamic core scaffold and their inherent adaptability. In this review article, we have compiled last five years research work including nitrogen containing heterocycles that have targeted RTK. Herein, the SAR and activity of various compounds containing diverse heterocyclic (pyrimidine, indole, pyridine, pyrazole, benzimidazole, and pyrrole) scaffolds are discussed, and they may prove useful in the future for designing new leads against RTKs. Our focus in this manuscript is to comprehensively review the latest research on the biological activity and structural activity relationship of nitrogen compounds as RTK inhibitors. We believe that this may be an important contribution to the field, as it can help guide future research efforts and facilitate the development of more effective cancer therapies.

Current Trends of Analytical Techniques for Bioactive Terpenoids: A Review.

Terpenes and terpenoids are the primary bioactive substances present in essential volatile oils, condensed liquids extracted from diverse plant parts. These substances demonstrate remarkable biological activity and are frequently used as medicines, food additives, and scent molecules. Terpenoids have a wide range of pharmacological effects on the human body, including the treatment, prevent, and reduce the discomfort associated with a number of chronic illnesses. Therefore, these bioactive substances are crucial to our everyday existence. As most terpenoids are present in complex form, coupled with many other raw plant elements, it is important to identify and characterize these molecules. This article addresses various classes of terpenoids, their biochemical processes, and their biological functions. Additionally, it includes a comprehensive description of several hyphenated procedures and recently popular analytical approaches used for isolation, identification, and absolute characterization. It also includes a discussion of the various advantages, drawbacks, and challenges encountered during the collection of the sample and throughout the entire research process.

Neutron Activation Analysis: An Excellent Nondestructive Analytical Technique for Trace Metal Analysis.

For proper functioning of the human body, several metals are required in different concentrations but if their concentration slightly elevates, because of any metal-contaminated environment or of other food sources, which leads to high toxicity and different chronic health issues. Different analytical techniques like atomic absorption spectroscopy, X-ray fluorescence, inductively coupled plasma- mass spectroscopy (ICP-MS) and flame atomic absorption spectroscopy are used for metals analysis present in different samples in different fields but nowadays neutron activation analysis (NAA) is preferred over other analytical techniques because it is an efficient, multi-elemental, nondestructive analytical technique having an ultralow minimum detection limit, therefore it can detect heavy metals (HMs) even if at a very trace level parts per billion (ppb) with a quite simple sample preparation technique. This technique is known as "referee technique" because of its accuracy and trustworthiness. There is a widespread use of this technique in biomedical science like in Alzheimer's disease, cancer, arthritis, metabolism study, brain tumor and in many more conditions where metals are actively present. For its typical sample sizes and due to a multitude of additional benefits, it also helps in mapping of pathophysiology of the disease. Besides all, mainly in biomedical science the biological samples can easily be analyzed irrespective of any form. In recent years NAA is preferred over other analytical techniques in several research fields, so this article focuses on the analytical technique, its general principle and recent applications.

Amivantamab: A New Hope in Targeting Non-small Cell Lung Cancer.

BACKGROUND: Amivantamab was approved on May 21st, 2021, by United States food and drug administration with the brand name Rybervant, used particularly for adult patients with exon20 insertion of epithelial growth factor receptor with locally advanced metastatic non-small cell lung cancer. OBJECTIVE: In this review, we explain the non-small cell lung cancer and molecular distinctions between non-small cell lung cancer and small cell lung cancer. We also conclude numerous components of non-small cell lung cancer, which include signs and symptoms of Amivantamab in inhibiting the cancer cell growth, various clinical trials on Amivantamab, adverse effects, and the contraindications of Amivantamab. METHODS: A comprehensive literature search was conducted in the relevant databases like ScienceDirect, PubMed, ResearchGate, and Google Scholar to identify studies. CONCLUSION: Amivantamab is a new bispecific antibody that targets non-small cell lung cancer through two different pathways, i.e., by binding to epithelial growth factor receptor and mesenchymal epithelial transition factor. Amivantamab gets tightly bound to Fcγ3R, and thus, mediates the macrophage and NK-cell for the killing of cancer cells. Biological treatment of Amivantamab shows effectiveness against the epithelial growth factor receptor Exon20 insertions according to the preclinical data of the animal model.

Spray Drying as an Effective Method in the Development of Solid Self- Emulsifying Drug Delivery Systems.

Most of the new drug candidates and present ones are lipophilic, which leads to low bioavailability. Self-emulsifying drug delivery systems (SEDDS) have emerged as promising formulation system for poorly water-soluble drug candidates. Over the last two decades, various such drug compounds were used by researchers for the development of SEDDS. At present, many SEDDS formulations are also available in the market. Though SEDDS offer many advantages but drawbacks like low drug loading, few dosage form choices, difficulty in handling and storage led to the solidification of this system by various methods. Solidification by spray drying technique offers a lot of advantages like scalability and stability. This particular method is the focus of this review. Adsorbent carriers have the most significant role in the fate of this formulation and its compatibility with the drug candidate. This review addresses the advantages, method of development, spray drying specifications, and characterization of S-SEDDS in detail. Furthermore, the prospect of turning spray-dried SEDDS into tablets by punching which offers potential advantages of increased bioavailability and stability has also been discussed.

Tivozanib: A New Hope for Treating Renal Cell Carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a diverse collection of malignancies with varying histological characteristics, molecular changes, prognosis, and therapeutic response. Tivozanib was first approved in March 2021 by USFDA with the brand name Fotivda. Tivozanib hydrochloride monohydrate is an oral medication that is used to treat relapsed or refractory renal cell carcinoma. OBJECTIVE: In this review, we explain renal cell carcinoma and its different types of treatment by the anti-renal carcinoma drugs. METHODS: A comprehensive literature search was conducted in the relevant databases, like ScienceDirect, PubMed, ResearchGate, and Google Scholar, to identify the studies. CONCLUSION: Tivozanib is an oral VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinase inhibitor that is extremely selective and powerful. It has much less affinity for other receptor tyrosine kinases than multi-targeted TKIs now in clinical use. Because of its long half-life in circulation, it may be able to block VEGFRs more consistently. Doserelated controllable hypertension is its most commonly seen drug-related side event. Fatigue, hoarseness, and diarrhea, which are all common side effects, are not dose-related. Because of its target specificity, tivozanib can work well with other medications that have low side effects. Blocking both the VEGF and mTOR signaling pathways at the same time provides the benefit of synergistic antitumor efficacy while also preventing treatment resistance. Thus, overall we can say that the drug tivozanib is suitable for treatment in patients with renal cell carcinoma and can be investigated in multi-center clinical trials.

Recent Advances in Biomedical Applications of Biogenic Nanomaterials.

The synthesis of biogenic nanoparticles from readily available natural resources may have large demand in numerous fields including pharmaceuticals and medicine. The biogenic nanoparticles catch the attention of the scientific community due to their low cytotoxicity and biocompatibility. Chemical, physical, and greener methods are used for the synthesis of biogenic nanoparticles. Researchers used eco-friendly and nontoxic approaches in the synthesis of this nanoparticle. This nanomaterial-based medicine plays a vital role in the management of public health, including earlier detection of disease, therapeutics candidates in the treatment of cancer. Biogenic nanocomposites are environmentally benign candidates that include fabrication of various composites, detoxification, and act as a catalyst in the biodegradation process. In this review article, we emphasize the recently reported methods used for synthesis, summarizing their biomedical applications and commercial and environmentally benign applications. Synthetic strategies include greener, chemical, physical, and biogenic methods and their role in surface modifiers involves various biomedical, commercial, and environmental-related applications. Moreover, we glimpse existing status, key contests, and future perspectives.

Design, synthesis of 1,2,4-triazine derivatives as antidepressant and antioxidant agents: In vitro, in vivo and in silico studies.

The novel series of substituted-N-(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides (R: 1-12) were designed, synthesized and evaluated for in-vitro and in-vivo antidepressant-like activity. In MAO-A inhibition assay, compound R: 5 and R: 9 displayed most potent activity with IC50 = 0.12 and 0.30 µM. R: 5 and R: 9 were also evaluated for in-vivo antidepressant using FST and TST. In both models, the test samples R: 5 and R: 9 showed noteworthy antidepressant effect. R: 5 showed 46.48 % and 45.96 % reduction in immobility in FST and TST respectively at dosage of 30 mg/kg (p.o). Whereas compound R: 9 reduced the immobility time by 52.76 % and 47.14 % as compared to control in FST and TST, respectively at same dosage. Both the compounds were also tested for behavioural study using actophotometer and grip tests. None of compounds exhibited decrease in locomotor activity. Further, these compounds were subjected to in silico studies to determine their ADME properties along with binding energies and binding orientions. In ADME studies none of the compounds violated the Lipinski rule and all other parameters were also within the acceptable ranges. In docking study R: 5 (-10.7) and R: 9 (-10.4) were also displayed highest docking score. These encouraging results present the pharmacophoric features of substituted-N-(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides as interesting lead for further development of new antidepressant drug molecules.

Exploring the Multitarget Potential of Iridoids: Advances and Applications.

Iridoids are secondary plant metabolites that are multitarget compounds active against various diseases. Iridoids are structurally classified into iridoid glycosides and non-glycosidic iridoids according to the presence or absence of intramolecular glycosidic bonds; additionally, iridoid glycosides can be further subdivided into carbocyclic iridoids and secoiridoids. These monoterpenoids belong to the cyclopentan[c]-pyran system, which has a wide range of biological activities, including antiviral, anticancer, antiplasmodial, neuroprotective, anti-thrombolytic, antitrypanosomal, antidiabetic, hepatoprotective, anti-oxidant, antihyperlipidemic and anti-inflammatory properties. The basic chemical structure of iridoids in plants (the iridoid ring scaffold) is biosynthesized in plants by the enzyme iridoid synthase using 8-oxogeranial as a substrate. With advances in phytochemical research, many iridoid compounds with novel structure and outstanding activity have been identified in recent years. Biologically active iridoid derivatives have been found in a variety of plant families, including Plantaginaceae, Rubiaceae, Verbenaceae, and Scrophulariaceae. Iridoids have the potential of modulating many biological events in various diseases. This review highlights the multitarget potential of iridoids and includes a compilation of recent publications on the pharmacology of iridoids. Several in vitro and in vivo models used, along with the results, are also included in the paper. This paper's systematic summary was created by searching for relevant iridoid material on websites such as Google Scholar, PubMed, SciFinder Scholar, Science Direct, and others. The compilation will provide the researchers with a thorough understanding of iridoid and its congeners, which will further help in designing a large number of potential compounds with a strong impact on curing various diseases.

Recent Advances in the Development of Nitrogen-containing Heterocyclic Anti-alzheimer's Agents.

Alzheimer's disease (AD) remains one of the major neurodegenerative diseases overwhelming the world today. Alzheimer's is the most complicated as well as perplexing disease encountering serious global health issues. Alzheimer's disease is well characterized as a general cause of dementia, which includes issues with memory, language, problem-solving, and other cognitive behaviours, such as disabled perception as well as trouble talking due to degeneration of neurons. According to the latest report, there are about 44 million individuals who are currently suffering from dementia, which has been prophesied to extensively grow up to 3-fold by 2050. Alzheimer's disease is usually triggered by numerous associated factors, including depleted amount of acetylcholine (ACh), excessive aggregation of ß-amyloid peptide (Aß), tau hyperphosphorylation with neurofibrillary tangle formation as well as deposition of feeble plaques in a specific portion of the brain (hippocampus and cortex). Besides these superior factors, sometimes AD can be induced or become complex due to several reasons, such as inflammatory mechanisms and oxidative stress. Furthermore, heterocyclic scaffolds comprise assorted implications in the drug design and development process. Heterocycles have also elicited their evolving role as core scaffolds in numerous synthetic derivatives with potent anti-Alzheimer's potential. There are only limited drugs that are present in the market to treat Alzheimer's disease in an efficacious manner. Hence, the identification, design, and development of new anti-Alzheimer's drugs are an emerging need to eradicate complex clinical indications associated with Alzheimer's disease. This review aims to summarize various recent advancements in the medicinal chemistry of heterocycle-based compounds with the following objectives: (1) to represent inclusive literature reports describing the anti-Alzheimer's potential of heterocyclic derivatives; (2) to cast light on recent advancements in the medicinal chemistry of heterocyclic compounds endowed with therapeutic potential against Alzheimer's disease; (3) to summarize the comprehensive correlation of structure-activity relationship (SAR) with the pharmacological responses, including in silico and mechanistic studies to provide ideas related to design and development of lead molecules.