Screening of natural products atlas for identification of lead molecule to treat angina pectoris using bioinformatics approaches.

Angina pectoris is amongst the most common diseases. There is a scarcity of effective treatments for this disease. As a result, there is a significant clinical and social interest in predicting and developing novel compounds to treat cardiovascular disorders. So, specific natural products have been screened in this study because they have protective effects against angiotensin-converting enzymes. When taken orally, natural products can help protect against or lessen the severity of angina and heart damage. Natural compounds inhibit regulatory enzymes for controlling Angina. For this, we used computational methods such as drug design to identify novel natural compounds against cardiovascular diseases. Drug design via computational methods is gaining popularity as a quick and effective method to identify lead compounds in a shorter time at a low cost. This research work aims to predict novel lead inhibitor compounds against ACE to treat angina pectoris. This would ensure that, in early preclinical studies, there will be lower failure rates due to the demonstrated safety profiles of the predicted compounds.

The discovery of the natural compound Boeravinone-C as a potential antiobesity drug candidate targeting pancreatic lipase using chemo-informatics-based approaches.

Obesity is a metabolic disorder distinguished by excess fat deposition in fatty tissues. Pancreatic lipase is one of the promising drug targets for treating obesity due to its critical role in the hydrolysis of triglycerides into mono-glycerides and free fatty acids. Due to unsatisfactory results and severe side effects of the current drugs available for treating obesity, there is an urgent need to identify novel therapeutic options. Boerhaavia diffusa is one of the widely known species of flowering plant commonly known as Punamava. Extracts from Punamava plants have been widely used in treating countless ailments in traditional medicine. Recently, multiple reports demonstrated the potential antiobesity activity of B. diffusa plant extracts. In this scenario, we have evaluated numerous reported B. diffusa against pancreatic lipase drug targets to identify which reported phytochemicals to have the most promising potential to act as an inhibitor for pancreatic lipase using computational approaches. All the twenty-four phytochemicals from Boerhaavia diffusa were identified as significantly strong binders with a range of binding energies between -6.0 to -8.0 Kcal/mol inside the pancreatic lipase active binding site. On the other hand, we calculated 2D Quantitative Structure-Activity Relationship (QSAR) molecular descriptor properties adhered to Lipinski's rule of five. Between twenty-four phytochemicals evaluated, Boeravinone-C, with a range binding energy of -8.0 Kcal/mol, was discovered as the best lead-like molecule, compared to marketed Orlistat, which has shown -5.6 Kcal/mol of binding energy. Conclusively, Boeravinone-C from B. diffusa extract showed promising inhibitory potential against pancreatic lipase worth further evaluation.

Nanostructured Lipid Carriers to Enhance the Bioavailability and Solubility of Ranolazine: Statistical Optimization and Pharmacological Evaluations.

Chronic stable angina pectoris is the primary indication for ranolazine (RZ), an anti-anginal drug. The drug has an anti-ischemic action that is unaffected by either blood pressure or heart rate. Due to the first-pass effect, the drug has a reduced bioavailability of 35 to 50%. The study emphasized developing a novel transdermal drug delivery system of nanostructured lipid carriers (NLCs) for delivering RZ. Many pharmaceutical companies employ lipid nanoparticles as biocompatible carriers for medicinal, cosmetic, and biochemical uses. These carriers are appropriate for many applications, such as topical, transdermal, parenteral, pulmonary, and oral administration, because of the large variety of lipids and surfactants that are readily available for manufacturing. RZ NLCs were made using high-pressure homogenization. Statistical analysis was utilized to find the best formula by varying the concentrations of Precirol ATO 5 (X1), oleic acid (X2), and Tween 80 (X3). Variables such as entrapment effectiveness (EE) (Y1), particle size (Y2), polydispersity index (PDI) (Y3), and zeta potential (Y4) were tested. A variety of tests were performed on the new formulation to ascertain how well it would be absorbed in the body. These tests included in vivo absorption studies, skin permeability assessments, in vitro drug release assessments, and physicochemical analyses. The particle size of RZ-NLCs was shown to be very small (118.4 ± 5.94 nm), with improved EE (88.39 ± 3.1%) and low ZP and PDI (-41.91 ± 0.38 and 0.118 ± 0.028). SEM and TEM analysis confirmed the structure of the NLCs and showed a smooth, spherical surface. Improved RZ-NLCs were used to create NLC gel, which was then tested for elasticity both physically and rheologically. The formulation's elasticity was investigated. Optimized RZ-NLCs and NLCG were found to have transdermal fluxes of 48.369 g/cm2/h and 38.383 g/cm2/h, respectively. These results showed that the transdermal delivery of RZ distribution through NLC's transdermal gel had more significant potential. According to in vivo experiments, the drug's bioavailability in Wistar rats increased when it was delivered through NLCs. The findings demonstrated that NLCs loaded with RZ successfully transported the RZ to the designated site with no interruptions and that a quadratic connection existed between the independent and dependent variables.

Potential anti-obesity/inflammatory flavonoid-derived biomolecules against Obesity to prevent WAT differentiation by targeting a DNA-binding protein inhibitor, ID-1.

A concoction of unhealthy eating, inactivity, and the adverse effects of specific drugs brings on obesity. The primary cause of Obesity is the storage of too much energy and triglycerides in adipocytes, particularly white adipose tissue (WAT). In addition to modifying one's lifestyle, anti-obesity medicines are increasingly used as adjuvant therapy. Flavonoids are the major class of compounds having significant biological impacts and health-improving properties. To find novel flavonoid compounds that fight obesity using computational drug design techniques. This work targets 1DI protein to predict new flavonoid compounds that fight obesity. The study uses computational approaches to anticipate potential anti-obesity/inflammatory flavonoid compounds against obesity to prevent WAT differentiation by targeting ID-1, a DNA-binding protein inhibitor. Our study led to the identification of the protein target inhibitor lead CID: 5280443, which was found to be a potent inhibitor of the receptor. According to the findings of this study, this bio-active molecule may be used as a lead for the development of drugs that preferentially fight obesity without interfering with the functions of the human proteasome. The scientific community will benefit from these discoveries, which could aid in the creation of new medications that treat obesity more successfully.

Nanotechnology-based gene therapy as a credible tool in the treatment of Alzheimer's disease.

Toxic aggregated amyloid-ß accumulation is a key pathogenic event in Alzheimer's disease. Treatment approaches have focused on the suppression, deferral, or dispersion of amyloid-ß fibers and plaques. Gene therapy has evolved as a potential therapeutic option for treating Alzheimer's disease, owing to its rapid advancement over the recent decade. Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets, including those that were once considered undruggable. However, lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application, necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the blood-brain barrier. Nanotechnology has emerged as a possible solution, and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery. By reducing the enzymatic breakdown of genetic components, nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy. Liposomes, polymeric nanoparticles, magnetic nanoparticles, dendrimers, and micelles are examples of nanocarriers that have been designed, and each has its own set of features. Furthermore, recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities. In this paper, we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer's disease.

Carotenoids: Role in Neurodegenerative Diseases Remediation.

Numerous factors can contribute to the development of neurodegenerative disorders (NDs), such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Oxidative stress (OS), a fairly common ND symptom, can be caused by more reactive oxygen species being made. In addition, the pathological state of NDs, which includes a high number of protein aggregates, could make chronic inflammation worse by activating microglia. Carotenoids, often known as "CTs", are pigments that exist naturally and play a vital role in the prevention of several brain illnesses. CTs are organic pigments with major significance in ND prevention. More than 600 CTs have been discovered in nature, and they may be found in a wide variety of creatures. Different forms of CTs are responsible for the red, yellow, and orange pigments seen in many animals and plants. Because of their unique structure, CTs exhibit a wide range of bioactive effects, such as anti-inflammatory and antioxidant effects. The preventive effects of CTs have led researchers to find a strong correlation between CT levels in the body and the avoidance and treatment of several ailments, including NDs. To further understand the connection between OS, neuroinflammation, and NDs, a literature review has been compiled. In addition, we have focused on the anti-inflammatory and antioxidant properties of CTs for the treatment and management of NDs.

Inhibition of Caspase 3 and Caspase 9 Mediated Apoptosis: A Multimodal Therapeutic Target in Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the significant causes of death and morbidity, and it is hence a focus of translational research. Apoptosis plays an essential part in the pathophysiology of TBI, and its inhibition may help overcome TBI's negative consequences and improve functional recovery. Although physiological neuronal death is necessary for appropriate embryologic development and adult cell turnover, it can also drive neurodegeneration. Caspases are principal mediators of cell death due to apoptosis and are critical for the required cleavage of intracellular proteins of cells committed to die. Caspase-3 is the major executioner Caspase of apoptosis and is regulated by a range of cellular components during physiological and pathological conditions. Activation of Caspase-3 causes proteolyzation of DNA repair proteins, cytoskeletal proteins, and the inhibitor of Caspase-activated DNase (ICAD) during programmed cell death, resulting in morphological alterations and DNA damage that define apoptosis. Caspase-9 is an additional crucial part of the intrinsic pathway, activated in response to several stimuli. Caspases can be altered post-translationally or by modulatory elements interacting with the zymogenic or active form of a Caspase, preventing their activation. The necessity of Caspase-9 and -3 in diverse apoptotic situations suggests that mammalian cells have at least four distinct apoptotic pathways. Continued investigation of these processes is anticipated to disclose new Caspase regulatory mechanisms with consequences far beyond apoptotic cell death control. The present review discusses various Caspase-dependent apoptotic pathways and the treatment strategies to inhibit the Caspases potentially.

Mechanism of Mesenchymal Stem Cells as a Multitarget Disease- Modifying Therapy for Parkinson's Disease.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, affecting the basal nuclei, causing impairment of motor and cognitive functions. Loss of dopaminergic (DAergic) neurons or their degeneration and the aggregation of Lewy bodies is the hallmark of this disease. The medications used to treat PD relieve the symptoms and maintain quality of life, but currently, there is no cure. There is a need for the development of therapies that can cease or perhaps reverse neurodegeneration effectively. With the rapid advancements in cell replacement therapy techniques, medical professionals are trying to find a cure by which restoration of dopamine neurotransmitters can occur. Researchers have started focusing on cell-based therapies using mesenchymal stem cells (MSCs) due to their abundance in the body, the ability of proliferation, and immunomodulation. Here we review the MSC-based treatment in Parkinson's disease and the various mechanisms it repairs DAergic neurons in parkinsonian patients.

Nanotechnology: A Promising Targeted Drug Delivery System for Brain Tumours and Alzheimer's Disease.

Nanotechnology is the process of modulating shape and size at the nanoscale to design and manufacture structures, devices, and systems. Nanotechnology's prospective breakthroughs are incredible, and some cannot even be comprehended right now. The blood-brain barrier, which is a prominent physiological barrier in the brain, limits the adequate elimination of malignant cells by changing the concentration of therapeutic agents at the target tissue. Nanotechnology has sparked interest in recent years as a way to solve these issues and improve drug delivery. Inorganic and organic nanomaterials have been found to be beneficial for bioimaging approaches and controlled drug delivery systems. Brain cancer (BC) and Alzheimer's disease (AD) are two of the prominent disorders of the brain. Even though the pathophysiology and pathways for both disorders are different, nanotechnology with common features can deliver drugs over the BBB, advancing the treatment of both disorders. This innovative technology could provide a foundation for combining diagnostics, treatments, and delivery of targeted drugs to the tumour site, further supervising the response and designing and delivering materials by employing atomic and molecular elements. There is currently limited treatment for Alzheimer's disease, and reversing further progression is difficult. Recently, various nanocarriers have been investigated to improve the bioavailability and efficacy of many AD treatment drugs. Nanotechnology-assisted drugs can penetrate the BBB and reach the target tissue. However, further research is required in this field to ensure the safety and efficacy of drug-loaded nanoparticles. The application of nanotechnology in the diagnosis and treatment of brain tumours and Alzheimer's disease is briefly discussed in this review.

Modelling the Interplay Between Neuron-Glia Cell Dysfunction and Glial Therapy in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complicated, interpersonally defined, static condition of the underdeveloped brain. Although the aetiology of autism remains unclear, disturbance of neuronglia interactions has lately been proposed as a significant event in the pathophysiology of ASD. In recent years, the contribution of glial cells to autism has been overlooked. In addition to neurons, glial cells play an essential role in mental activities, and a new strategy that emphasises neuron-glia interactions should be applied. Disturbance of neuron-glia connections has lately been proposed as a significant event in the pathophysiology of ASD because aberrant neuronal network formation and dysfunctional neurotransmission are fundamental to the pathology of the condition. In ASD, neuron and glial cell number changes cause brain circuits to malfunction and impact behaviour. A study revealed that reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Recent discoveries also suggest that dysfunction or changes in the ability of microglia to carry out physiological and defensive functions (such as failure in synaptic elimination or aberrant microglial activation) may be crucial for developing brain diseases, especially autism. The cerebellum, white matter, and cortical regions of autistic patients showed significant microglial activation. Reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Replacement of defective glial cells (Cell-replacement treatment), glial progenitor cell-based therapy, and medication therapy (inhibition of microglia activation) are all utilised to treat glial dysfunction. This review discusses the role of glial cells in ASD and the various potential approaches to treating glial cell dysfunction.

3-Methoxy Carbazole Impedes the Growth of Human Breast Cancer Cells by Suppressing NF-κB Signaling Pathway.

Breast cancer represents the most frequently occurring cancer globally among women. As per the recent report of the World Health Organization (WHO), it was documented that by the end of the year 2020, approximately 7.8 million females were positively diagnosed with breast cancer and in 2020 alone, 685,000 casualties were documented due to breast cancer. The use of standard chemotherapeutics includes the frontline treatment option for patients; however, the concomitant side effects represent a major obstacle for their usage. Carbazole alkaloids are one such group of naturally-occurring bioactive compounds belonging to the Rutaceae family. Among the various carbazole alkaloids, 3-Methoxy carbazole or C13H11NO (MHC) is obtained from Clausena heptaphylla as well as from Clausena indica. In this study, MHC was investigated for its anti-breast cancer activity based on molecular interactions with specific proteins related to breast cancer, where the MHC had predicted binding affinities for NF-κB with −8.3 kcal/mol. Furthermore, to evaluate the biological activity of MHC, we studied its in vitro cytotoxic effects on MCF-7 cells. This alkaloid showed significant inhibitory effects and induced apoptosis, as evidenced by enhanced caspase activities and the cellular generation of ROS. It was observed that a treatment with MHC inhibited the gene expression of NF-kB in MCF-7 breast cancer cells. These results suggest that MHC could be a promising medical plant for breast cancer treatment. Further studies are needed to understand the molecular mechanisms behind the anticancer action of MHC.

Development and Characterization of PEGDA Microneedles for Localized Drug Delivery of Gemcitabine to Treat Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is one of the most belligerent types of breast cancer. While various modalities exist in managing/treating IBC, drug delivery using microneedles (MNs) is considered to be the most innovative method of localized delivery of anti-cancer agents. Localized drug delivery helps to treat IBC could limit their adverse reactions. MNs are nothing but small needle like structures that cause little or no pain at the site of administration for drug delivery via layers of the skin. The polyethylene glycol diacrylate (PEGDA) based MNs were fabricated by using three dimensional (3D) technology called Projection Micro-Stereo Lithography (PµSL). The fabricated microneedle patches (MNPs) were characterized and coated with a coating formulation comprising of gemcitabine and sodium carboxymethyl cellulose by a novel and inventive screen plate method. The drug coated MNPs were characterized by various instrumental methods of analysis and release profile studies were carried out using Franz diffusion cell. Coat-and-poke strategy was employed in administering the drug coated MNPs. Overall, the methods employed in the present study not only help in obtaining MNPs with accurate dimensions but also help in obtaining uniformly drug coated MNPs of gemcitabine for treatment of IBC. Most importantly, 100% drug release was achieved within the first one hour only.

Development of Dapagliflozin Solid Lipid Nanoparticles as a Novel Carrier for Oral Delivery: Statistical Design, Optimization, In-Vitro and In-Vivo Characterization, and Evaluation.

Controlling hyperglycemia and avoiding glucose reabsorption are significant goals in type 2 diabetes treatments. Among the numerous modes of medication administration, the oral route is the most common. Introduction: Dapagliflozin is an oral hypoglycemic agent and a powerful, competitive, reversible, highly selective, and orally active human SGLT2 inhibitor. Dapagliflozin-loaded solid lipid nanoparticles (SLNs) are the focus of our present investigation. Controlled-release lipid nanocarriers were formulated by integrating them into lipid nanocarriers. The nanoparticle size and lipid utilized for formulation help to regulate the release of pharmaceuticals over some time. Dapagliflozin-loaded nanoparticles were formulated by hot homogenization followed by ultra-sonication. The morphology and physicochemical properties of dapagliflozin-SLNs have been characterized using various techniques. The optimized dapagliflozin-SLNs have a particle size ranging from 100.13 ± 7.2 to 399.08 ± 2.4 nm with 68.26 ± 0.2 to 94.46 ± 0.7% entrapment efficiency (%EE). Dapagliflozin-SLNs were optimized using a three-factor, three-level Box-Behnken design (BBD). Polymer concentration (X1), surfactant concentration (X2), and stirring duration (X3) were chosen as independent factors, whereas %EE, cumulative drug release (%CDR), and particle size were selected as dependent variables. Interactions between drug substances and polymers were studied using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and atomic force microscopy (AFM) analysis indicated the crystalline change from the drug to the amorphous crystal. Electron microscope studies revealed that the SLNs' structure is nearly perfectly round. It is evident from the findings that dapagliflozin-SLNs could lower elevated blood glucose levels to normal in STZ-induced diabetic rats, demonstrating a better hypoglycemic impact on type 2 diabetic patients. The in vivo pharmacokinetic parameters of SLNs exhibited a significant rise in Cmax (1258.37 ± 1.21 mcg/mL), AUC (5247.04 mcg/mL), and oral absorption (2-fold) of the drug compared to the marketed formulation in the Sprague Dawley rats.

Promising Role of Phytochemicals in the Prevention and Treatment of Cancer.

Cancer has a significant social consequence all around the globe. In 2020, approximately 19.3 million new cases of cancer were diagnosed worldwide, with about 10 million cancer deaths. In the next two decades, suspected cases are anticipated to increase by roughly 47%. The rising number of cancer patients, as well as the inadequacy of traditional chemotherapeutic agents, radiation, and invasive surgical procedures, all rely on massive cell death with hardly any selectivity, causing severe toxicities. In comparison to synthetic medications, there has subsequently been a surge in international interest in non-synthetic and alternative remedies, owing to improved adaptability and reduced side effects of drug responses. Several people with cancer prefer alternative and complementary therapy treatments, and natural remedies play a crucial role in cancer chemoprevention as they are thought to be harmless, offer fewer negative effects, and become less sufficient to evoke addiction by the wider population. Chemopreventive, antimetastatic, cytotoxic, and anti-angiogenic actions are among the promising clinical advantages, which have been established in vitro research and certain clinical trials; nevertheless, additional clinical trials are needed. This review examines several phytochemicals that may have anti-cancer and chemopreventive properties.

Recent Advances in Epidermal Growth Factor Receptor Inhibitors (EGFRIs) and their Role in the Treatment of Cancer: A Review.

Tyrosine kinases are known to play a role in tumour growth and proliferation, and they have become common drug targets. Tyrosine kinase inhibitors (TKIs) prohibit associated kinases from phosphorylating tyrosine residues in their substrates, preventing downstream signaling pathways from being activated. Multiple robust and well-tolerated TKIs targeting single or multiple targets, including EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT, have been developed over the last two decades, contributing to our understanding of precision cancer medicine based on a patient's genetic alteration profile. The epidermal growth factor receptor (EGFR) family consists of four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3, and Her4/ErbB4) and thirteen polypeptide ligands produced by them. Multiple solid tumours, including breast, pancreatic, head and neck, kidney, vaginal, renal, colon, and non-small cell lung cancer, overexpress EGFRs. Overexpression of these genes stimulates downstream signaling channels, causing cell proliferation, differentiation, cell cycle progression, angiogenesis, cell motility, and apoptosis inhibition. EGFRs' high expression and/or adaptive activation coincide with the pathogenesis and development of many tumours, making them appealing candidates for both diagnosis and therapy. Several strategies for targeting these receptors and/or the EGFR-mediated effects in cancer cells have been established. The majority of methods include the development of anti-EGFR antibodies and/or small-molecule EGFR inhibitors. This review presents the recent advances in EGFR TKIs and their role in the treatment of cancer.

Investigation of phytoconstituents of Enicostemma littorale as potential glucokinase activators through molecular docking for the treatment of type 2 diabetes mellitus.

Glucokinase (GK) is an enzyme involved in synthesising glucose into glucose-6 phosphate and serves a crucial function in glucose sensing. Therefore, agents that induce GK activation could be used to treat T2DM. The present work has been carried out to investigate the GK activation potential of phytoconstituents of Enicostemma littorale through molecular docking. All the phytoconstituents have been screened through the Lipinski rule of 5, Veber's rule, and ADMET properties. From these initial screening, only Apigenin, Ferulic acid, Genkwanin, p-coumaric acid, Protocatechuic acid, Syringic acid, and Vanillic acid have been selected to perform molecular docking studies. The binding free energy and binding mode of the native ligand in the allosteric site of the enzyme have been considered the reference for the other molecules' validation. The native ligand has exhibited - 7.2 kcal/mol binding free energy, whereas; it has formed four hydrogen bonds with THR-228, LYS-169, ASP-78, and GLY-81. Based on these findings, the interactions of phytoconstituents have been justified. Apigenin, genkwanin, and swertiamarin exhibited - 8.7, - 7.5, and - 8.3 kcal/mol binding free energy, respectively, which indicates better enzyme activation than the native ligand. Swertiamarin has formed 08 hydrogen bonds with allosteric amino acid residues, which confirms the excellent enzyme activation by these phytoconstituents. We concluded that if we can isolate and consume the exact active phytoconstituents (GK activators) from this plant, we can use them effectively to treat T2DM. More GK activators can be developed by considering them as a natural lead moiety.