Small molecule anticancer drugs approved during 2021-2022: Synthesis and clinical applications.

Drugs have structural homology across similar biological targets. Small molecule drugs have the efficacy to target specific molecular targets within the cancer cells with enhanced cell membrane permeability, oral administration, selectivity, and specific affinity. The objective of this review is to highlight the clinical importance and synthetic routes of new small molecule oncology drugs approved by the FDA during the period 2021-2022. These marketed drugs are listed based on the month and year of approval in chronological order. We believed that an in-depth insight into the synthetic approaches for the construction of these chemical entities would enhance the ability to develop new drugs more efficiently.

Network pharmacology-based approach to elucidate the pharmacologic mechanisms of natural compounds from Dictyostelium discoideum for Alzheimer's disease treatment.

Alzheimer's disease (AD) is increasingly becoming a major public health concern in our society. While many studies have explored the use of natural polyketides, alkaloids, and other chemical components in AD treatment, there is an urgent need to clarify the concept of multi-target treatment for AD. This study focuses on using network pharmacology approach to elucidate how secondary metabolites from Dictyostelium discoideum affect AD through multi-target or indirect mechanisms. The secondary metabolites produced by D. discoideum during their development were obtained from literature sources and PubChem. Disease targets were selected using GeneCards, DisGeNET, and CTD databases, while compound-based targets were identified through Swiss target prediction and Venn diagrams were used to find intersections between these targets. A network depicting the interplay among disease, drugs, active ingredients, and key target proteins (PPI network) was formed utilizing the STRING (Protein-Protein Interaction Networks Functional Enrichment Analysis) database. To anticipate the function and mechanism of the screened compounds, GO and KEGG enrichment analyses were conducted and visually presented using graphs and bubble charts. After the screening phase, the top interacting targets in the PPI network and the compound with the most active target were chosen for subsequent molecular docking and molecular dynamic simulation studies. This study identified nearly 50 potential targeting genes for each of the screened compounds and revealed multiple signaling pathways. Among these pathways, the inflammatory pathway stood out. COX-2, a receptor associated with neuroinflammation, showed differential expression in various stages of AD, particularly in pyramidal neurons during the early stages of the disease. This increase in COX-2 expression is likely induce by higher levels of IL-1, which is associated with neuritic plaques and microglial cells in AD. Molecular docking investigations demonstrated a strong binding interaction between the terpene compound PQA-11 and the neuroinflammatory receptor COX2, with a substantial binding affinity of -8.4 kcal/mol. Subsequently, a thorough analysis of the docked complex (COX2-PQA11) through Molecular Dynamics Simulation showed lower RMSD, minimal RMSF fluctuations, and a reduced total energy of -291.35 kJ/mol compared to the standard drug. These findings suggest that the therapeutic effect of PQA-11 operates through the inflammatory pathway, laying the groundwork for further in-depth research into the role of secondary metabolites in AD treatment.

Marine polychaete Namalycastis sp. extracts enhance proliferation and regeneration of mice 3T3 fibroblast and MCR-5 human fibroblast cells.

The Nereidid worm is a marine polychaete commonly found near the Nipa palm (Nypa fructicans) along the mangrove estuary. Recently, many usages have been documented for this polychaete family. Nevertheless, the true potentials of these marine worms, especially Namalycastis sp., from the medical perspective are still unknown. The current study investigated the cytotoxicity effect of Namalycastis sp. crude extracts on mice 3T3 fibroblast cells and human lung MRC-5 fibroblast cells. Thirteen concentrations (2, 4, 8, 16, 31, 63 µg/mL and 0.1, 0.3, 0.5, 1, 2, 4, 8 mg/mL) of the extracts were used as a treatment for 24 h, and cell viability was measured via the MTT assay. None of the 13 concentrations of Namalycastis sp. crude extracts showed cytotoxicity effects on the cell types investigated. However, based on the live images captured by the IncuCyte™ imaging system, the cells treated with Namalycastis sp. crude extracts showed an increased proliferation and growth rate in less than 10 h Furthermore, the extract concentration of 8 µg/mL induced the highest cell proliferation rate whereas 8 mg/mL led to the lowest cell proliferation rate following the treatment. Overall, Namalycastis sp. crude extracts were non-toxic on mice and human cells within the tested concentrations set. Still, it increased cell viability and proliferation compared with the control. This finding could pave the way for an alternative therapeutic strategy to treat debilitating disorders such as ageing, cardiovascular diseases, and neurodegenerative diseases.

Green synthesis of Piper nigrum copper-based nanoparticles: in silico study and ADMET analysis to assess their antioxidant, antibacterial, and cytotoxic effects.

Nanobiotechnology is a popular branch of science that is gaining interest among scientists and researchers as it allows for the green manufacturing of nanoparticles by employing plants as reducing agents. This method is safe, cheap, reproducible, and eco-friendly. In this study, the therapeutic property of Piper nigrum fruit was mixed with the antibacterial activity of metallic copper to produce copper nanoparticles. The synthesis of copper nanoparticles was indicated by a color change from brown to blue. Physical characterization of Piper nigrum copper nanoparticles (PN-CuNPs) was performed using UV-vis spectroscopy, FT-IR, SEM, EDX, XRD, and Zeta analyzer. PN-CuNPs exhibited potential antioxidant, antibacterial, and cytotoxic activities. PN-CuNPs have shown concentration-dependent, enhanced free radical scavenging activity, reaching maximum values of 92%, 90%, and 86% with DPPH, H2O2, and PMA tests, respectively. The antibacterial zone of inhibition of PN-CuNPs was the highest against Staphylococcus aureus (23 mm) and the lowest against Escherichia coli (10 mm). PN-CuNPs showed 80% in vitro cytotoxicity against MCF-7 breast cancer cell lines. Furthermore, more than 50 components of Piper nigrum extract were selected and subjected to in silico molecular docking using the C-Docker protocol in the binding pockets of glutathione reductase, E. coli DNA gyrase topoisomerase II, and epidermal growth factor receptor (EGFR) tyrosine to discover their druggability. Pipercyclobutanamide A (26), pipernigramide F (32), and pipernigramide G (33) scored the highest Gibbs free energy at 50.489, 51.9306, and 58.615 kcal/mol, respectively. The ADMET/TOPKAT analysis confirmed the favorable pharmacokinetics, pharmacodynamics, and toxicity profiles of the three promising compounds. The present in silico analysis helps us to understand the possible mechanisms behind the antioxidant, antibacterial, and cytotoxic activities of CuNPs and recommends them as implicit inhibitors of selected proteins.

Evaluation of anti-hyperuricemic effects of Alocasia longiloba Miq. (Keladi Candik) extracts in potassium oxonate induced rat model.

Hyperuricemia has become a significant public-health concern in recent years, and the available treatments have been reported to have an adverse side effect on patients. Alocasia longiloba has been used traditionally in Malaysia for treating gout, inflammation, and wounds. However, the plant has not been investigated for its effects on hyperuricemia. This study investigated the anti-hyperuricemic and anti-inflammatory effects of A. longiloba extracts in hyperuricemic rats induced by potassium oxonate (250 mg/kg body weight). Rats were given A. longiloba extracts or a standard drug for two-week, and blood and tissue samples were collected for analysis. Results show that A. longiloba extracts significantly reduced serum uric acid levels in hyperuricemic rats and inhibited xanthine oxidase (XOD) activity in the liver and kidney, which could be the mechanism underlying the urate-lowering effects. The extracts also significantly (p < 0.05) reduced the levels of proinflammatory cytokines (IL-18 and IL-1ß) in serum samples and had hepatoprotective and nephroprotective effects in hyperuricemic rats. The study supports the use of A. longiloba as a complementary therapy for treating hyperuricemia.

Polyherbal formulation conjugated to gold nanoparticles induced ferroptosis in drug-resistant breast cancer stem cells through ferritin degradation.

Aim: Due to their minimal side effects, the anti-cancer properties of the polyherbal formulation are being investigated. However, due to their low absorption potential, the administration of polyherbal formulations is restricted. Loading the polyherbal formulation into gold nanoparticles enhances the bioavailability of the polyherbal formulation (PHF) accompanied by reducing the concentration of doxorubicin (dox). Ferroptosis is one of the novel pathways that specifically target cancer stem cells due to high ferritin levels. Hence, in the present study, we conjugated polyherbal formulation with gold nanoparticles and studied its effect on inducing ferroptosis in drug-resistant breast cancer cell lines. Materials and methods: PHF and dox conjugated to gold nanoparticles were characterized using FTIR, UV-Vis spectrophotometer, DLS, particle size analyzer, and XRD. The drug entrapment and efficiency studies were performed to assess the biodegradable potential of the synthesized gold nanoparticles. Paclitaxel-resistant breast cancer stem cells were generated, and an MTT assay was performed to evaluate the cytotoxicity potential of AuNP-PHF and AuNP-dox. Scratch assay and clonogenic assay were performed to assess the migration and proliferation of the cells after treatment with chosen drug combinations. The ability of PHF and dox conjugated to gold nanoparticles to induce ferritinophagy was evaluated by RT-PCR. Finally, image analysis was performed to check apoptosis and cellular ROS using inverted fluorescent microscope. The ability to induce cell cycle arrest was assessed by cell cycle analysis using flow cytometer. Results and conclusion: PHF and dox conjugated to gold nanoparticles showed high stability and showed to induce ferritin degradation in drug resistant breast cancer stem cells through ferritin degradation. AuNP-PHF in combination with low dose of AuNP-Dox nanoconjugate could be used as an effective cancer therapeutic agent, by targeting the autophagy necroptosis axis.

Neurological infection and complications of SARS-CoV-2: A review.

The primary target of severe acute respiratory syndrome coronavirus 2 is the respiratory system including the nose and lungs, however, it can also damage the kidneys, cardiovascular system and gastrointestinal system. Many recent reports suggested that severe acute respiratory syndrome coronavirus 2 infections can also affect the central nervous system as well as peripheral nervous system that lead to the several neurological complications. The virus can break the blood brain barrier and enters the brain via haematological route or directly by the angiotensin-converting enzyme 2 receptors present on endothelial cells of many cerebral tissues. The neurological complications are manifested by headache, dizziness, encephalopathy, encephalitis, cerebrovascular disease, anosmia, hypogeusia, muscle damage, etc. This review article described the possible routes and mechanism of nervous system infection and the range of neurological complications of COVID-19 that may help the medical practitioners and researchers to improve the clinical treatment and reduce the mortality rate among patients with viral diseases.

Mechanistic Insights and Potential Therapeutic Approaches in PolyQ Diseases via Autophagy.

Polyglutamine diseases are a group of congenital neurodegenerative diseases categorized with genomic abnormalities in the expansion of CAG triplet repeats in coding regions of specific disease-related genes. Protein aggregates are the toxic hallmark for polyQ diseases and initiate neuronal death. Autophagy is a catabolic process that aids in the removal of damaged organelles or toxic protein aggregates, a process required to maintain cellular homeostasis that has the potential to fight against neurodegenerative diseases, but this pathway gets affected under diseased conditions, as there is a direct impact on autophagy-related gene expression. The increase in the accumulation of autophagy vesicles reported in neurodegenerative diseases was due to an increase in autophagy or may have been due to a decrease in autophagy flux. These reports suggested that there is a contribution of autophagy in the pathology of diseases and regulation in the process of autophagy. It was demonstrated in various disease models of polyQ diseases that autophagy upregulation by using modulators can enhance the dissolution of toxic aggregates and delay disease progression. In this review, interaction of the autophagy pathway with polyQ diseases was analyzed, and a therapeutic approach with autophagy inducing drugs was established for disease pathogenesis.

A Review on Psychrophilic ß-D-Galactosidases and Their Potential Applications.

The majority of the Earth's ecosystem is frigid and frozen, which permits a vast range of microbial life forms to thrive by triggering physiological responses that allow them to survive in cold and frozen settings. The apparent biotechnology value of these cold-adapted enzymes has been targeted. Enzymes' market size was around USD 6.3 billion in 2017 and will witness growth at around 6.8% CAGR up to 2024 owing to shifting consumer preferences towards packaged and processed foods due to the rising awareness pertaining to food safety and security reported by Global Market Insights (Report ID-GMI 743). Various firms are looking for innovative psychrophilic enzymes in order to construct more effective biochemical pathways with shorter reaction times, use less energy, and are ecologically acceptable. D-Galactosidase catalyzes the hydrolysis of the glycosidic oxygen link between the terminal non-reducing D-galactoside unit and the glycoside molecule. At refrigerated temperature, the stable structure of psychrophile enzymes adjusts for the reduced kinetic energy. It may be beneficial in a wide variety of activities such as pasteurization of food, conversion of biomass, biological role of biomolecules, ambient biosensors, and phytoremediation. Recently, psychrophile enzymes are also used in claning the contact lens. ß-D-Galactosidases have been identified and extracted from yeasts, fungi, bacteria, and plants. Conventional (hydrolyzing activity) and nonconventional (non-hydrolytic activity) applications are available for these enzymes due to its transgalactosylation activity which produce high value-added oligosaccharides. This review content will offer new perspectives on cold-active ß-galactosidases, their source, structure, stability, and application.

LC-TOF-MS/MS and GC-MS based phytochemical profiling and evaluation of wound healing activity of Oroxylum Indicum (L.) Kurz (Beka).

Background: Beka (Oroxylum indicum (L.) Kurz) has been used as a culinary herb and natural remedy by the local communities in Malaysia. The leaf of O. indicum is traditionally used for the treatment of diarrhea, high blood pressure, and improving digestive health. Objectives: The present study was conducted to evaluate the phytochemical constituents and wound healing properties (in vitro and in vivo models) of aqueous and ethanol extracts of O. indicum leaves. Methods: The total phenolic (TPC) and total flavonoid (TFC) contents in the plant extracts were determined by the spectrophotometric methods. Further, the extract was characterized by Liquid Chromatography Time-of-Flight Mass Spectrometry (LC-TOF-MS/MS) and Gas Chromatography-Mass Spectrometry (GC-MS). The wound healing activity was assessed using the in vitro scratch wound-healing assay and in vivo excisional wound model. Results: The results show the ethanol leaves extract had the higher TPC (164 mg GAE/g) when compared with the aqueous leaves extract (30 mg gallic acid equivalents/g). The ethanol leaves extract was also found to have higher TFC (101 mg Catechin equivalents/g) than the aqueous leaves extract (76 mg Catechin equivalents/g). The ethanol leaves extract was then used for further chemical analysis. The LC-TOF-MS/MS analysis showed that the leaves extracts of O. indicum contains many important compounds such as Orientin, Chrysin, Pinoquercetin, Cupressuflavone, Puerarin xyloside, Forsythiaside and Paederoside. In GC-MS analysis, 19 compounds were identified in ethanolic leaves extract. The wound healing studies shows that O. indicum has promising wound healing activity by increasing the rate of wound contraction significantly (p < 0.05). Conclusion: In conclusion, the present study showed that O. indicum leaf contains important phytochemicals and the wound healing potential of the O. indicum extract may probably be as a result of the presence of various phytoconstituents.

Volatile Organic Compounds of Bryophytes from Peninsular Malaysia and Their Roles in Bryophytes.

Volatile emissions from 22 bryophyte species from Peninsular Malaysia were collected using a dynamic headspace technique and analyzed by gas chromatography-mass spectrometry (GC-MS). Thirty organic compounds (VOCs) from eight different groups were detected in bryophytes from the montane forest in Cameron Highlands and the lowland dipterocarp forest in Lata Belatan. The headspace of bryophytes in Cameron Highlands was dominated by tetradecane, 2-ethyl-1-hexanol, decanal, pentanoic acid, 2,2,4-trimethyl-3-carboxyisopropyl, isobutyl ester, D-limonene and naphthalene. On the contrary, in the bryophyte headspace of Lata Belatan, naphthalene and tetradecane were dominant compounds. The elevational pattern detected in VOC composition of bryophytes appears to be an evolutionary feature at the family level that needs verification at other sites. The results also confirmed that the VOC composition of bryophytes is species-specific. The roles of VOCs in bryophytes are presented, including plant-plant communication and plant-insect interaction and as an additional taxonomic character in chemotaxonomy.

Effect of Exercise Training on Serum Transaminases in Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Background/Purpose: Nonalcoholic fatty liver disease (NAFLD) constitutes a spectrum of liver diseases associated with various metabolic disorders. Exercise interventions reportedly manage the clinical outcomes of NAFLD, but their efficacy depends on exercise as well as characteristics of patient. We hypothesized that exercise could alleviate the elevated transaminases level, which may be associated with the characteristics of patients (age/bodyweight/sex) or exercise variables (frequency/intensity/duration). Therefore, we examined the effect of exercise on serum transaminases, and identified the variables influencing transaminases in NAFLD patients. Methods: Article search was conducted using electronic databases (PubMed, Web of Science, EMBASE, ScienceDirect, Google Scholar) until December 2021. Studies that involved examination and comparison of the effect of an exercise intervention on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in NAFLD/nonalcoholic steatohepatitis patients were included. We calculated pooled effect upon a meta-analysis, determined correlations (between transaminases and characteristics of patients/exercise) by meta-regression, and assessed the influencing variable through subgroup analysis. Results: A total of 18 studies (22 trials) with 1098 NAFLD patients (exercise = 568; control = 530) were included. The pooled outcomes revealed that exercise intervention significantly decreased both ALT (p = 0.004) and AST (p = 0.001) levels in NAFLD patients. Meta-regression analysis showed decreased ALT (coef. = 1.138, p < 0.01) and AST (coef. = 0.459, p = 0.041) after intervention was correlated with the age of patients. Particularly, patients aged 30-39 years (MD: -25.89 U/L, 95% CI: -36.40 to -15.37, p < 0.00001) and 40-49 years (MD: -12.17 U/L, 95% CI: -20.38 to -3.96, p = 0.004) represented a substantial decrease in ALT levels. Additionally, the 50-59 years age group tended to have decreased ALT levels (MD: -3.94 U/L, 95% CI: -8.19 to 0.31, p = 0.07); however, patients above 60 years did not respond (p = 0.92) to exercise intervention. In contrast, exercise-induced AST reduction was found in only the 30-39 years age group (MD: -11.92 U/L, 95% CI: -16.78 to -7.06, p < 0.00001) and not in patients under the 40-49 (p = 0.19), and 50-59 groups (p = 0.12) and above 60 years (p = 0.15). Conclusion: Our findings suggest that the age of NAFLD patients may be an important variable in improving the levels of serum transaminases, and clinically young patients may have greater benefits from exercise than older patients.

Acute oral toxicity assessment and anti-hyperuricemic activity of Alocasia longiloba extracts on Sprague-Dawley rats.

Hyperuricemia is defined as a metabolic abnormality that occurs when serum uric acid (UA) level is abnormally high in the body. We previously reported that A. longiloba possesses various important phytochemicals and in vitro xanthine oxidase activity. Despite A. longiloba ethnomedicinal benefits, its toxicity and anti-hyperuricemic effects have not been reported. The present study was carried out to ensure the safety and investigate the anti-hyperuricemic effects of A. longiloba fruit and petiole ethanolic extracts on rats. In the acute toxicity study, extracts were orally administered at a dose of 2000 mg/kg bodyweight and closely monitored for 2-week for any toxicity effects. The rats were then sacrificed and samples were collected and analyzed for hematological, biochemical, and histopathological parameters. The anti-hyperuricemic effect of A. longiloba fruit or petiole extract was investigated through determination of UA levels on potassium oxonate (PO)-induced hyperuricemic rats. Extracts or standard drug treatments were orally administrated 1-h after PO administration for 14-day. Animals were euthanized and samples were collected for further experiments. The toxicity results show, no significant changes were observed in behavioral, bodyweight changes in experimental groups compared to the control. Moreover, there were no significant changes in hematological, biochemical, and histological parameters between extracts treated and control group. In the anti-hyperuricemia study, the fruit and petiole extracts treatments significantly reduced the level of UA in serum compared to the hyperuricemic model group. This study demonstrated that the extracts of A. longiloba have anti-hyperuricemic activity and was found to be non-toxic to rats in acute toxicity test.

Seafood Discards: A Potent Source of Enzymes and Biomacromolecules With Nutritional and Nutraceutical Significance.

In recent times, the seafood industry is found to produce large volumes of waste products comprising shrimp shells, fish bones, fins, skins, intestines, and carcasses, along with the voluminous quantity of wastewater effluents. These seafood industry effluents contain large quantities of lipids, amino acids, proteins, polyunsaturated fatty acids, minerals, and carotenoids mixed with the garbage. This debris not only causes a huge wastage of various nutrients but also roots in severe environmental contamination. Hence, the problem of such seafood industry run-offs needs to be immediately managed with a commercial outlook. Microbiological treatment may lead to the valorization of seafood wastes, the trove of several useful compounds into value-added materials like enzymes, such as lipase, protease, chitinase, hyaluronidase, phosphatase, etc., and organic compounds like bioactive peptides, collagen, gelatin, chitosan, and mineral-based nutraceuticals. Such bioconversion in combination with a bio-refinery strategy possesses the potential for environment-friendly and inexpensive management of discards generated from seafood, which can sustainably maintain the production of seafood. The compounds that are being produced may act as nutritional sources or as nutraceuticals, foods with medicinal value. Determining utilization of seafood discard not only reduces the obnoxious deposition of waste but adds economy in the production of food with nutritional and medicinal importance, and, thereby meets up the long-lasting global demand of making nutrients and nutraceuticals available at a nominal cost.

Novel Coronavirus (SARS-CoV-2) in Water and Environment-A Scoping Review.

A pneumonia outbreak was primarily reported in the fall of 2019 in Wuhan, Hubei province, China, with the identity SARS-CoV-2, a novel coronavirus. It quickly grew from a local epidemic to a global pandemic and was declared a public health emergency by the WHO. A total of three prominent waves were identified across the globe, with a slight temporal variability as per the geographical locations, and has impacted several sectors which connect the world. By March 2022, the coronavirus had infected 444.12 million people and claimed 6.01 million human lives worldwide, and these numbers have not yet stabilized. Our paper enlightens readers on the seven strains of human coronaviruses, with special emphasis on the three severe deadliest outbreaks (SARS-2002, MERS-2012, and COVID-19). This work attempts a comprehensive understanding of the coronavirus and its impact on the possible sectors that link the world through the economic chain, climate conditions, SDGs, recycling of the event, and mitigations. There are many points that are raised by the authors in the possible sectors, which are emerging or are as yet unnoticed and thus have not been taken into consideration. This comprehension will leave sets of new challenges and opportunities for the researchers in various streams, especially in earth sciences. Science-integrated research may help to prevent upcoming disasters as a by-product of (existing) epidemics in the form of coronavirus.