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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.
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Menopausa , Osteoporose Pós-Menopausa , Fitoterapia , Humanos , Feminino , Osteoporose Pós-Menopausa/tratamento farmacológico , Menopausa/efeitos dos fármacos , Qualidade de Vida , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
In this study, an efficient method for hydrogenation reactions has been reported in a short reaction time using a two-chamber reactor. This process involves the ex situ generation of H2 gas using aluminum-water in the presence of NaOH. This technique was applied to reduce various functional groups, including carbonyl, nitro, alkene, alkyne, and azide. The method is also utilized for the chemoselective reduction of the double bonds in α, ß-unsaturated carbonyl compounds. The potential of the technique has been demonstrated through the quick delivery of several key starting materials and marketed drugs. Additionally, the method was further extended to isotope labeling using D2O. The entire process is safe and operated in standard fume hood settings, ensuring practicality and convenience for researchers in the field of organic synthesis.
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A phosphine-free, efficient protocol for aminocarbonylation and carbonylative Suzuki-Miyaura coupling has been developed using a novel palladium complex, [PdII(DMAP)2(OAc)2]. The complex was successfully synthesized using a stoichiometric reaction between PdII(OAc)2 and DMAP in acetone at room temperature and characterized using single-crystal X-ray analysis. Only 5 mol % catalyst loading was sufficient for effective carbonylative transformations. "Chloroform-COware" chemistry was utilized for safe and facile insertion of the carbonyl unit using chloroform as an inexpensive CO source in a two-chamber setup. Various value-added pharmaceutically relevant compounds such as CX-516, CX-546, and farampator were synthesized using the technique. Furthermore, the commercially designed COware was engineered to COware-RB setup for sequential one-pot synthesis of indenoisoquinolines (topoisomerase I inhibitors).
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BACKGROUND: Lung cancer is one of the highly lethal forms of cancer whose incidence has worldwide rapidly increased over the past few decades. About 80-85% of all lung cancer cases constitute non-small cell lung cancer (NSCLC), with adenocarcinoma, squamous cell carcinoma and large cell carcinoma as the main subtypes. Immune checkpoint inhibitors have led to significant advances in the treatment of a variety of solid tumors, significantly improving cancer patient survival rates. METHODS AND RESULTS: The cytotoxic drugs in combination with anti-PD-(L)1 antibodies is a new method that aims to reduce the activation of immunosuppressive and cancer cell prosurvival responses while also improving direct cancer cell death. The most commonly utilized immune checkpoint inhibitors for patients with non-small cell lung cancer are monoclonal antibodies (Atezolizumab, Cemiplimab, Ipilimumab, Pembrolizumab etc.) against PD-1, PD-L1, and CTLA-4. Among them, Atezolizumab (TECENTRIQ) and Cemiplimab (Libtayo) are engineered monoclonal anti programmed death ligand 1 (PD-L1) antibodies that inhibit binding of PD-L1 to PD-1 and B7.1. As a result, T-cell proliferation and cytokine synthesis are inhibited leading to restoring the immune homeostasis to fight cancer cells. CONCLUSIONS: In this review article, the path leading to the introduction of immunotherapeutic options in lung cancer treatment is described, with analyzing the benefits and shortages of the current immunotherapeutic drugs. In addition, possibilities to co-administer immunotherapeutic agents with standard cancer treatment modalities are also considered.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Antígeno B7-H1 , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1 , Imunoterapia/métodosRESUMO
Despite the advancements in the management of Diabetes mellitus, the design and synthesis of drug molecule which ameliorates the hyperglycemia and associated secondary complications in diabetic patients, still remains a challenge. Herein, we report the synthesis, characterization and anti-diabetic evaluation of pyrimidine-thiazolidinedione derivatives. The synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and Mass Spectroscopic analytical techniques. The in-silico ADME studies depicted that the compounds were within the permissible limits of the Lipinski's rule of five. The compounds 6e and 6m showing the best results in OGTT were evaluated for in-vivo anti-diabetic evaluation in STZ induced diabetic rats. Administration of 6e and 6m for four weeks decreased the blood glucose levels significantly. Compound 6e (4.5 mg/kg p.o.) was the most potent compound of the series. It reduced the level of blood glucose to 145.2 ± 1.35 compared to the standard Pioglitazone (150.2 ± 1.06). Moreover, the 6e and 6m treated group did not show increase in bodyweight. The biochemical estimations showed that the levels of ALT, ASP, ALP, urea, creatinine, blood urea nitrogen, total protein and LDH restored to normal in 6e and 6m treated groups as compared to STZ control group. The histopathological studies supported the results obtained in biochemical estimations. Both the compounds did not show any toxicity. Moreover, the histopathological studies of pancreas, liver, heart and kidney revealed that the structural integrity of these tissues restored to almost normal in 6e and 6m treated groups as compared to STZ control group. Based upon these findings it can be concluded that the pyrimidine-based thiazolidinedione derivatives represent novel anti-diabetic agents with least side effects.
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Diabetes Mellitus Experimental , Tiazolidinedionas , Ratos , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Tiazolidinedionas/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêuticoRESUMO
In the last few decades, targeting cancer by the use of dietary phytochemicals has gained enormous attention. The plausible reason and believe or mind set behind this fact is attributed to either lesser or no side effects of natural compounds as compared to the modern chemotherapeutics, or due to their conventional use as dietary components by mankind for thousands of years. Silibinin is a naturally derived polyphenol (a flavonolignans), possess following biochemical features; molecular formula C25H22O10, Molar mass: 482.44 g/mol, Boiling point 793 °C, with strikingly high antioxidant and anti-tumorigenic properties. The anti-cancer properties of Silibinin are determined by a variety of cellular pathways which include induction of apoptosis, cell cycle arrest, inhibition of angiogenesis and metastasis. In addition, Silibinin controls modulation of the expression of aberrant miRNAs, inflammatory response, and synergism with existing anti-cancer drugs. Therefore, modulation of a vast array of cellular responses and homeostatic aspects makes Silibinin an attractive chemotherapeutic agent. However, like other polyphenols, the major hurdle to declare Silibinin a translational chemotherapeutic agent, is its lesser bioavailability. After summarizing the chemistry and metabolic aspects of Silibinin, this extensive review focuses on functional aspects governed by Silibinin in chemoprevention with an ultimate goal of summarizing the evidence supporting the chemopreventive potential of Silibinin and clinical trials that are currently ongoing, at a single platform.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias/tratamento farmacológico , Silibina/farmacologia , Animais , Humanos , Polifenóis/farmacologiaRESUMO
The carbonyl group forms an integral part of several drug molecules and materials; hence, synthesis of carbonylated compounds remains an intriguing area of research for synthetic and medicinal chemists. Handling toxic CO gas has several limitations; thus, using safe and effective techniques for in or ex situ generation of carbon monoxide from nontoxic and cheap precursors is highly desirable. Among several precursors that have been explored for the generation of CO gas, chloroform can prove to be a promising CO surrogate due to its cost-effectiveness and ready availability. However, the one-pot chloroform-based carbonylation reaction requires strong basic conditions for hydrolysis of chloroform that may affect functional group tolerability of substrates and scale-up reactions. These limitations can be overcome by a two-chamber reactor (COware) that can be utilized for ex situ CO generation through hydrolysis of chloroform in one chamber and facilitating safe carbonylation reactions in another chamber under mild conditions. The versatility of this "Chloroform-COware" technique is explored through palladium-catalyzed aminocarbonylation of medicinally relevant heterocyclic cores, viz., isoquinoline and quinoline.
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Clorofórmio , Paládio , Paládio/química , Catálise , Monóxido de Carbono/química , IsoquinolinasRESUMO
As a landmark, scientific investigation in cytokine signaling and interferon-related anti-viral activity, signal transducer and activator of transcription (STAT) family of proteins was first discovered in the 1990s. Today, we know that the STAT family consists of several transcription factors which regulate various molecular and cellular processes, including proliferation, angiogenesis, and differentiation in human carcinoma. STAT family members play an active role in transducing signals from cell membrane to nucleus through intracellular signaling and thus activating gene transcription. Additionally, they are also associated with the development and progression of human cancer by facilitating inflammation, cell survival, and resistance to therapeutic responses. Accumulating evidence suggests that not all STAT proteins are associated with the progression of human malignancy; however, STAT3/5 are constitutively activated in various cancers, including multiple myeloma, lymphoma, breast cancer, prostate hepatocellular carcinoma, and non-small cell lung cancer. The present review highlights how STAT-associated events are implicated in cancer inflammation, angiogenesis and non-coding RNA (ncRNA) modulation to highlight potential intervention into carcinogenesis-related cellular processes.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Inflamação/genética , Inflamação/metabolismo , Masculino , Neovascularização Patológica/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Cardiovascular diseases are the most disturbing problems throughout the world. The side effects of existing drugs are continuously compelling the scientist to look for better options in terms of safety, efficacy and cost-effectiveness. Our study is also a move in this direction. We have chosen D-pinitol to see its cardioprotective role in isoproterenol-induced myocardial infarction in Swiss albino mice. Grouping was made by dividing mice into eight groups (n = 6). Group I, control; Group II, isoproterenol (ISO) (150 mg/kg, i.p.); Group III, D-pinitol (PIN) (25 mg); Group IV, PIN (50 mg); Group V, PIN (100 mg) per kg per oral, respectively with ISO; Group VI, PIN per se (100 mg D-pinitol only); Group VII, Propranolol (PRO) (20 mg/kg/oral) with ISO; and Group VIII, PRO per se (20 mg/kg, p.o.). After 24 h of the last dose, the blood sample was collected for biochemical parameters, then mice were, killed through cervical dislocation under anaesthesia and cardiac tissue was collected for biochemical, histopathological and ultrastructural evaluation. Administration of ISO in mice altered the level of antioxidant markers, cardiac injury markers and inflammatory markers, which were significantly restored towards normal by D-pinitol at the dose of 50 and 100 mg. 25 mg of D-pinitol dosage, did not produce significant cardio protection. The histopathological and ultrastructural analysis further confirmed these findings. Our study showed that D-pinitol significantly protected myocardial damage which was induced by ISO and reverted oxidative stress and inflammation considerably.
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Antioxidantes , Infarto do Miocárdio , Animais , Antioxidantes/metabolismo , Arritmias Cardíacas/tratamento farmacológico , Cardiotônicos/efeitos adversos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inositol/análogos & derivados , Isoproterenol/toxicidade , Camundongos , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , Estresse Oxidativo , Propranolol/efeitos adversos , Propranolol/metabolismo , Ratos , Ratos WistarRESUMO
Dementia is a neurodegenerative condition that is considered a major factor contributing to cognitive decline that reduces independent function. Pathophysiological pathways are not well defined for neurodegenerative diseases such as dementia; however, published evidence has shown the role of numerous inflammatory processes in the brain contributing toward their pathology. Microglia of the central nervous system (CNS) are the principal components of the brain's immune defence system and can detect harmful or external pathogens. When stimulated, the cells trigger neuroinflammatory responses by releasing proinflammatory chemokines, cytokines, reactive oxygen species, and nitrogen species in order to preserve the cell's microenvironment. These proinflammatory markers include cytokines such as IL-1, IL-6, and TNFα chemokines such as CCR3 and CCL2 and CCR5. Microglial cells may produce a prolonged inflammatory response that, in some circumstances, is indicated in the promotion of neurodegenerative diseases. The present review is focused on the involvement of microglial cell activation throughout neurodegenerative conditions and the link between neuroinflammatory processes and dementia.
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Demência/etiologia , Inflamação/complicações , Sistema Nervoso/patologia , Animais , Disfunção Cognitiva/diagnóstico , Humanos , Mediadores da Inflamação/metabolismo , Fatores de RiscoRESUMO
Cyclophosphamide (CP) is commonly used as antineoplastic and immunosuppressant drug with noticeable gonadotoxic profile. Nerolidol (NER) is a sesquiterpene with potent antioxidant and anti-inflammatory properties. Thus, the present study was designed to explore its possible gonadal protective potential against cyclophosphamide-induced testicular, epididymal, seminal and spermatozoal toxicities. Animals were divided into five groups: control (normal saline for 14 days), treatment group (NER 200 and 400 mg/kg, p.o) for 14 days along with a single dose of cyclophosphamide (200 mg/kg, i.p) on 7th day, toxic and Per se groups (cyclophosphamide 200 mg/kg i.p) on 7th day and NER 400 mg/kg for 14 days respectively. Animals were sacrificed on the 15 day, and body weight, weight of reproductive organs, testosterone level, sperm count, biochemical parameters, histopathological and immunohistochemical studies were performed in the testes, epididymis and in the serum. CP administration induced oxidative stress, nitrative stress, inflammation, reduced testosterone level, sperm count, increased expression of MPO and caused histological aberrations in the testes, epididymis and seminal vesicles. CP caused reduced sperm count, sperm motility and testosterone level which got reversed upon treatment with nerolidol in a dose-dependent manner. Nerolidol thus acted as a gonadoprotective molecule and prevented the gonadotoxicity of CP.
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Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Doenças dos Genitais Masculinos/prevenção & controle , Sesquiterpenos/uso terapêutico , Testículo/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Doenças dos Genitais Masculinos/induzido quimicamente , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Sesquiterpenos/farmacologia , Testículo/metabolismo , Testosterona/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Objectives: Cardiovascular diseases are widespread across the globe, and heart failure (HF) accounts for the majority of heart-associated deaths. Target-based drug therapy is much needed for the management of heart failure. We have designed this study to evaluate icariin for its cardioprotective activity in the isoproterenol (ISO) induced postinfarction model. We have randomly distributed Wistar rats into seven groups, i.e., vehicle control; isoproterenol-treated; icariin per se; sildenafil per se; ISO + icariin 5; ISO + icariin 10; and ISO + sildenafil groups. ISO (85 mg/kg, subcutaneous) was administered at 24 hr for two consecutive days to produce cardiac injury, followed by icariin administration at 5 mg/kg and 10 mg/kg orally for 56 days. Materials and Methods: Rats were subjected to hemodynamic measurements biweekly. After 24 hr of the completion of dosing, animals were sacrificed, and markers for oxidative stress, fibrosis, inflammation, and cell death were measured. Transmission electron microscopy (TEM), histopathology, and MT staining of cardiac tissue were also done to assess the pathological and fibrotic architectural damage. Results: A significant decline in hemodynamics and an anti-oxidant collapse were found in ISO-intoxicated rats. Alterations in the levels of cyclic guanosine monophosphate (cGMP), interleukin-10 (IL-10), Tumor necrosis factor (TNF-α), and brain natriuretic peptide (BNP) were also observed in serum. Up-regulation of caspase-3, nuclear factor (NF-ĸB), and decline in expression of nuclear factor (NrF-2) contribute to cardiac damage. The treatment with icariin and sildenafil considerably reversed the toxic changes toward normal. Conclusion: Increased cGMP and Nrf2 expression and suppressed NF-ĸB-caspase-3 signaling play a pivotal role in icariin-mediated cardioprotection.
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Insulin, a well-known hormone, has been implicated as a regulator of blood glucose levels for almost a century now. Over the past few decades, the non-glycemic actions of insulin i.e. neuronal growth and proliferation have been extensively studied. In 2005, Dr. Suzanne de La Monte and her team reported that insulin might be involved in the pathogenesis of Alzheimer's Disease (AD) and thus coined a term "Type-3 diabetes" This hypothesis was supported by several subsequent studies. The nuclear factor erythroid 2- related factor 2 (Nrf2) triggers a cascade of events under the regulation of distinct mechanisms including protein stability, phosphorylation and nuclear cytoplasmic shuttling, finally leading to the protection against oxidative damage. The Nrf2 pathway has been investigated extensively in relevance to neurodegenerative disorders, particularly AD. Many studies have indicated a strong correlation between insulin and Nrf2 signalling pathways both in the periphery and the brainbut merely few of them have focused on elucidating their inter-connective role in AD. The present review emphasizes key molecular pathways that correlate the role of insulin with Nrf2 during AD. The review has also identified key unexplored areas that could be investigated in future to further establish the insulin and Nrf2 influence in AD.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Insulina/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Transdução de Sinais/fisiologiaRESUMO
Cyclophosphamide (CP) is one of the most extensively used antineoplastic drug, but the nephrotoxicity caused by this drug is a major limiting factor for its use. Nerolidol (NERO) is a natural bioactive compound with diverse pharmacological actions. In Vitro and in vivo study was performed using HK-2 renal cells and Swiss Albino mice. Cell lines and animals were treated with NERO 25 and 50 µM + 30 µM CP (in vitro), 200 and 400 mg/kg, p.o. NERO from day 1 to day 15 + 200 mg/kg, i.p. CP on day 17 as single intraperitoneal injection (in vivo). The makers of oxidative stress, renal-specific injury markers, inflammation, apoptosis, fibrosis, and histopathological changes were studied. The study's outcome showed a significant reduction in the level of malonaldehyde and interleukin-6 (p < 0.01), tumor necrosis factor-α, IL-1ß (p < 0.001), and an increase in the superoxide dismutase, catalase, glutathione and interleukin-10 level (p < 0.01), in the in vivo study when treated with NERO 400 and compared with CP 200. In Vitro study showed reduced expression of nuclear factor kappa light chain enhancer of activated B cells, cleaved caspase-3, kidney injury molecule-1 and transforming growth factor-ß-1 (p < 0.001), when treated with NERO 50 µM whereas NERO 25 µM only reduced the level of cleaved caspase-3 (p < 0.05) when compared with 30 µM. NERO 400 also reduced uric acid (p < 0.05), urea (p < 0.01), blood urea nitrogen, and serum creatinine levels (p < 0.001) and increased the level of blood-urea-nitrogen/creatinine ratio (p < 0.001). Additionally, the level of fibrosis-specific markers such as transforming growth factor-ß1, hyaluronic acid (p < 0.01), 4-hydroxyproline, a collagen-rich area in Masson's' trichome stain, and Smad3 expression was also significantly reduced (p < 0.001). Furthermore, the outcome of multiple renal staining showed structural reversal aberrations, reduction of the thick basement membrane, and glycogen level toward normal when treated with NERO 400. Thus, the study showed a novel mechanistic modality of NERO against cyclophosphamide-induced renal toxicity. The outcome of this study can be considered a step closer to the development of an adjuvant to mitigate cyclophosphamide-induced renal toxicity among patients treated with cyclophosphamide.
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Rim , NF-kappa B , Animais , Camundongos , Apoptose , Caspase 3/metabolismo , Ciclofosfamida/efeitos adversos , Fibrose , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo , Ureia/metabolismoRESUMO
Coronavirus disease (COVID-19) was reported to be transmitted from bats to humans and, became a pandemic in 2020. COVID-19 is responsible for millions of deaths worldwide and still, the numbers are increasing. Further, despite the availability of vaccines, mutation in the virus continuously poses a threat of re-emergence of the more lethal form of the virus. So far, the repurposing of drugs has been exercised heavily for the identification of therapeutic agents against COVID-19, which led FDA to approve many drugs for the same e.g., remdesivir, favipiravir, ribavirin, etc. The anti-COVID drugs explored via other approaches include nirmatrelvir (used in combination with ritonavir as Paxlovid), tixagevimab and cilgavimab (both used in combination with each other) and others. However, these approved drugs failed to achieve a significant clinical outcome. Globally, natural bioactive have also been explored for anti-COVID-19 effects, based on their traditional medicinal values. Although the clinical findings suggest that FDA-approved drugs and natural bioactives can help reducing the overall mortality rate but the significant clinical outcome was not achieved. Therefore, the focus has been shifted towards new drug development. In line with that, a lot of work has been done and still going on to explore heterocyclic compounds as potent anti- COVID-19 drugs. Several heterocyclic scaffolds have been previously reported with potent antiinflammatory, anticancer, anti-viral, antimicrobial and anti-tubercular effects. Few of them are under consideration for clinical trials whereas others are under preclinical investigation. Hence, this review discusses the evidence of rationally designed and tested heterocyclic compounds acting on different targets against COVID-19. The present article will help the researches and will serve as a pivotal resource in the design and development of novel anti-COVID-19 drugs.
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COVID-19 , Compostos Heterocíclicos , Humanos , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêuticoRESUMO
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. The etiology and pathology of AD are complicated, variable, and yet to be completely discovered. However, the involvement of inflammasomes, particularly the NLRP3 inflammasome, has been emphasized recently. NLRP3 is a critical pattern recognition receptor involved in the expression of immune responses and has been found to play a significant role in the development of various immunological and neurological disorders such as multiple sclerosis, ulcerative colitis, gout, diabetes, and AD. It is a multimeric protein which releases various cytokines and causes caspase-1 activation through the process known as pyroptosis. Increased levels of cytokines (IL-1ß and IL-18), caspase-1 activation, and neuropathogenic stimulus lead to the formation of proinflammatory microglial M1. Progressive researches have also shown that besides loss of neurons, the pathophysiology of AD primarily includes amyloid beta (Aß) accumulation, generation of oxidative stress, and microglial damage leading to activation of NLRP3 inflammasome that eventually leads to neuroinflammation and dementia. It has been suggested in the literature that suppressing the activity of the NLRP3 inflammasome has substantial potential to prevent, manage, and treat Alzheimer's disease. The present review discusses the functional composition, various models, signaling molecules, pathways, and evidence of NLRP3 activation in AD. The manuscript also discusses the synthetic drugs, their clinical status, and projected natural products as a potential therapeutic approach to manage and treat NLRP3 mediated AD.
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Doença de Alzheimer , Inflamassomos , Humanos , Inflamassomos/metabolismo , Doença de Alzheimer/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peptídeos beta-Amiloides , Citocinas/metabolismo , CaspasesRESUMO
Generally, herbal medicines having remarkable popularity for treating liver ailments, but they are still unacceptable because of the deprivation of herbal drug standardization. Therefore, there is a need for promising synthetic drugs to overcome the critical liver problem. We introduce 1, 3, 4-oxadiazine ring in this study to identify better anti-hepatotoxic agents via a suitable synthetic route. These oxadiazine-based derivatives were structurally confirmed by analytical and spectral data and evaluated for their anti-hepatotoxic potential. Further, in vitro hepatotoxicity studies have been done to check the toxicity level in the synthesized compound. Compounds 5a, 5b, 5c and 9d were selected for further biological evaluation according to in vitro results. After that, CCl4-induced animal model was used to evaluate in vivo anti-hepatotoxicity activity. Compound 5a with 52.99%, 59.3%, 79.34% and 5b with 52.16%, 57.65%, 75.10% revealed to be most promising for reduction in level of SGPT, SGOT and ALKP, respectively. Moreover, it was also observed that the compound 5a with 411.01%, 53.39% and 5b with 378.63%, 48.9% level of albumin and total protein were respectively. The induced-fit docking results of the compounds 5a and 5b reveal some essential binding information and exhibited desirable ADME properties, and obeyed Lipinski's rule of five. In addition, molecular dynamics studies for 100 ns further confirm the protein-ligand complex's stability, supporting the in vitro and in vivo data, and help in establishing the SAR of synthesized compounds. Two compounds, 5a and 5 b, exhibited higher anti-hepatotoxic activity than the standard drug silymarin.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Simulação de Dinâmica Molecular , Animais , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
Pyrimidine is an aromatic and heterocyclic organic compound containing a 6-membered ring consisting of four carbon and two nitrogen atoms on alternative positions. Pyrimidine scaffolds described their existence in the medicinal chemist's cause for their synthesizing practicability and nonpoisonous nature. However, the reason behind neurological disorders is still an open challenge for scientific research and development organizations. Efficacy voids are widespread before researchers, despite high throughput research in the field of anti-Alzheimer's drugs.Researchers have constantly investigated all the probabilities for restraining the unwanted adverse effects of the anti-Alzheimer's agents and are focusing more extensively to rehabilitate neurological disorders. The scientific literature on drug development has been an aspiration to medicinal chemists and other researchers to facilitate further research. Therefore, this review emphasizes the structure-activity relationship (SAR) based approach and the pharmacological advancements of pyrimidine moiety in the new era of therapeutics as anti-Alzheimer's agents.
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Anti-Hipertensivos , Pirimidinas , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Cancer is the second cause of mortality worldwide, and the currently available conventional treatment approach is associated with serious side effects and poor clinical outcomes. Based on the outcome of the exploratory preclinical and clinical studies, it was found that therapeutic response increases multiple folds when anticancer drugs are used in combination. However, the conventional combination of anticancer drugs was associated with various limitations such as increased cost of treatment, systemic toxicity, drug resistance, and reduced pharmacokinetic attributes. Hence, attempts were made to formulate nanocarrier fabricated combinatorial drugs (NFCDs) to effectively manage and treat cancer. This approach offers several advantages, such as improved stability, lower drug exposure, targeted drug delivery, low side effects, and improved clinical outcome. Hence, in this review, first time, we have discussed the recent advancement and various types of nano carrier-based combinatorial drug delivery systems in a different type of cancer and highlighted the personalized combinatorial theranostic medicine as a futuristic anticancer treatment approach.
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Antineoplásicos , Nanopartículas , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Sports-related traumatic brain injury (TBI) is one of the common neurological maladies experienced by athletes. Earlier, the term 'punch drunk syndrome' was used in the case TBI of boxers and now this term is replaced by chronic traumatic encephalopathy (CTE). Sports-related brain injury can either be short-term or long-term. A common instance of brain injury encompasses subdural hematoma, concussion, cognitive dysfunction, amnesia, headache, vision issue, axonopathy, or even death, if it remains undiagnosed or untreated. Further, chronic TBI may lead to pathogenesis of neuroinflammation and neurodegeneration via tauopathy, the formation of neurofibrillary tangles, and damage to the blood-brain barrier, microglial, and astrocyte activation. Thus, altered pathological, neurochemical, and neurometabolic attributes lead to the modulation of multiple signaling pathways and cause neurological dysfunction. Available pharmaceutical interventions are based on one drug one target hypothesis and are thereby unable to cover altered multiple signaling pathways. However, in recent times, pharmacological intervention of nutrients and nutraceuticals have been explored as they exert a multifactorial mode of action and maintain over homeostasis of the body. There are various reports available showing the positive therapeutic effect of nutraceuticals in sport-related brain injury. Therefore, in the current article, we have discussed the pathology, neurological consequence, sequelae, and perpetuation of sports-related brain injury. Further, we have discussed various nutraceutical supplements as well as available animal models to explore the neuroprotective effect/ upshots of these nutraceuticals in sports-related brain injury.