RESUMEN
BACKGROUND: Gliomas are the most frequent, heterogeneous group of tumors arising from glial cells, characterized by difficult monitoring, poor prognosis, and fatality. Tissue biopsy is an established procedure for tumor cell sampling that aids diagnosis, tumor grading, and prediction of prognosis. MATERIALS AND METHODS: We studied and compared the levels of liquid biopsy markers in patients with different grades of glioma. Also, we tried to prove the potential association between glioma and specific blood group antigens. RESULTS: 78 patients were found, among whom the maximum percentage with glioblastoma had blood group O+ (53.8%). The second highest frequency had blood group A+ (20.4%), followed by B+ (9.0%) and A- (5.1%), and the least with O-. Liquid biopsy biomarkers included Alanine Aminotransferase (ALT), Lactate Dehydrogenase (LDH), lymphocytes, Urea, Alkaline phosphatase (AST), Neutrophils, and C-Reactive Protein (CRP). The levels of all the components increased significantly with the severity of the glioma, with maximum levels seen in glioblastoma (grade IV), followed by grade III and grade II, respectively. CONCLUSION: Gliomas have significant clinical challenges due to their progression with heterogeneous nature and aggressive behavior. A liquid biopsy is a non-invasive approach that aids in setting up the status of the patient and figuring out the tumor grade; therefore, it may show diagnostic and prognostic utility. Additionally, our study provides evidence to prove the role of ABO blood group antigens in the development of glioma. However, future clinical research on liquid biopsy will improve the sensitivity and specificity of these tests and confirm their clinical usefulness to guide treatment approaches.
.RESUMEN
Cardiovascular diseases (CVD) cause significant global morbidity, mortality and public health burden annually. CVD alters richness, diversity, and composition of Gut microbiota along with RAS and histopathological differences. Present study explores Metformin role in mitigating doxorubicin induced cardiovascular toxicity/remodeling. Animals were divided into 4 groups with n=6: Group I (N. Control) free access to diet and water; Group II (MET. Control) on oral Metformin (250â¯mg/kg) daily; Group III (DOX. Control) alternate day intraperitoneal Doxorubicin (3â¯mg/kg) totaling 18â¯mg/kg; Group IV (DOX. MET. Control) received both daily oral Metformin (250â¯mg/kg) and alternate day Doxorubicin (3â¯mg/kg). Gut microbial analysis was made from stool before animals were sacrificed for biochemical and histopathological analysis. Significant alterations were observed in É and ß-diversity with new genus from Firmicutes, specifically Clostridia_UCG-014, Eubacterium ruminantium, and Tunicibacter, were prevalent in both the DOX. Control and DOX.MET groups. Proteobacteria, represented by Succinivibrio, were absent in all groups. Additionally, Parabacteroides from the Bacteroidia phylum was absent in all groups except the N. control. In the DOX.MET Control group, levels of Angiotensin II ( 7.75± 0.49 nmol/min, p<0.01) and Renin (2.60±0.26â¯ng/ml/hr) were significantly reduced. Conversely, levels of CK-MB, Fibrinogen, Troponin, CRP ( p < 0.0001), and TNFÉ (p < 0.05) were elevated. Histopathological examination revealed substantial cardiac changes, including Fibrinogen and fat deposition and eosinophilic infiltration, as well as liver damage characterized by binucleated cells and damaged hepatocytes, along with altered renal tissues in the DOX.MET.Control group. The findings suggest that MET. significantly modifies gut microbiota, particularly impacting the Firmicutes and Proteobacteria phyla. The reduction in Angiotensin II levels, alongside increased inflammatory markers and myocardial damage, highlights the complex interactions and potential adverse effects associated with MET therapy on cardiovascular health.
RESUMEN
BACKGROUND: Clinical endocrinology has observed emerging endocrine complications following COVID-19 vaccination, amidst successful reductions in COVID-19 hospitalizations and deaths. The Pfizer-BioNTech and Moderna mRNA vaccines have demonstrated efficacy. Reports indicate a potential association between SARS-CoV-2 vaccination and diabetes, exploring interactions with ACE-2 receptors and molecular mimicry. Additionally, altered liver and kidney function tests post-vaccination prompt investigation into their role in predicting type 2 diabetes. This study aims to explore these biochemical abnormalities in a case-control, single-centre prospective study. MATERIALS AND METHODS: This prospective study aimed to evaluate a total of five hundred healthy donors, out of which 203 qualified for final analysis. Participants were selected based on their vaccination status with a COVID-19 vaccine and prior exposure to the SARS-CoV-2 virus. Donors without prior SARS-CoV-2 infection were excluded from the study. Included participants were adults who had received three doses of the COVID-19 vaccine. RESULTS: A total of 203 individuals were included in the study, comprising 104 with type 2 diabetes mellitus (T2DM) and 99 without. Demographic characteristics including age, sex, nationality, Rh factors, ABO blood groups, liver function tests (LFT), kidney function tests (KFT), lactate dehydrogenase (LDH), and mineral ion levels were analysed. Among the participants, the distribution based on HbA1c levels showed 47.8% with HbA1c <7% classified as normal, 38.48% with HbA1c 8-10% classified as high, and 16.64% with HbA1c <10% classified as uncontrolled diabetes. Significant findings included a decrease in magnesium levels to 0.77±0.82 mmol/L (p<0.04*), an increase in LDH levels to 420.70±356.26 µL (p<0.01*), and elevated levels of alkaline phosphatase (143.22 ± 142.62 µL, p<0.001), gamma-glutamyl transferase (GGT) (55.70 ± 32.20 µL, p<0.001), and serum bilirubin (9.23 ± 4.87 µmol/L, p<0.001). Creatinine levels were significantly lower at 116.75 ± 101.94 µmol/L (p#60;0.001), while uric acid levels were significantly elevated at 305.92 ± 145.04 µmol/L (p<0.001) in individuals with uncontrolled HbA1c <10%. A majority of these individuals belonged to the O+ blood group. CONCLUSION: This study underscores significant shifts in serum biomarkers and their complex interplay with mRNA-based SARS-CoV-2 vaccination and diabetes, particularly in uncontrolled cases. The findings suggest potential autoimmune reactions triggered by the self-adjuvant properties of mRNA and polyethylene glycol lipid conjugates. Variations observed among different blood groups may correspond to racial disparities influencing molecular mimicry mechanisms. Despite these insights, the underlying pathophysiological mechanisms remain unclear, highlighting the critical need for further research to validate and expand upon these findings.
RESUMEN
Today, one of the most prevalent reasons for death among people is carcinoma. Because it is still on the increase throughout the world, there is a critical need for in- -depth research on the pathogenic mechanisms behind the disease as well as for efficient treatment. In the field of epigenetics, gene expression alterations that are inherited but not DNA sequence changes are investigated. Three key epigenetic changes, histone modifications, DNA methylation and non-coding RNA (ncRNA) expression, are principally responsible for the initiation and progression of different tumors. These changes are interconnected and constitute many epigenetic changes. A form of polyphenolic chemical obtained from plants called curcumin has great bioactivity against several diseases, specifically cancer. A naturally occurring substance called thymoquinone is well-known for its anticancer properties. Thymoquinone affects cancer cells through a variety of methods, according to preclinical studies. We retrieved information from popular databases, including PubMed, Google Scholar, and CNKI, to summarize current advancements in the efficiency of curcumin against cancer and its epigenetic regulation in terms of DNA methylation, histone modifications, and miRNA expression. The present investigation offers thorough insights into the molecular processes, based on epigenetic control, that underlie the clinical use of curcumin and thymoquinone in cancerous cells.
RESUMEN
BACKGROUND: Cardiovascular diseases (CVDs) continue to exert a substantial global influence in specific areas due to population growth, aging, microbiota, and genetic/environmental factors. Drinking water has a strong impact on the health of an individual. Further, emerging evidence has highlighted the therapeutic potential and benefits of Zamzam water (Zam). OBJECTIVE: We investigated the influence of Zam on doxorubicin-induced cardiac toxicity, elucidating its consequential effects on GUT microbiota dysbiosis and hepatic and renal functions. METHODS: Male rats were categorized into four groups: Group 1 as Normal control (NC), Group 2 as Zamzam control (ZC), Group 3 Disease control (DC) and Group 4 as Therapeutic control (DZ) treated with Zam against doxorubicin-induced disease at a dose of 1mg/kg boy weight) intraperitoneally (i.p). RESULTS: Significant dysbiosis in the composition of GM was observed in the DC group along with a significant decrease (p < 0.05) in serum levels of Zinc, interleukin-10 (IL-10), IL-6 and Angiotensin II (Ang II), while C-reactive protein (CRP), fibrinogen, and CKMB increased significantly (restoration of Zinc ions (0.72 ± 0.07 mcg/mL) compared to NC. Treatment with Zamzam exhibited a marked abundance of 18-times to 72% in Romboutsia, a genus of firmicutes, along with lowering of Proteobacteria in DZ followed by significant restoration of Zinc ions (0.72 ± 0.07 mcg/mL), significant (p Ë 0.05) reduction in CRP (7.22 ± 0.39 mg/dL), CKMB (118.8 ± 1.02 U/L) and Fibrinogen (3.18 ± 0.16 mg/dL), significant (p < 0.05) increase in IL-10 (7.22 ± 0.84 pg/mL) and IL-6 (7.18 ± 0.40 pg/ml), restoration of Ang II (18.62 ± 0.50 nmol/mL/min), marked increase in renin with normal myocyte architecture and tissue orientation of kidney, and restoration of histological architecture of hepatocyte. CONCLUSION: Zam treatment mitigated cardiac toxicity risk through the modulation of GUT microbiota and the renin-angiotensin system and tissue histology effectively.
Asunto(s)
Microbioma Gastrointestinal , Sistema Renina-Angiotensina , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Ratas , Sistema Renina-Angiotensina/efectos de los fármacos , Doxorrubicina/farmacología , Agua/químicaRESUMEN
BACKGROUND: Much increasing evidence has suggested that long-term complications post vaccination of SARS-CoV-2 experience a wide range of complication including diabetes. The risk and burden of type 1 diabetes is extensively reported, but type 2 diabetes mellitus (T2D) has yet to be characterized. To address this gap, we aimed to examine trends of long-term complications post SARS-CoV-2 infection and vaccination in diabetes incidence among the Saudi population. METHODS: In this cross-sectional hospital-based study, we analyzed the blood profile of first-time blood donors from the University Hospital of King Abdulaziz University, Jeddah. Saudi Arabia. Various blood parameters, HbA1c was measured in the month of May 2023. All the donors were non-diabetic and were never diagnosed with T2D before the current blood donation. 203 healthy subjects donated their blood, out of which 104 had abnormally high HbA1c tending towards diagnosis of T2D and 99 had with blood profiles. The study followed the STROBE reporting guidelines. RESULTS: Out of 203 donors 104 (male 50(48.1%), female 54(51.9%)) were diagnosed with increased HbA1c (8.24 in males) compared to 7.61 of HbA1c in females. 35.6% were above Ë65 years, with 52.9% with O+ from the ABO blood group. Liver functions indicated significant pË0.05, 0.04, increased amount of GGT (46.47 U/L), Alkaline phosphatase (99.93 ±64.26 uL) respectively in HbA1c elevated donors KFT represented significant pË0.05, 0.02 elevated levels of urea (6.73 ±5.51 mmol/L), creatinine (129.97 ±195.17 umol/L) respectively along with elevated values of Lactate dehydrogenase (LDH) (263.72± 196.70 uL) and triglycerides (1.66 ±0.74mmol/L) when compared to normal value of HbA1c donors. DISCUSSION: In the present cross-sectional study, significant increase in HbA1c, trending towards increased cases of T2D post SARS-CoV-2 infection and vaccination. Males are much affected compared to females. Further maximum number of cases were from donors above the age of 65 years with altered partial LFT (GGT, Alkaline phosphatase), KFT (urea, creatinine), lipid profile (TG) and LDH in post SARS-CoV-2 and vaccination blood donors. CONCLUSION: Increase in HbA1c in 50% of donors, irrespective of gender, is an alarming figure for health authorities, with altered LFT, KFT and LDH tests and, in the near future, may increase the incidence of T2D. Large-scale population-based studies are required to prevent future incidences of T2D in young children who will be vaccinated.
Asunto(s)
Donantes de Sangre , Vacunas contra la COVID-19 , COVID-19 , Diabetes Mellitus Tipo 2 , Hemoglobina Glucada , SARS-CoV-2 , Humanos , Masculino , Femenino , COVID-19/prevención & control , COVID-19/epidemiología , COVID-19/sangre , Donantes de Sangre/estadística & datos numéricos , Arabia Saudita/epidemiología , Adulto , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Hemoglobina Glucada/análisis , Persona de Mediana Edad , Vacunación/estadística & datos numéricos , Adulto JovenRESUMEN
Breast cancer (BC) is one of the most common cancers in women and is a major cause of female cancer-related deaths. BC is a multifactorial disease caused by the dysregulation of many genes, raising the need to find novel drugs that function by targeting several signaling pathways. The antitumoral drug thymoquinone (TQ), found in black seed oil, has multitargeting properties against several signaling pathways. This study evaluated the inhibitory effects of TQ on the MCF7 and T47D human breast cancer cell lines and its antitumor activity against BC induced by a single oral dose (65 mg/kg) of 7,12-dimethylbenzanthracene (DMBA) in female rats. The therapeutic activity was evaluated in DMBA-treated rats who received oral TQ (50 mg/kg) three times weekly. TQ-treated MCF7 and T47D cells showed concentration-dependent inhibition of cell proliferation and induction of apoptosis. TQ also decreased the expression of DNA methyltransferase 1 (DNMT1) in both cancer cell types. In DMBA-treated animals, TQ inhibited the number of liver and kidney metastases. These effects were associated with a reduction in DNMT1 mRNA expression. These results indicate that TQ has protective effects against breast carcinogens through epigenetic mechanisms involving DNMT1 inhibition.
Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Animales , Ratas , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Benzoquinonas/farmacología , 9,10-Dimetil-1,2-benzantraceno/toxicidad , ApoptosisRESUMEN
BACKGROUND: Fungal mycotoxins are the secondary metabolite and are harmful to plants, animals, and humans. Common aflatoxins present and isolated from feeds and food comprises aflatoxins B1, B2, G1, and G2. Public health threats or risk of foodborne disease posed by mycotoxins, especially the export or import of such meat products are of primary concern. This study aims to determine the concentration of the level of aflatoxins B1, B2, G1, G2 M1, and M2 respectively in imported burger meat. METHOD: The present work is designed to select and collect the various sample of meat products from different sources and subjected to mycotoxin analysis by LCMS/MS. Random selection was made on sites of burger meat that was for sale. RESULTS: Simultaneous presence of several mycotoxins in the same sample of imported meat under the set conditions of LCMS/MS detected 26% (18 samples) were positive for various mycotoxins. The most frequent mycotoxins proportion in the analyzed samples was aflatoxin B1 (50%) followed by aflatoxin G1 (44%), aflatoxin G2 (38.8%), aflatoxin B2 (33%) respectively were least among all with 16.66 and 11.11%. DISCUSSION: A positive correlation is deduced between CVD and mycotoxin present in burger meat. Isolated mycotoxins initiate death receptor-mediated apoptosis, death receptor-mediated necrosis, mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, and immunogenic cell deaths through various pathways that can damage the cardiac tissues. CONCLUSION: The presence of these toxins in such samples is just the tip of the iceberg. Further investigation is necessary for complete clarifications of toxins on human health especially on CVD and other related metabolic complications.
RESUMEN
Neoplasm (Glioblastoma) and Alzheimer's disease (AD) comprise two of the most chronic psychological ailments. Glioblastoma is one of the aggressive and prevalent malignant diseases characterized by rapid growth and invasion resulting from cell migration and degradation of extracellular matrix. While the latter is characterized by extracellular plaques of amyloid and intracellular tangles of tau proteins. Both possess a high degree of resistance to treatment owing to the restricted transport of corresponding drugs to the brain protected by the blood-brain barrier (BBB). Development of optimized therapies using advanced technologies is a great need of today. One such approach is the designing of nanoparticles (NPs) to facilitate the drug delivery at the target site. The present article elaborates the advances in nanomedicines in treatment of both AD as well as Gliomas. The intention of this review is to provide an overview of different types of NPs with their physical properties emphasizing their importance in traversing the BBB and hitting the target site. Further, we discuss the therapeutic applications of these NPs along with their specific targets. Multiple overlapping factors with a common pathway in development of AD and Glioblastoma are discussed in details that will assist the readers in developing the conceptual approach to target the NP for an aging population in the given circumstances with limitations of currently designed NPs, and the challenges to meet and the future perspectives.
Asunto(s)
Enfermedad de Alzheimer , Glioblastoma , Glioma , Nanopartículas , Humanos , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Nanomedicina , Glioma/tratamiento farmacológico , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Sistemas de Liberación de Medicamentos , Nanopartículas/uso terapéuticoRESUMEN
Inflammation is a complex defense process that maintains tissue homeostasis. However, this complex cascade, if lasts long, may contribute to pathogenesis of several diseases. Chronic inflammation has been exhaustively studied in the last few decades, for its contribution in development and progression of cancer. The intrinsic limitations of conventional anti-inflammatory and anti-cancer therapies triggered the development of nanomedicines for more effective and safer therapies. Targeting inflammation and tumor cells by nanoparticles, encapsulated with active therapeutic agents, offers a promising outcome with patient survival. Considerable technological success has been achieved in this field through exploitation of tumor microenvironment, and recognition of molecules overexpressed on endothelial cells or macrophages, through enhanced vascular permeability, or by rendering biomimetic approach to nanoparticles. This review focusses on the inflammatory pathways in progression of a tumor, and advancement in nanotechnologies targeting these pathways. We also aim to identify the gaps that hinder the successful clinical translation of nanotherapeutics with further clinical studies that will allow oncologist to precisely identify the patients who may be benefited from nanotherapy at time when promotion or progression of tumor initiates. It is postulated that the nanomedicines, in near future, will shift the paradigm of cancer treatment and improve patient survival.
Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Nanomedicina , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/metabolismo , Sistemas de Liberación de Medicamentos , Células Endoteliales/metabolismo , Neoplasias/metabolismo , Inflamación/tratamiento farmacológico , Microambiente TumoralRESUMEN
Malignant breast cancers are responsible for a growing number of deaths among women globally. The latest research has demonstrated that Wnt signaling is pivotal in this disease, regulating a safe microenvironment for the growth and proliferation of cancer cells, sustained stemness, resistance to therapy, and aggregate formation. The three highly conserved Wnt signaling pathways, Wnt-planar cell polarity (PCP), Wnt/ß-catenin signaling and Wnt-Ca2+ signaling, assume various roles in the maintenance and amelioration of breast cancer. In this review, we examine ongoing studies on the Wnt signaling pathways and discuss how dysregulation of these pathways promotes breast cancers. We also look at how Wnt dysregulation could be exploited to foster new treatments for malignant breast cancers.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Vía de Señalización Wnt , Proteínas Wnt/metabolismo , Proliferación Celular , Línea Celular Tumoral , Microambiente TumoralRESUMEN
The updated affiliation information can be seen in the affiliation part of this correction [...].
RESUMEN
It is well-documented that pro-inflammatory cytokines and inflammation play a significant role in the expansion of cancer disease. Gallic acid (GA), a natural compound, and metformin (Met), a synthetic drug exhibit potent anticancer potential via the distinct molecular mechanism. However, whether both these compounds can act synergistically to preclude and treat cancer is still unknown. This prompted us to scrutinize, the synergism between GA and Met, and that of a new co-drug synthesizing of GA and Met (GA-Met) and investigated the chemo-protective effect against breast cancer with possible intervention of cytokines. In vivo studies were based on chemical carcinogenesis, challenging breast tissue by dimethylbenz[α]anthracene (DMBA). Tumour incidence, tumour burden, pro-inflammatory cytokines in serum, breast, hepatic tissue, macroscopically and histological analysis of mammary tumours were carried out and estimated. GA, Met and GA-Met co-drug exhibited the inhibition of cell proliferation; higher reduction of cell proliferation was observed by GA-Met. The inhibitory effect of GA-Met was linked to cell cycle arrest at G0/G1 phase, along with induction of apoptosis and accumulation in the sub-G1 phase. GA-Met significantly inhibited the cytokines production along with protection against DMBA-induced hyperplasia. Taken altogether, the current result suggests that GA-Met co-drug endows a safe and protective effect against cancer metastasis and can possibly use for the treatment of human breast cancer.
Asunto(s)
Neoplasias de la Mama , Metformina , Humanos , Femenino , Citocinas , Ácido Gálico/farmacología , Ácido Gálico/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Desarrollo de Medicamentos , ApoptosisRESUMEN
BACKGROUND: The development of a vaccine for SARS-CoV-2 is primarily focused on the structure of the spike (S) protein. The heavy glycosylation of S with flexible hinges at the stalk shields from antibody attachment. OBJECTIVE: This study deciphers the flexible nature of hinges responsible for binding the odorant receptor on neurons responsible for the loss of smell in COVID-19 patients. METHODS: The 3D structure via EPIK in Maestro, protein docking with ligands via Maestro protein analysis tool, and molecular dynamic simulation at 30 ns run using DESMOND was prepared. RESULTS: The data of the study strongly suggest that strong and stable bond formation results from the reaction between R:14: Trp and Phe at the residue, targeting the flexible hinges of SARS-CoV-2. The difference in the conformational structure of the S protein and its binding with the odorant receptor in COVID-19 is the prime factor for the loss of smell and taste in patients, as supported by the concept of Antigen (epitope) Antibody interaction by the stable formation of a hydrogen bond among odorant receptor and the S protein. The flexibility of structural proteins determines the binding potential of antibodies or other defense proteins produced to participate in the antigen-antibody reaction. CONCLUSION: Molecular and atomic details potentiate the design and screening of small molecules that can inhibit the fusion at entry level or odorant receptors and potentially be used in the prevention and treatment of infection, particularly when formulated as nasal drops, paving a new approach for pharmacologists in the treatment of COVID-19 infection.
Asunto(s)
Anosmia , COVID-19 , Receptores Odorantes , Humanos , Anosmia/virología , COVID-19/complicaciones , Unión Proteica , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del CoronavirusRESUMEN
Human serum albumin (HSA), an abundant plasma protein, binds to various ligands, acting as a transporter for numerous endogenous and exogenous substances. Galantamine (GAL), an alkaloid, treats cognitive decline in mild to moderate Alzheimer's disease and other memory impairments. A vital step in pharmacological profiling involves the interaction of plasma protein with the drugs, and this serves as an essential platform for pharmaceutical industry advancements. This study is carried out to understand the binding mechanism of GAL with HSA using computational and experimental approaches. Molecular docking revealed that GAL preferentially occupies Sudlow's site I, i.e., binds to subdomain IIIA. The results unveiled that GAL binding does not induce any conformational change in HSA and hence does not compromise the functionality of HSA. Molecular dynamics simulation (250 ns) deciphered the stability of the HSA-GAL complex. We performed the fluorescence binding and isothermal titration calorimetry (ITC) to analyze the actual binding of GAL with HSA. The results suggested that GAL binds to HSA with a significant binding affinity. ITC measurements also delineated thermodynamic parameters associated with the binding of GAL to HSA. Altogether, the present study deciphers the binding mechanism of GAL with HSA.
RESUMEN
Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP's). MARK4 is known for its major role in tau phosphorylation via phosphorylating Ser262 residue in the KXGS motif, which results in the detachment of tau from microtubule. In lieu of this vital role in tau pathology, a hallmark of Alzheimer's disease (AD), MARK4 is a druggable target to treat AD and other neurodegenerative disorders (NDs). There is growing evidence that NDs and diabetes are connected with many pieces of literature demonstrating a high risk of developing AD in diabetic patients. Metformin (Mtf) has been a drug in use against type 2 diabetes mellitus (T2DM) for a long time; however, recent studies have established its therapeutic effect in neurodegenerative diseases (NDs), namely AD, Parkinson's disease (PD) and amnestic mild cognitive impairment. In this study, we have explored the MARK4 inhibitory potential of Mtf, employing in silico and in vitro approaches. Molecular docking demonstrated that Mtf binds to MARK4 with a significant affinity of -6.9 kcal/mol forming interactions with binding pocket's critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into the binding of Mtf with MARK4. ATPase assay of MARK4 in the presence of Mtf shows that it inhibits MARK4 with an IC50 = 7.05 µM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 × 106 M-1. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Metformina , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Metformina/farmacología , Microtúbulos/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Proteínas Serina-Treonina QuinasasRESUMEN
There is emerging evidence exhibiting the strong association of gut microbiota with cardiovascular metabolic functions. Cardiac diseases may alter the richness, diversity, and composition of the gut microbiome. Vitamin C (Vit C) plays an important role in many metabolic activities in cardiovascular diseases. In this study, we induced cardiac remodeling by the forced swim stress model in rats, which resulted in dysbiosis. Adult male Wistar rats were designated into the following groups: (i) normal control (NC), (ii) forced swim induced stress (FSIS) control, (iii) FSIS + Vit C treatment, and (iv) Vit C control. Stool samples were collected for estimation for 90 days, and at the end of the study, the animals were killed and heart tissue was isolated for histochemical analysis. We observed a sharp fall in the operational taxonomic unit in the FSIS control animals as compared to NC animals. Treatment with Vit C exhibited a decrease in Bacteroidetes while raising the abundance of spirochetes. Plasma levels of creatine kinase myocardial band (CKMB) in the treatment group reduced to 175.7 ± 3.41 U/L, from 317.7 ± 34.48 U/L in the diabetic control group. Also, the C-reactive protein level in the disease control group was 18 ± 0.93 mg/dl, which reduced to the normal level of 7.53 ± 0.20 mg/dl on treatment with Vit C administration. Our results suggest that FSIS induced cardiac complication is also associated with changes in gut microbial abundance. Higher doses of Vit C, which strengthens the immunity, have shown some positive outcomes on cardiac complications. The abundance of gut microbiota is also associated with the immune system, which in turn marks the impact of a disease. More the richness and diversity of the gut microbiome, healthier is the composition that can withstand the external threats of disease and other major challenges in the environment. Hence microbiome abundance plays an important role in the therapies or future prospects of disease. Histopathological studies support the serological and microbiome examination and warrant the cardioprotective influence of Vit C in the stress-induced cardiac dysfunction model.
Asunto(s)
Microbioma Gastrointestinal , Cardiopatías , Animales , Ácido Ascórbico/farmacología , Disbiosis , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND: Corona Virus Disease-19 (COVID-19), a current worldwide pandemic is the cause of serious concern. Risk-adjusted differences in outcomes of the patients are not well characterized. Therefore, susceptibility to infection with respect to blood group, blood pressure, pulse rate, hemoglobin, age, and BMI is analyzed in this study. METHODS: Blood donors of all ages and gender, who recovered from COVID-19 infection, were selected for the study. Samples were collected from the regional laboratory and the central blood bank of Hafr al Batin, Saudi Arabia. Out of 1508 healthy blood donors, 134 had recovered from corona without any preexisting diseases. RESULTS: Major donors were male (85.1%). 28% of donors were in the age range of 26-35 years. O+(32.8%) donors were in majority. Systolic and diastolic blood pressure and pulse rate elevated significantly in the age group 46-55 (p<0.05) and 56-65 (p<0.001). Systolic blood pressure in males (134.13 ± 9.57) was significantly higher (p<0.05) than in females (129.35 ± 10.61). Donors with Rh+ had significantly higher systolic (p<0.05) and pulse rate (p<0.05) as compared to Rh-. DISCUSSION: O+ donors were found to be highly susceptible. Blood pressure, pulse rate and Hb altered with age. Males exhibited higher variation in systolic blood pressure, with the Rh+ factor playing a predominant role. Donors above 45-years of age and with a high BMI had significantly elevated blood pressure and pulse. These results are challenging or contradictory to the results of Turkish and Chinese studies where blood group A+ was more predominantly affected by the SARS-CoV-2 with the minimum infection rate in females and Rh- donors. CONCLUSION: Factors like blood group, age, physical characteristics and BMI should be taken into account before initiating any therapeutic approach to obtain the best possible outcomes with minimum adverse effects from the current drugs utilized for SARS CoV-2 treatment, especially with the age group of 45 years and above.