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The kidneys are radiosensitive and dose-limiting organs for radiotherapy (RT) targeting abdominal and paraspinal tumors. Excessive radiation doses to the kidneys ultimately lead to radiation nephropathy. Our prior work unmasked a novel role for the lipid-modifying enzyme, sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), in regulating the response of renal podocytes to radiation injury. In this study, we investigated the role of SMPDL3b in DNA double-strand breaks (DSBs) repair in vitro and in vivo. We assessed the kinetics of DSBs recognition and repair along with the ATM pathway and nuclear sphingolipid metabolism in wild-type (WT) and SMPDL3b overexpressing (OE) human podocytes. We also assessed the extent of DNA damage repair in SMPDL3b knock-down (KD) human podocytes, and C57BL6 WT and podocyte-specific SMPDL3b-knock out (KO) mice after radiation injury. We found that SMPDL3b overexpression enhanced DSBs recognition and repair through modulating ATM nuclear shuttling. OE podocytes were protected against radiation-induced apoptosis by increasing the phosphorylation of p53 at serine 15 and attenuating subsequent caspase-3 cleavage. SMPDL3b overexpression prevented radiation-induced alterations in nuclear ceramide-1-phosphate (C1P) and ceramide levels. Interestingly, exogenous C1P pretreatment radiosensitized OE podocytes by delaying ATM nuclear foci formation and DSBs repair. On the other hand, SMPDL3b knock-down, in vitro and in vivo, induced a significant delay in DSBs repair. Additionally, increased activation of apoptosis was induced in podocytes of SMPDL3b-KO mice compared to WT mice at 24 h post-irradiation. Together, our results unravel a novel role for SMPDL3b in radiation-induced DNA damage response. The current work suggests that SMPDL3b modulates nuclear sphingolipid metabolism, ATM nuclear shuttling, and DSBs repair.
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Podócitos , Lesões por Radiação , Animais , Ceramidas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3 , Quebras de DNA de Cadeia Dupla , Humanos , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Podócitos/metabolismo , Lesões por Radiação/genética , Lesões por Radiação/metabolismo , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismoRESUMO
The intracellular molecular pathways involved in radiation-induced nephropathy are still poorly understood. Glomerular endothelial cells are key components of the structure and function of the glomerular filtration barrier but little is known about the mechanisms implicated in their injury and repair. The current study establishes the response of immortalized human glomerular endothelial cells (GEnC) to ionizing radiation (IR). We investigated the role of sphingolipids and the lipid-modifying enzyme sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in radiation-induced GEnC damage. After delivering a single dose of radiation, long and very-long-chain ceramide species, and the expression levels of SMPDL3b were elevated. In contrast, levels of ceramide-1-phosphate (C1P) dropped in a time-dependent manner although mRNA and protein levels of ceramide kinase (CERK) remained stable. Treatment with C1P or knocking down SMPDL3b partially restored cell survival and conferred radioprotection. We also report a novel role for the NADPH oxidase enzymes (NOXs), namely NOX1, and NOX-derived reactive oxygen species (ROS) in radiation-induced GEnC damage. Subjecting cultured endothelial cells to radiation was associated with increased NOX activity and superoxide anion generation. Silencing NOX1 using NOX1-specific siRNA mitigated radiation-induced oxidative stress and cellular injury. In addition, we report a novel connection between NOX and SMPDL3b. Treatment with the NOX inhibitor, GKT, decreased radiation-induced cellular injury and restored SMPDL3b basal levels of expression. Our findings indicate the importance of SMPDL3b as a potential therapeutic target in radiation-induced kidney damage.
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Células Endoteliais/metabolismo , Nefropatias/metabolismo , Glomérulos Renais/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Animais , Linhagem Celular , Humanos , Glomérulos Renais/efeitos da radiação , Masculino , Camundongos Endogâmicos C57BL , NADPH Oxidase 1/metabolismo , RNA Mensageiro/metabolismo , Radiação , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismoRESUMO
The success of nanoparticle-mediated delivery of antioxidant and antiinflammatory-based neuroprotectants to the brain to improve neuronal functions in neurodegenerative diseases has demonstrated lesser impact instead of achieving its full potential. We hypothesized that these failures were due to a combination of parameters, such as: (i) unavailability of a delivery vehicle, which can reproducibly and efficiently transport through the brain capillary endothelium; (ii) inefficient uptake of therapeutic nanoparticles in the neuronal cell population; and (iii) limited ability of a single nanoparticle to cross the two most-impermeable biological barriers, the blood-brain barrier and mitochondrial double membrane, so that a nanoparticle can travel through the brain endothelial barrier to the mitochondria of target cells where oxidative damage is localized. Herein, we demonstrate optimization of a biodegradable nanoparticle for efficient brain accumulation and protection of astrocytes from oxidative damage and mitochondrial dysfunctions to enhance the neuroprotection ability of astrocytes toward neurons using neurodegeneration characteristics in SOD1G93A rats. This biodegradable nanomedicine platform with the ability to accumulate in the brain has the potential to bring beneficial effects in neurodegenerative diseases by modulating the stars, astrocytes in the brain, to enhance their neuroprotective actions.
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Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Nanotecnologia/métodos , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Nanomedicina , Nanopartículas/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Neuroproteção/fisiologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos TransgênicosRESUMO
Swelling of astrocytes represents a major component of the brain edema associated with many neurological conditions, including acute hepatic encephalopathy (AHE), traumatic brain injury (TBI) and ischemia. It has previously been reported that exposure of cultured astrocytes to ammonia (a factor strongly implicated in the pathogenesis of AHE), oxygen/glucose deprivation, or to direct mechanical trauma results in an increase in cell swelling. Since dietary polyphenols have been shown to exert a protective effect against cell injury, we examined whether resveratrol (RSV, 3,5,4'-trihydroxy-trans-stilbene, a stilbenoid phenol), has a protective effect on astrocyte swelling following its exposure to ammonia, oxygen-glucose deprivation (OGD), or trauma in vitro. Ammonia increased astrocyte swelling, and pre- or post-treatment of astrocytes with 10 and 25 µM RSV displayed an additive effect, while 5 µM did not prevent the effect of ammonia. However, pre-treatment of astrocytes with 25 µM RSV slightly, but significantly, reduced the trauma-induced astrocyte swelling at earlier time points (3 h), while post-treatment had no significant effect on the trauma-induced cell swelling at the 3 h time point. Instead, pre- or post-treatment of astrocytes with 25 µM RSV had an additive effect on trauma-induced astrocyte swelling. Further, pre- or post-treatment of astrocytes with 5 or 10 µM RSV had no significant effect on trauma-induced astrocyte swelling. When 5 or 10 µM RSV were added prior to, or during the process of OGD, as well as post-OGD, it caused a slight, but not statistically significant decline in cell swelling. However, when 25 µM RSV was added during the process of OGD, as well as after the cells were returned to normal condition (90 min period), such treatment showed an additive effect on the OGD-induced astrocyte swelling. Noteworthy, a higher concentration of RSV (25 µM) exhibited an additive effect on levels of phosphorylated forms of ERK1/2, and p38MAPK, as well as an increased activity of the Na+-K+-Cl- co-transporter-1 (NKCC1), factors known to induce astrocytes swelling, when the cells were treated with ammonia or after trauma or ischemia. Further, inhibition of ERK1/2, and p38MAPK diminished the RSV-induced exacerbation of cell swelling post-ammonia, trauma and OGD treatment. These findings strongly suggest that treatment of cultured astrocytes with RSV enhanced the ammonia, ischemia and trauma-induced cell swelling, likely through the exacerbation of intercellular signaling kinases and ion transporters. Accordingly, caution should be exercised when using RSV for the treatment of these neurological conditions, especially when brain edema is also suspected.
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Amônia/toxicidade , Antioxidantes/toxicidade , Astrócitos/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Resveratrol/toxicidade , Animais , Animais Recém-Nascidos , Antioxidantes/administração & dosagem , Astrócitos/metabolismo , Astrócitos/patologia , Edema Encefálico/induzido quimicamente , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Lesões Encefálicas Traumáticas/induzido quimicamente , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hipóxia Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Glucose/deficiência , Ratos , Resveratrol/administração & dosagemRESUMO
Cisplatin is a major chemotherapeutic that continues to have a significant impact in the treatment of more than 50% of all cancers. Since its Food and Drug Administration approval in 1978 for the treatment of advanced ovarian and bladder cancer, this chemotherapeutic has made significant strides and its application has been extended to a large variety of other cancers. However, the vast majority of patients who receive cisplatin therapy often suffer from nephrotoxicity, neurotoxicity, nausea, and ototoxicity. Numerous methods currently exist for overcoming nephrotoxicity- and nausea-related side effects, but there is no clear prevention to fight ototoxicity and neurotoxicity. In this work, we examined Platin- A, a prodrug of cisplatin and aspirin, using preclinical mouse- and guinea pig-based models and demonstrated its efficacy with reduced ototoxicity. In addition, in vitro studies documented that when Platin- A is used in combination with a clinically relevant dose of radiation, its efficacy can further be improved by attacking cellular bioenergetic profiles, producing multiple modes of DNA damage, and delaying repair of damaged DNA. These studies demonstrated novel properties of the prodrug, Platin- A, highlighting its superior efficacy with reduced toxicity.
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Cisplatino/farmacologia , Otopatias/prevenção & controle , Doenças do Sistema Nervoso/prevenção & controle , Neoplasias Ovarianas/tratamento farmacológico , Pró-Fármacos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Apoptose , Aspirina/farmacologia , Proliferação de Células , Feminino , Cobaias , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The molecular mechanisms responsible for the development of proteinuria and glomerulosclerosis in radiation nephropathy remain largely unknown. Podocytes are increasingly recognized as key players in the pathogenesis of proteinuria in primary and secondary glomerular disorders. The lipid-modulating enzyme sphingomyelin phosphodiesterase acid-like 3B (SMPDL3b) is a key determinant of podocyte injury and a known off target of the anti-CD20 antibody rituximab (RTX). The current study investigates the role of sphingolipids in radiation-induced podocytopathy. After a single dose of radiation (8 Gy), several ceramide species were significantly elevated. In particular, C16:00, C24:00, and C24:1 ceramides were the most abundant ceramide species detected. These changes were paralleled by a time-dependent drop in SMPDL3b protein, sphingosine, and sphingosine-1-phosphate levels. Interestingly, SMPDL3b-overexpressing podocytes had higher basal levels of sphingosine-1-phosphate and maintained basal ceramide levels after irradiation. Morphologically, irradiated podocytes demonstrated loss of filopodia and remodeling of cortical actin. Furthermore, the actin binding protein ezrin relocated from the plasma membrane to the cytosol as early as 2 h after radiation. In contrast, SMPDL3b overexpressing podocytes were protected from radiation-induced cytoskeletal remodeling. Treatment with RTX before radiation exposure partially protected podocytes from SMPDL3b loss, cytoskeletal remodeling, and caspase 3 cleavage. Our results demonstrate that radiation injury induces early cytoskeletal remodeling, down-regulation of SMPDL3b, and elevation of cellular ceramide levels. Overexpression of SMPDL3b and pretreatment with RTX confer a radioprotective effect in cultured podocytes. These findings indicate a potential role for SMPDL3b and RTX in radiation-induced podocytopathy.-Ahmad, A., Mitrofanova, A., Bielawski, J., Yang, Y., Marples, B., Fornoni, A., Zeidan, Y. H. Sphingomyelinase-like phosphodiesterase 3b mediates radiation-induced damage of renal podocytes.
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Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Podócitos/metabolismo , Podócitos/efeitos da radiação , Esfingomielina Fosfodiesterase/metabolismo , Animais , Ceramidas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Rituximab/administração & dosagem , Rituximab/farmacologia , Esfingomielina Fosfodiesterase/genéticaRESUMO
Bowel obstruction is rare in pregnancy, and delay in recognition can lead to serious maternal and fetal complications. Most reported causes of bowel obstruction in pregnancy (adhesions, intussusception, hernia, and carcinoma) require surgical intervention. Sigmoid volvulus is an acute surgical cause that can now be managed successfully without surgery. We report the case of 33-year-old lady who presented with a sigmoid volvulus that was successfully managed with urgent endoscopic decompression.
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Volvo Intestinal/diagnóstico , Volvo Intestinal/cirurgia , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/cirurgia , Doenças do Colo Sigmoide/diagnóstico , Doenças do Colo Sigmoide/cirurgia , Adulto , Descompressão Cirúrgica , Diagnóstico Precoce , Feminino , Humanos , GravidezRESUMO
This study aimed to assess the dynamic simulation models provided by Aspen adsorption (ASPAD) and artificial neural network (ANN) in understanding the adsorption behavior of atenolol (ATN) on gasified Glyricidia sepium woodchips activated carbon (GGSWAC) within fixed bed columns for wastewater treatment. The findings demonstrated that increasing the bed height from 1 to 3 cm extended breakthrough and exhaustion times while enhancing adsorption capacity. Conversely, higher initial ATN concentrations resulted in shorter breakthrough and exhaustion times but increased adsorption capacity. Elevated influent flow rates reduced breakthrough and exhaustion times while maintaining constant adsorption capacity. The ASPAD software demonstrated competence in accurately modeling the crucial exhaustion points. However, there is room for enhancement in forecasting breakthrough times, as it exhibited deviations ranging from 6.52 to 239.53% when compared to the actual experimental data. ANN models in both MATLAB and Python demonstrated precise predictive abilities, with the Python model (R2 = 0.985) outperforming the MATLAB model (R2 = 0.9691). The Python ANN also exhibited superior fitting performance with lower MSE and MAE. The most influential factor was the initial ATN concentration (28.96%), followed by bed height (26.39%), influent flow rate (22.43%), and total effluent time (22.22%). The findings of this study offer an extensive comprehension of breakthrough patterns and enable accurate forecasts of column performance.
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Poluentes Químicos da Água , Purificação da Água , Adsorção , Atenolol , Carvão Vegetal , Redes Neurais de Computação , Purificação da Água/métodosRESUMO
Cancer is a life-threatening malignancy and one of the leading global causes of human mortality. New approaches are required for cancer therapy due to the unique properties of cancer cells and the side effects of chemotherapy. Probiotics have gained significant attention in the prevention and treatment of various diseases, including cancer. Therefore, the current study aimed to investigate the anti-cancer effects of probiotics, such as marine Lactobacillus species and their proteins. Five marine Lactobacillus species were isolated and identified from the Tamil Nadu Mangrove Pichavaram (TLMP) forest and named TLMP1, TLMP2, TLMP3, TLMP4, and TLMP5. The Lactobacillus isolates, and their proteins were administered to male golden Syrian hamsters. Tumor formation was effectively controlled in hamsters treated with crude Lactobacillus, extending their lifespan. Additionally, Lactobacillus proteins demonstrated an inhibitory effect on tumor formation in the treated group compared to the control. Molecular docking analysis revealed that Lactobacillus proteins interacted significantly with the cAMP-dependent protein kinase catalytic subunit alpha. Amino acid residues LYS791, MET793, ARG841, ARG842, and LEU844 were involved in active site binding and played a crucial role in inhibiting cAMP-dependent protein kinase.
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Neoplasias Bucais , Probióticos , Masculino , Humanos , Lactobacillus/metabolismo , Índia , Simulação de Acoplamento Molecular , Probióticos/uso terapêutico , Probióticos/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismoRESUMO
Advances in assisted reproductive technologies have enabled postmenopausal women to achieve pregnancy beyond their reproductive lifespan. Although rare, these pregnancies are challenging and require a multidisciplinary approach due to the higher prevalence of medical comorbidities in this population. The placenta accreta spectrum is characterized by an abnormal invasion of chorionic villi into the myometrium. Risk factors associated with the placenta accreta spectrum include prior uterine surgeries, advanced maternal age, multiparity, in vitro fertilization, and placenta previa. We present a case of a 59-year-old postmenopausal woman with chronic hypertension, stage II chronic kidney injury, and superimposed pre-eclampsia who underwent cesarean delivery complicated by suspected focal placenta accreta. Histopathological examination revealed significant deviations from normative placental architecture, emphasizing the invasion of the villi. Further, congested blood vessels and the presence of inflammatory cells, along with heightened collagen deposition, suggest an underlying pathological process affecting placental health. These findings underscore a perturbation of placental homeostasis, emphasizing the necessity for further investigation into the mechanisms contributing to placental pathology in postmenopausal pregnancies.
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BACKGROUND: Radiation nephropathy (RN) can be a severe late complication for patients treated with radiotherapy (RT) targeting abdominal and paraspinal tumors. Recent studies investigating the mechanisms of RT-mediated injury in the kidney have demonstrated that RT disrupts the cellular integrity of renal podocytes leading to cell death and loss of renal function. AIM: To determine if RT-induced renal dysfunction is associated with alterations in podocyte and glomerular function, and whether RT-induced podocyte alterations were associated with changes in the glomerular basement membrane (GBM). METHODS: C57BL/6 mice were treated with focal bilateral X-irradiation using a single dose (SD) of 4 Gy, 10 Gy, or 14 Gy or fractionated dosing (FD) of 5x6Gy or 24x2Gy. Then, 10-40 weeks after RT parameters of renal function were measured, along with glomerular filtration rate (GFR) and glomerular histology, as well as ultrastructural changes in GBM by transmission electron microscopy. RESULTS: RT treatment resulted in persistent changes in renal function beginning at 10 weeks with little recovery up to 40 weeks post RT. Dose dependent changes were seen with increasing SD but no functional sparing was evident after FD. RT-induced loss of renal function was associated with expansion of the GBM and significant increases in foot process width, and associated with significant reduction in GFR, podocyte loss, and renal fibrosis. CONCLUSION: For the first time, these data show that expansion of the GBM is one consequence of radiation injury, and disarrangement of the GBM might be associated with the death of podocytes. These data shed new light on the role podocyte injury and GBM in RT-induced renal dysfunction.
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Nefropatias , Podócitos , Lesões por Radiação , Camundongos , Animais , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Podócitos/metabolismo , Podócitos/patologia , Podócitos/ultraestrutura , Lesões por Radiação/patologiaRESUMO
This research was designed to evaluate the pharmaceutical potentials of various proportions of nanoemulsions, Cardiospermum halicacabum Nanoemulsion A and Cardiospermum halicacabum Nanoemulsion B (CHE-NE-A & CHE-NE-B) prepared from the hydroalcoholic extract of Cardiospermum halicacabum through in vitro approach, and their physicochemical properties were characterized using standard scientific analytical techniques. The physicochemical and morphological properties of CHE-NE-A and CHE-NE-B were characterized by FTIR, SEM, TEM, zeta potential, and scattering light intensity analyses. The results revealed that the size, shape, and exterior conditions of nano-droplets of the CHE-NE-A nanoemulsion were suitable as a drug carrier. The reports obtained from in vitro drug releasing potential analysis support this as well. CHE-NE-A nanoemulsion constantly removes the drug from the dialysis bag than CHE-NE-B. Moreover, the CHE-NE-A showed considerable dose-dependent antioxidant activity on DPPH, ABTS, and FRAP free radicals. CHE-NE-A and CHE-NE-B were tested for their antibacterial activity with various bacterial strains. The results demonstrated that the CHE-NE-A nanoemulsion showed remarkable antibacterial activity (zone of inhibition) against test bacterial pathogens than CHE-NE-B. The antibacterial activity of CHE-NE-A at a concentration of 200 µg mL-1was in the following order, P. aeruginosa > S. aureus > S. typhimurium > S. pneumoniae > E. coli. Furthermore, CHE-NE-A has the lowest MIC values against these test bacterial pathogens than CHE-NE-B. Moreover, the CHE-NE-A also demonstrated good antifungal activity against the test fungal pathogens such as Cryptococcus neoformans, Aspergillus niger, Candida pneumonia, and Penicillium expansum than CHE-NE-B. These results strongly suggest that the CHE-NE-A nanoemulsion possesses considerable pharmaceutical potential. Interestingly, the physicochemical properties also rope that the CHE-NE-A nanoemulsion may be considered a drug carrier and useful for drug formulation.
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The lack of a sensitive diagnostic tool for tuberculosis (TB) is the main reason for increasing cause of death in many developing countries. The routine diagnostic tests are either time-consuming or equivocal in terms of results. Hence, there is a need for quicker and accurate diagnostic tests. Certain studies have documented the usage of proteins secreted by Mycobacterium tuberculosis (MTB) in developing a sensitive tool for diagnosing TB. The study aimed to employ PPE41, MPT53, LPQH, CFP10, ESAT6 and TB18.5 proteins and analyze their usage as early diagnostic markers. The proteins were cloned, expressed, purified and applied in ELISA platforms in separate as well as combined systems to assess their early diagnostic features. The results of our study revealed that a cocktail of all six antigen combinations was identified in the maximum number of TB cases. Thus, proteins such as PPE41, MPT53, LPQH, CFP10, ESAT6, and TB18.5 incorporated detection tools could be optimized for an improvised early detection of MTB infections. Moreover, the results suggested that 95.7 % of the MTB-positive serum samples reacted with all the selected antigens of Mycobacterium tuberculosis, while the control serum samples did not react with those antigens. The hexavalent antigen system yielded a novel ELISA platform for better diagnosing MTB infections. Our study yielded a novel technology to diagnose TB, which warrants testing in clinical settings.
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Mycobacterium tuberculosis , Tuberculose , Humanos , Mycobacterium tuberculosis/genética , Tuberculose/diagnóstico , Transporte Biológico , Ensaio de Imunoadsorção Enzimática , TecnologiaRESUMO
Picloram (PC) is a systemic herbicide that controls herbaceous weeds and woody plants. HSA, the most abundant protein in human physiology, binds to all exogenic and endogenic ligands. PC is a stable molecule (t1/2â¼157-513 days) and a potential threat to human health via the food chain. HSA and PC binding study has been done to decipher the location and thermodynamics of binding. It has been studied with prediction tools like autodocking and MD simulation and then confirmed with fluorescence spectroscopy. HSA fluorescence was quenched by PC at pH 7.4 (N state), pH 3.5 (F state), and pH 7.4 with 4.5 M urea (I state) at temperatures 283 K, 297 K, and 303 K. The location of binding was found to be interdomain between II and III which overlaps with drug binding site 2. The binding was spontaneous, and entropy-driven that show a noticeable increase in binding with the increase in temperature. No secondary structure change at the native state has been observed due to binding. The binding results are important to understand the physiological assimilation of PC. In silico predictions and the results of spectroscopic studies unambiguously indicate the locus and nature of the binding.
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Picloram , Albumina Sérica Humana , Humanos , Albumina Sérica Humana/química , Ligação Proteica , Simulação de Acoplamento Molecular , Termodinâmica , Espectrometria de Fluorescência , Sítios de Ligação , Dicroísmo CircularRESUMO
Dicranopteris linearis (DL) is a fern in the Gleicheniaceae family, locally known as resam by the Malay community. It has numerous pharmacological benefits, with antiulcer and gastroprotective properties. Peptic ulcer is a chronic and recurring disease that significantly impacts morbidity and mortality, affecting nearly 20 % of the world's population. Despite the effectiveness of peptic ulcer drugs, there is no perfect treatment for the ailment. Encapsulation is an advanced technique that can treat peptic ulcers by incorporating natural sources. This work aims to encapsulate DL extract using different types of cellulose particles by the solvent displacement technique for peptic ulcer medication. The extract was encapsulated using methyl cellulose (MC), ethyl cellulose (EC), and a blend of ethyl methyl cellulose through a dialysis cellulose membrane tube and freeze-dried to yield a suspension of the encapsulated DL extracts. The microencapsulated methyl cellulose chloroform extract (MCCH) has a considerably greater level of total phenolic (84.53 ± 6.44 mg GAE/g), total flavonoid (84.53 ± 0.54 mg GAE/g), and antioxidant activity (86.40 ± 0.63 %). MCCH has the highest percentage of antimicrobial activity against Escherichia coli (2.42 ± 107 × 0.70 CFU/mL), Bacillus subtilis (5.21 ± 107 × 0.90 CFU/mL), and Shigella flexneri (1.25 ± 107 × 0.66 CFU/mL), as well as the highest urease inhibitory activity (50.0 ± 0.21 %). The MCCH particle size was estimated to be 3.347 ± 0.078 µm in diameter. It has been proven that DL elements were successfully encapsulated in the methyl cellulose polymer in the presence of calcium (Ca). Fourier transform infrared (FTIR) analysis indicated significant results, where the peak belonging to the CO stretch of the carbonyl groups of methyl cellulose (MC) shifted from 1638.46 cm-1 in the spectrum of pure MC to 1639.10 cm-1 in the spectrum of the MCCH extract. The shift in the wavenumbers was due to the interactions between the phytochemicals in the chloroform extract and the MC matrix in the microcapsules. Dissolution studies in simulated gastric fluid (SGF) and model fitting of encapsulated chloroform extracts showed that MCCH has the highest EC50 of 6.73 ± 0.27 mg/mL with R2 = 0.971 fitted by the Korsmeyer-Peppas model, indicating diffusion as the mechanism of release.
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Antiulcerosos , Úlcera Péptica , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Clorofórmio , Diálise Renal , Antiulcerosos/farmacologia , Antiulcerosos/química , Celulose/química , MetilceluloseRESUMO
The investigation of the micellization of a mixture of cetylpyridinium bromide (CPB) and levofloxacin hemihydrate (LFH) was carried out by a conductivity technique in aqueous and aq. additive mixtures, including NaCl, NaOAc, NaBenz, 4-ABA, and urea. The aggregation behavior of the CPB + LFH mixture was studied considering the variation in additive contents and the change in experimental temperature. The micelle formation of the CPB + LFH mixture was examined from the breakpoint observed in the specific conductivity versus surfactant concentration plots. Different micellar characteristics, such as the critical micelle concentration (CMC) and the extent of counter ion bound (ß), were evaluated for the CPB + LFH mixture. The CMC and ß were found to undergo a change with the types of solvents, composition of solvents, and working temperatures. The ΔG0m values of the CPB + LFH system in aqueous and aq. additive solutions were found to be negative, which denotes a spontaneous aggregation phenomenon of the CPB + LFH system. The changes in ΔH0m and ΔS0m for the CPB + LFH mixture were also detected with the alteration in the solvent nature and solution temperature. The ΔH0m and ΔS0m values obtained for the association of the CPB + LFH mixture reveal that the characteristic interaction forces may possibly be ion-dipole, dipole-dipole, and hydrophobic between CPB and LFH. The thermodynamics of transfer and ΔH0m-ΔS0m compensation variables were also determined. All the parameters computed in the present investigation are illustrated with proper logic.
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The Siddha system of medicine is an ancient medical lineage that is practiced primarily in the southern part of India. Siddha system of medicine has been in practice for thousands of years with documented evidence dating back to the 6th century BCE. According to siddha system of medicine's basic fundamental principle, the human body is made up of 96 thathuvam (primary components), which encompass physical, physiological, psychological, and intellectual aspects. Medicine (marunthu) is classified as a wide range of internal and external medicines. The major components of its medical formulations include plant parts, minerals and animal products. Various methods were carried out for the purification process to eliminate the toxins. Choornam, Guligai, Tailam, Parpam, Chendooram, Kattu, Pasai and Poochu are the most common medicines used in Siddha system of medicine for the treatment of various diseases. The pathophysiological classification of diseases is elaborated in detail in the classical Siddha literature. Siddha system of medicine plays an important role in protecting people from diseases such as COVID-19 by providing immune-protecting and immune-boosting medicines in today's world. Mathan tailam and maha megarajanga tailam are the two unique preparations used widely for various skin diseases including chronic wounds and burns. Scientific validation of both medicines will help in understanding their effectiveness against a typical wound condition. In the present study physio-chemical and phytochemical, HPTLC, and GC-MS analyses were carried out and discussed in detail on the multifunctional properties exhibited in the patient communities.
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Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate that SGLT2i affects energy metabolism and podocyte lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that the SGLT2 protein was expressed in human and mouse podocytes to a similar extent in tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wild-type podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes but not in AS tubular cells. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with a decline in renal function. In summary, empagliflozin reduces podocyte lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.