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Neuropathic pain generally affects 7-10% population worldwide and an estimated â¼1 in every 20 individuals in western countries suffer and burden to society. The most limiting factor with existing therapies includes dose escalation issues, off-target side effects and poor translation of randomized trials into clinical practice. Neuropathic pain is a broad term that comprises direct injury/damage to the central and/or peripheral nervous system, leads to maladaptive changes in neuronal as well as in non-neuronal cells, which further contributes to the spontaneous pain, sensory and motor deficit along with altered sensitivity towards the noxious as well as non-noxious stimulus. Transient receptor potential (TRP) channels are polymodal, non-specific cation channels that operate as biosensors to various mechanical and chemical stimuli, including hyperosmolarity, shear stress, heat, mechanical stretch, extracellular ATP, and other products of inflammation. Modulation of these channels leads to various physiological and pathophysiological manifestations at molecular and cellular levels, leading to diseases including neuropathic pain. There are several molecules targeting TRP channels for neuropathic pain in pre-clinical studies, clinical trials and in the market. This review highlights the critical involvement of various pharmacological modulators for TRP channels targeting neuropathic pain and their possible outcomes to harness the therapeutic potential of TRP channels.
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Neuralgia , Canais de Potencial de Receptor Transitório , Humanos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Animais , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Terapia de Alvo MolecularRESUMO
In the past decade, a new family of ternary chalcogenide absorber (TCA) materials MIMIIX2 (where MI = Cu, Ag, Pb; MII = Sb, Bi, In; and X = S, Se, Te) have been studied. The copper family of ternary chalcogenide CuSbS2 CuSbSe2 CuBiS2, and CuBiSe2 is an amazing absorber material for thin-film solar cells because of their suitable band gap, high absorption coefficient and inexpensive, nontoxic, environment friendly and sustainable nature. In the presented work, first time simulated defect density of copper vacancies in CuSbS2 (CAS), CuSbSe2 (CASe), CuBiS2 (CBS) and CuBiSe2 (CBSe) has based heterojunction thin-film solar cells (HJTFSCs) with buffer CdS, intrinsic i-ZnO, window ZnO: Al and back contact Mo and set the cell scheming ZnO: Al/i-ZnO/n-CdS/p-TCA/Mo using SCAPS 1D. Major focus of this paper is on the influence of copper vacancies defect density that impact on the performance of ternary chalcogenide with various parameters of solar cells, i.e. short-circuit current density (Jsc), open-circuit voltage (Voc), form factor (FF) and efficiency (η). The cell parameter set at constant temperature 300 K, thickness 2.5 µm, carrier density 5 × 1016 cm-3, front internal transmission coefficient 1 and illumination intensity 100 mW/cm2 with AM1.5 sun light. This study clarifies the potential benefits to utilizing of ternary chalcogenide compounds as absorber material for solar cell fabrication.
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AIM: Chronic sympathetic stimulation has been identified as a primary factor in the pathogenesis of cardiac hypertrophy (CH). However, there is no appropriate treatment available for the management of CH. Recently, it has been revealed that pyruvate kinase M2 (PKM2) plays a significant role in cardiac remodeling, fibrosis, and hypertrophy. However, the therapeutic potential of selective PKM2 inhibitor has not yet been explored in cardiac hypertrophy. Thus, in the current study, we have studied the cardioprotective potential of Compound 3K, a selective PKM2 inhibitor in isoproterenol-induced CH model. METHODS: To induce cardiac hypertrophy, male Wistar rats were subcutaneously administered isoproterenol (ISO, 5 mg/kg/day) for 14 days. Compound 3K at dosages of 2 and 4 mg/kg orally was administered to ISO-treated rats for 14 days to explore its effects on various parameters like ECG, ventricular functions, hypertrophic markers, histology, inflammation, and protein expression were performed. RESULTS: Fourteen days administration of ISO resulted in the induction of CH, which was evidenced by alterations in ECG, ventricular dysfunctions, increase in hypertrophy markers, and fibrosis. The immunoblotting of hypertrophy heart revealed the significant rise in PKM2 and reduction in PKM1 protein expression. Treatment with Compound 3K led to downregulation of PKM2 and upregulation of PKM1 protein expression. Compound 3K showed cardioprotective effects by improving ECG, cardiac functions, hypertrophy markers, inflammation, and fibrosis. Further, it also reduced cardiac expression of PKM2-associated splicing protein, HIF-1α, and caspase-3. CONCLUSION: Our findings suggest that Compound 3K has a potential cardioprotective effect via PKM2 inhibition in isoproterenol-induced CH.
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Cardiomegalia , Isoproterenol , Piruvato Quinase , Animais , Masculino , Ratos , Cardiomegalia/induzido quimicamente , Cardiomegalia/tratamento farmacológico , Cardiomegalia/prevenção & controle , Cardiomegalia/metabolismo , Cardiotônicos/farmacologia , Fibrose , Isoproterenol/toxicidade , Piruvato Quinase/metabolismo , Piruvato Quinase/antagonistas & inibidores , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder associated with mitochondrial dysfunctions and oxidative stress. However, to date, therapeutics targeting these pathological events have not managed to translate from bench to bedside for clinical use. One of the major reasons for the lack of translational success has been the use of classical model systems that do not replicate the disease pathology and progression with the same degree of robustness. Therefore, we employed a more physiologically relevant model involving alpha-synuclein-preformed fibrils (PFF) exposure to SH-SY5Y cells and Sprague Dawley rats. We further explored the possible involvement of transient receptor potential canonical 5 (TRPC5) channels in PD-like pathology induced by these alpha-synuclein-preformed fibrils with emphasis on amelioration of oxidative stress and mitochondrial health. We observed that alpha-synuclein PFF exposure produced neurobehavioural deficits that were positively ameliorated after treatment with the TRPC5 inhibitor clemizole. Furthermore, Clemizole also reduced p-alpha-synuclein and diminished oxidative stress levels which resulted in overall improvements in mitochondrial biogenesis and functions. Finally, the results of the pharmacological modulation were further validated using siRNA-mediated knockdown of TRPC5 channels, which also decreased p-alpha-synuclein expression. Together, the results of this study could be superimposed in the future for exploring the beneficial effects of TRPC5 channel modulation for other neurodegenerative disorders and synucleopathies.
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Mitocôndrias , Estresse Oxidativo , Ratos Sprague-Dawley , Canais de Cátion TRPC , alfa-Sinucleína , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Animais , Ratos , Estresse Oxidativo/efeitos dos fármacos , Humanos , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/antagonistas & inibidores , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Linhagem Celular Tumoral , Masculino , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/induzido quimicamente , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológicoRESUMO
BACKGROUND AND OBJECTIVES: Acute liver failure (ALF) is an uncommon but potentially dramatic syndrome characterized by massive hepatic necrosis and has a very high mortality rate of 50% to 75% without liver transplantation. This study is aimed at analyzing the etiological spectrum of ALF patients and compare these with ALF mimics such as malaria, dengue fever and other tropical infectious diseases. METHODS: The study population included patients who presented with ALF and ALF mimics in a tertiary care center over two years. We retrospectively analyzed the patient case files and a comparison was made concerning the baseline demographic details, clinical profile, laboratory values and outcomes. RESULTS: Sixty-three patients were assessed, with 32 in ALF and 31 in ALF mimics group. The most common cause for ALF was hepatitis A virus (25%), followed by hepatitis B virus (18.7%), drug-induced liver injury (12.7%), autoimmune hepatitis (12.5%), hepatitis E virus (9.3%) and Wilson's disease (6.25%). In the ALF mimics group, malaria (58.06%) was the most common cause, followed by dengue fever (16.1%), leptospirosis (12.9%) and scrub typhus (12.9%). Patients in the ALF mimics group had significantly higher incidence of fever (p = 0.001), hepatosplenomegaly (p = 0.01), anemia (p = 0.02) and shorter jaundice to encephalopathy duration (p = 0.032) as compared to the ALF group, while higher transaminase levels (p = 0.03), bilirubin (p = 0.01), prothrombin time (p = 0.01), serum ammonia (p = 0.02) and mortality (p = 0.02) were observed in ALF patients. CONCLUSIONS: The most common cause for ALF was hepatitis A virus, followed by hepatitis B virus, while in ALF mimics it was malaria followed by dengue fever, in our study. Patients of ALF mimics can have similar presentation, but a high index of suspicion and awareness is required to identify the common infectious ALF mimics for early diagnosis.
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Dengue , Falência Hepática Aguda , Malária , Humanos , Falência Hepática Aguda/etiologia , Estudos Retrospectivos , Feminino , Masculino , Adulto , Malária/complicações , Diagnóstico Diferencial , Pessoa de Meia-Idade , Dengue/complicações , Dengue/diagnóstico , Hepatite A/complicações , Hepatite A/diagnóstico , Hepatite B/complicações , Hepatite Autoimune/complicações , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/diagnóstico , Hepatite E/complicações , Adulto Jovem , AdolescenteRESUMO
Myocardial infarction (MI) or heart attack arises from acute or chronic prolonged ischemic conditions in the myocardium. Although several risk factors are associated with MI pathophysiology, one of the risk factors is an imbalance in the oxygen supply. The current available MI therapies are still inadequate due to the complexity of MI pathophysiology. Pyruvate kinase M2 (PKM2) has been implicated in numerous CVDs pathologies. However, the effect of specific pharmacological intervention targeting PKM2 has not been studied in MI. Therefore, in this study, we explored the effect of compound 3K, a PKM2-specific inhibitor, in isoproterenol-induced acute MI model. In this study, in order to induce MI in rats, isoproterenol (ISO) was administered at a dose of 100 mg/kg over two days at an interval of 24 h. Specific PKM2 inhibitor, compound 3K (2 and 4 mg/kg), was administered in MI rats to investigate its cardioprotective potential. After the last administration of compound 3K, ECG and hemodynamic parameters were recorded using a PV-loop system. Cardiac histology, western blotting, and plasmatic cardiac damage markers were evaluated to elucidate the underlying mechanisms. Treatment of compound 3K significantly reduced ISO-induced alterations in ECG, ventricular functions, cardiac damage, infarct size, and cardiac fibrosis. Compound 3K treatment produced significant increase in PKM1 expression and decrease in PKM2 expression. In addition, HIF-1α, caspase-3, c-Myc, and PTBP1 expression were also reduced after compound 3K treatment. This study demonstrates the cardioprotective potential of compound 3K in MI, and its mechanisms of cardioprotective action.
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Cardiotônicos , Isoproterenol , Infarto do Miocárdio , Piruvato Quinase , Animais , Isoproterenol/toxicidade , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/patologia , Masculino , Ratos , Piruvato Quinase/metabolismo , Piruvato Quinase/antagonistas & inibidores , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Ratos Wistar , Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/enzimologia , Modelos Animais de Doenças , Ratos Sprague-Dawley , Inibidores de Proteínas Quinases/farmacologia , Hormônios TireóideosRESUMO
Post-traumatic stress disorder (PTSD) and depressive disorders represent two significant mental health challenges with substantial global prevalence. These are debilitating conditions characterized by persistent, often comorbid, symptoms that severely impact an individual's quality of life. Both PTSD and depressive disorders are often precipitated by exposure to traumatic events or chronic stress. The profound impact of PTSD and depressive disorders on individuals and society necessitates a comprehensive exploration of their shared and distinct pathophysiological features. Although the activation of the stress system is essential for maintaining homeostasis, the ability to recover from it after diminishing the threat stimulus is also equally important. However, little is known about the main reasons for individuals' differential susceptibility to external stressful stimuli. The solution to this question can be found by delving into the interplay of stress with the cognitive and emotional processing of traumatic incidents at the molecular level. Evidence suggests that dysregulation in these signalling cascades may contribute to the persistence and severity of PTSD and depressive symptoms. The treatment strategies available for this disorder are antidepressants, which have shown good efficiency in normalizing symptom severity; however, their efficacy is limited in most individuals. This calls for the exploration and development of innovative medications to address the treatment of PTSD. This review delves into the intricate crosstalk among multiple signalling pathways implicated in the development and manifestation of these mental health conditions. By unravelling the complexities of crosstalk among multiple signalling pathways, this review aims to contribute to the broader knowledge base, providing insights that could inform the development of targeted interventions for individuals grappling with the challenges of PTSD and depressive disorders.
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Transtorno Depressivo , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/psicologia , Qualidade de Vida , Comorbidade , Saúde Mental , Transtorno Depressivo/tratamento farmacológicoRESUMO
BACKGROUND AND OBJECTIVES: Prolonged biliary stenting may lead to complications such as cholangitis, stentolith and stent migration. There is limited data on forgotten biliary stents for more than five years in literature. The aim of this retrospective study was to analyze the complications and outcomes in patients who forgot to get their biliary stents removed or exchanged for more than five years. METHODS: The study population included patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) and plastic biliary stent placements in a tertiary care center from 1990 to 2022 for benign biliary diseases. Loss to follow-up and subsequent forgotten stent for more than five years were observed in 40 patients who underwent ERCP during this study period. We retrospectively analyzed the indications of stenting, present status of stent, complications and outcomes in the study patients. RESULTS: The mean age of the study patients was 51.5 ± 11.5 years with 27 females. Indications of biliary stent placement were choledocholithiasis (33, 82.5%), bile leak (3, 7.5%), benign biliary stricture (2, 5%) and choledochal cyst (2, 5%). The mean duration of forgotten stent was 5.9 ± 3.6 years. Presenting symptoms were abdominal pain (37, 92.5%), fever (26, 65%) and jaundice (32, 80%). Most commonly placed stent was 7 French double pigtail of 10 cm length. Complications in the study patients were cholangitis (35, 87.5%), internal migration (2, 5%), pancreatitis (1, 2.5%) and portal hypertension (1, 2.5%). The outcomes were stone removal (30, 90.9%), stent removal (31, 77.5%), stent reinsertion (19, 47.5%), broken stent (3, 7.5%) and surgery (2, 5%). CONCLUSIONS: Prolonged duration (> 5 years) of forgotten stent is uncommon and is observed most commonly in patients with choledocholithiasis. The most common complication of long duration of forgotten stents was cholangitis followed by internal migration, pancreatitis and portal hypertension. Stone and stent removal was successful in a majority of patents, while surgery was required in less number of patients.
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Colangiopancreatografia Retrógrada Endoscópica , Stents , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Stents/efeitos adversos , Estudos Retrospectivos , Fatores de Tempo , Adulto , Resultado do Tratamento , Remoção de Dispositivo , Idoso , Coledocolitíase/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Colangite/etiologia , Migração de Corpo Estranho/etiologia , Migração de Corpo Estranho/epidemiologia , Doenças Biliares/cirurgia , Doenças Biliares/etiologiaRESUMO
Myocardial infarction (MI) is a major cause of mortality and disability globally. MI results from acute or chronic myocardial ischemia characterized by an imbalance of oxygen demand and supply, leading to irreversible myocardial injury. Despite several significant efforts in the understanding of MI, the therapy of MI is not satisfactory due to its complicated pathophysiology. Recently, therapeutic potential of targeting pyruvate kinase M2 (PKM2) has been postulated in several cardiovascular diseases. PKM2 gene knockout and expression studies implicated the role of PKM2 in MI. However, the effects of pharmacological interventions targeting PKM2 have not been investigated in MI. Therefore, in the present study, effect of PKM2 inhibitor has been investigated in the MI along with elucidation of possible mechanism(s). MI in rats was induced by administrations of isoproterenol (ISO) at a dose of 100 mg/kg s.c. for two consecutives days at 24-h interval. At the same time, shikonin (PKM2 inhibitor) was administered at 2 and 4 mg/kg in ISO-induced MI rats. After the shikonin treatment, the ventricular functions were measured using a PV-loop system. Plasma MI injury markers, cardiac histology, and immunoblotting were performed to elucidate the molecular mechanism. Treatment of shikonin 2 and 4 mg/kg ameliorated cardiac injury, reduced infarct size, biochemical alterations, ventricular dysfunction, and cardiac fibrosis in ISO-induced MI. Expression of PKM2 in the ventricle was reduced while PKM1 expression increased in the shikonin treated group, indicating PKM2 inhibition restores PKM1 expression. In addition, PKM splicing protein (hnRNPA2B1 & PTBP1), HIF-1α, and caspase-3 expression were reduced after shikonin treatment. Our findings suggest that pharmacological inhibition of PKM2 with shikonin could be a potential therapeutic strategy to treat MI.
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Infarto do Miocárdio , Piruvato Quinase , Ratos , Animais , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Isoproterenol/toxicidade , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Hipóxia , Apoptose , Fibrose , InflamaçãoRESUMO
The 21st-century beginning remarked with the huge success of monospecific MAbs, however, in the last couple of years, polyspecific MAbs (PsAbs) have been an interesting topic and show promise of being biobetter than monospecific MAbs. Polyspecificity, in which a single antibody serves multiple specific target binding, has been hypothesized to contribute to the development of a highly effective antibody repertoire for immune defence. This polyspecific MAb trend represents an explosion that is gripping the whole pharmaceutical industry. This review is concerned with the current development and quality enforcement of PsAbs. All provided literature on monospecific MAbs and polyspecific MAbs (PsAbs) were searched using various electronic databases such as PubMed, Google Scholar, Web of Science, Elsevier, Springer, ACS, Google Patent and books via the keywords Antibody engineering, Polyspecific antibody, Conventional antibody, non-conventional antibody, and Single domain antibody. In the literature, there are more than 100 different formats to construct PsAb by quadroma technology, chemical conjugation and genetic engineering. Till March 2023, nine PsAb have been approved around the world, and around 330 are in advanced developmental stages, showing the dominancy of PsAb in the growing health sector. Recent advancements in protein engineering techniques and the fusion of non-conventional antibodies have made it possible to create complex PsAbs that demonstrate higher stability and enhanced potency. This marks the most significant achievement for cancer immunotherapy, in which PsAbs have immense promise. It is worth mentioning that seven out of the nine PsAbs have been approved as anti-cancer therapy. As PsAbs continue to acquire prominence, they could pave the way for the development of novel immunotherapies for multiple diseases.
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Anticorpos Monoclonais , Anticorpos Monoclonais/uso terapêuticoRESUMO
Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and their affordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Endostatinas/farmacologia , Endostatinas/uso terapêutico , Endostatinas/fisiologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológicoRESUMO
Mechanical allodynia is a serious complication of painful diabetic neuropathy (PDN) with limited treatment options. The transient receptor potential canonical 5 (TRPC5) channel is a promising target in pain; however, its role in painful diabetic neuropathy has not yet been elucidated. In this study, we have investigated the role of TRPC5 channels using BTD [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4-benzothiadiazin-3-yl)-propanamide)],a potent TRPC5 activator and HC070, as TRPC5 channel inhibitor in rat model of PDN. In this study, streptozotocin was used to induce diabetes in male Sprague-Dawley rats. The alterations in mechanical and thermal pain thresholds, nerve functional deficits in diabetic animals were assessed by various behavioral and functional parameters.TRPC5 involvement was investigated by treating neuropathic rats with BTD, TRPC5 channel activator (1 and 3 mg/kg, i.p. for 14 days) and HC070, a TRPC5 channel inhibitor (1 and 3 mg/kg). BTD and HC070 effects in pain reduction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the lumbar spinal cord. BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated mechanical allodynia but not thermal hyposensation or nerve functional deficit in diabetic neuropathic rats. BTD treatment down-regulated TRPC5 expression by increasing the activity of protein kinase C. It also subsequently down-regulated the downstream pain markers (CAMKII, ERK) in the spinal cord. Additionally, a decrease in inflammatory cytokines (TNF-α, IL-6) also demonstrated BTD's potent anti-inflammatory properties in reducing mechanical allodynia. On the other hand, HC070 did not exert any beneficial effects on behavioural and nerve functional parameters. The study concludes that BTD ameliorated mechanical allodynia in a rat model of painful diabetic neuropathy not only through modulation of the TRPC5-CAMKII-ERK pathway but also through its anti-inflammatory and anti-apoptotic properties. Overall, BTD is a promising therapeutic molecule in the treatment of mechanical allodynia in painful diabetic neuropathy.
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Diabetes Mellitus , Neuropatias Diabéticas , Ratos , Masculino , Animais , Hiperalgesia/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ratos Sprague-Dawley , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Sistema de Sinalização das MAP Quinases , Dor , Canais de Cátion TRPC/metabolismoRESUMO
AIMS: Transient receptor potential canonical 5 (TRPC5) channels are redox-sensitive cation-permeable channels involved in temperature and mechanical sensation. Increased expression and over-activation of these channels has been implicated in several central nervous system disorders such as epilepsy, depression, traumatic brain injury, anxiety, Huntington's disease and stroke. TRPC5 channel activation causes increased calcium influx which in turn activates numerous downstream signalling pathways involved in the pathophysiology of neurological disorders. Therefore, we hypothesized that pharmacological blockade and knockdown of TRPC5 channels could attenuate the behavioural deficits and molecular changes seen in CNS disease models such as MPTP/MPP+ induced Parkinson's disease (PD). MATERIALS AND METHODS: In the present study, PD was induced after bilateral intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the Sprague Dawley rats. Additionally, SH-SY5Y neurons were exposed to 1-methyl-4-phenylpyridinium (MPP+) to further determine the role of TRPC5 channels in PD. KEY FINDINGS: We used clemizole hydrochloride, a potent TRPC5 channel blocker, to reverse the behavioural deficits, molecular changes and biochemical parameters in MPTP/MPP+-induced PD. Furthermore, knockdown of TRPC5 expression using siRNA also closely phenocopies these effects. We further observed restoration of tyrosine hydroxylase levels and improved mitochondrial health following clemizole treatment and TRPC5 knockdown. These changes were accompanied by diminished calcium influx, reduced levels of reactive oxygen species and decreased apoptotic signalling in the PD models. SIGNIFICANCE: These findings collectively suggest that increased expression of TRPC5 channels is a potential risk factor for PD and opens a new therapeutic window for the development of pharmacological agents targeting neurodegeneration and PD.
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Neuroblastoma , Doença de Parkinson , Canais de Potencial de Receptor Transitório , Animais , Humanos , Ratos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , 1-Metil-4-fenilpiridínio , Cálcio/metabolismo , Neurônios Dopaminérgicos , Neuroblastoma/metabolismo , Oxirredução , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Ratos Sprague-Dawley , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismoRESUMO
Our study to evaluate the aetiological and clinical spectrum of gastric outlet obstruction (GOO) in North-west India showed malignant cause (54.9%) was more common than benign (45.1%). Common causes of malignancy were gall bladder (37.5%), gastric (31.8%) and pancreatic carcinoma (19.6%); commonest benign causes were opioid abuse (29%), peptic ulcer disease (21.6%), ingestion of corrosives (20.2%) and chronic pancreatitis (12.3%).
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Obstrução da Saída Gástrica , Neoplasias Pancreáticas , Úlcera Péptica , Humanos , Obstrução da Saída Gástrica/diagnóstico , Obstrução da Saída Gástrica/epidemiologia , Obstrução da Saída Gástrica/etiologia , Úlcera Péptica/complicações , Úlcera Péptica/epidemiologia , Índia/epidemiologiaRESUMO
BACKGROUND: Diabetic cardiac autonomic neuropathy (DCAN) is a serious diabetic complication with no approved pharmacological agents for its treatment. Parasympathetic system dysfunction characterized by vagal nerve damage is one of the major drivers of DCAN. The TRPC5 or transient receptor potential canonical 5 channel is a promising target in autonomic dysfunction; however, its role in vagal nerve damage and subsequent DCAN has not yet been elucidated. The present study investigated the role of the TRPC5 channel in DCAN using [N-{3-(adamantan-2-yloxy)-propyl}-3-(6-methyl-1,1-dioxo-2H-1λ6,2,4-benzothiadiazin-3-yl) propanamide)] or BTD, which is a potent TRPC5 activator. OBJECTIVES: The role of the TRPC5 channel and its activator, BTD, was investigated in the treatment of parasympathetic dysfunction associated with DCAN. METHODS: Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin. The alterations in cardiac autonomic parameters in diabetic animals were assessed by heart rate variability, hemodynamic parameters, and baroreflex sensitivity. TRPC5's role in DCAN was investigated by treating diseased rats with BTD (1 and 3 mg/kg, i.p. for 14 days). BTD's beneficial effects in parasympathetic dysfunction were assessed by western blotting, estimating oxidative stress and inflammatory markers in the vagus nerve. RESULTS: BTD treatment (3 mg/kg, i.p.) once daily for 14 days ameliorated heart rate variability, hemodynamic dysfunction, and baroreflex sensitivity in diseased rats. BTD treatment down regulated TRPC5 expression by increasing the activity of protein kinase C in the vagus nerve. It also down-regulated the apoptotic marker CASPASE-3 and also exerted potent anti-inflammatory action on pro-inflammatory cytokines levels in the vagus. CONCLUSION: BTD ameliorated parasympathetic dysfunction associated with DCAN by virtue of its TRPC5 modulatory, anti-inflammatory, and anti-apoptotic properties.
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Diabetes Mellitus Experimental , Neuropatias Diabéticas , Canais de Cátion TRPC , Animais , Masculino , Ratos , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/tratamento farmacológico , Coração/inervação , Frequência Cardíaca , Ratos Sprague-Dawley , Canais de Cátion TRPC/agonistasRESUMO
Organophosphates (OPs) are highly neurotoxic compounds and certain OP-compounds are also exploited as a weapon of mass destruction and chemical warfare in terrorist attacks. Available prophylactic and post-exposure treatments are less effective and also have serious side-effects. Thus, there is a dire need to develop effective and safe prophylactic agent(s) against OP-poisoning. Human Paraoxonase 1 (hPON1) can hydrolyze a wide range of OP molecules and can be developed as an effective and safe prophylactic agent. Thus, there is a dire need in the art to develop variant(s) of rhPON1 that not only possess 'good' OP-hydrolyzing activity but also have improved pharmacokinetic properties. In this report, we describe the characterization of the fused hPON1 (FHP) variant that not only exhibit enhanced in vivo pharmacokinetic properties but also delay / prevent the symptoms of OP-poisoning and prevents OP-induced mortality in rats.
Assuntos
Arildialquilfosfatase , Intoxicação por Organofosfatos , Animais , Humanos , Ratos , Intoxicação por Organofosfatos/prevenção & controle , OrganofosfatosRESUMO
Mitochondrial dysfunction is closely linked with the pathophysiology of several neurodegenerative disorders including Parkinson's disease (PD). Despite several therapeutic advancements related to symptomatic modification of PD pathology, strategies targeting mitochondrial dysfunctions remain largely elusive. Recently, transient receptor potential (TRP) channels have been shown to play a pivotal role in the control of mitochondrial and neuronal functioning in PD. In this study, the effect of 2-aminoethoxydiphenyl borate (2-APB), TRP channel blocker was investigated in the context of mitochondrial dysfunctions in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administered Sprague Dawley rats. MPP+-treated SH-SY5Y cells exhibited reductions in cell viability, generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Co-treatment with 2-APB led to an increase in cell viability, reduction in intracellular and mitochondrial ROS and improvement in mitochondrial membrane potential compared to MPP+-treated SH-SY5Y cells. In addition, intranigral administration of MPTP led to a significant reduction in motor function in the rats. Fourteen days of 2-APB (3 and 10 mg/kg, i.p.) treatment improved behavioural parameters. MPTP-induced decrease in complex I activity and mitochondrial potential were also blocked by 2-APB in the mitochondria isolated from the brain regions i.e. midbrain and striatum. MPTP-induced decrease in tyrosine hydroxylase levels were also restored by 2-APB. Moreover, MPTP-induced reduction in proteins involved in mitochondrial biogenesis, viz. peroxisome proliferator-activated-receptor-gamma coactivator and mitochondrial transcription factor-A were increased after 2-APB treatment in vivo. In summary, 2-APB has a promising neuroprotective role in the MPP+/MPTP models of PD via targeting mitochondrial dysfunctions and biogenesis.
Assuntos
Neuroblastoma , Doença de Parkinson , Humanos , Ratos , Animais , Camundongos , 1-Metil-4-fenilpiridínio/metabolismo , 1-Metil-4-fenilpiridínio/farmacologia , Doença de Parkinson/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Ratos Sprague-Dawley , Neuroblastoma/metabolismo , Mitocôndrias/metabolismo , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Neurônios DopaminérgicosRESUMO
Decreased bifidobacterial abundance, disrupted gut barrier function, dysregulated immune response and ulceration have been reported in the gut microbiota of IBD patients. Non-digestible carbohydrates with bifidogenic effect enrich the gut microbiota with Bifidobacterium spp. and could help in overcoming inflammatory gut conditions. In this study, the protective effect of Bifidobacterium longum Bif10 and Bifidobacterium breve Bif11; isomaltooligosaccharides (IMOS); Finger millet arabinoxylan (FM-AX) and their Synbiotic mix were evaluated against dextran sodium sulphate (DSS) induced UC in male Balb/c mice for 25 days. All the interventions ameliorated symptoms of colitis such as disease activity index (DAI), histological damage to the colon, gut-bacterial dysbiosis and inflammation. However, the synbiotic mix was more potent in amelioration of some of the parameters such as decreased TNF-α and lipocalin levels; increased anti-inflammatory markers (IL-10 and IL-22), and improved short chain fatty acids (SCFAs) levels in the cecum content. Furthermore, mouse colitis histological scoring (MCHI) also suggested the preventive role of synbiotic mix. All the dietary interventions aid in improving the DAI and immune parameters; restoration or regeneration of the altered selected gut bacteria, enhances the SCFA production, strengthens gut barrier, prevents gut inflammation and decreases the colonic MCHI score in DSS fed mice.
Assuntos
Bifidobacterium breve , Bifidobacterium longum , Colite Ulcerativa , Colite , Eleusine , Simbióticos , Camundongos , Masculino , Animais , Colite Ulcerativa/microbiologia , Dextranos/farmacologia , Colite/microbiologia , Colo , Inflamação/patologia , Bifidobacterium , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Different rare-earth (RE) metal-oxides nano-particles (NPs) viz. Samarium (III) oxide (Sm2O3), Neodymium (III) oxide (Nd2O3), and Gadolinium (III) oxide (Gd2O3) were synthesized using co-precipitation route, and investigated by structural, optical, and morphological studies. Findings and supporting studies were presented to understand the role of RE-metal-oxides NPs as photo-anode material for dye sensitized solar cells (DSSCs) applications. Structural analysis of prepared RE-metaloxides, by X-ray diffraction (XRD), reveals the crystalline nature of the particles ranging from 24 to 37 nm. Morphological study by field emission scanning electron microscopy (FESEM) supports the crystalline nature in the nano range of the prepared RE-metal oxides particles. The observed d values of each sample support the growth of Gd2O3, Nd2O3, and Sm2O3 material. The band-gap of prepared material was estimated from the UV-VIS absorption data and Tauc relation. The observed band gap values are 3.55 eV, 3.31 eV, and 3.52 eV for Gd2O3, Nd2O3, and Sm2O3 respectively. These values are reasonably high compare to the bulk values, indicates the nanostructure formation. Optimized RE-metal oxides NPs employed in the form of TiO2 photo anode for the fabrication of DSSCs. FESEM confirms that the Gd2O3-based photo-anode shows more uniform and decent coverage with more porosity on the TiO2. The EIS measurements of prepared DSSCs also supported the improvement in the photovoltaic output for the modified photo-anode devices as cells with modified photo-anode exhibited less charge recombination at the photo-anode/dye/electrolyte interface with increased electron lifetime leading to improved device performance as compared to the unmodified-based DSSCs. The highest efficiency 5.51% was demonstrated by [Formula: see text]/[Formula: see text] photo-anode-based DSSCs compare to Sm2O3, and Nd2O3 activated photo-anode.
Assuntos
Nanoestruturas , Energia Solar , Óxidos/química , Corantes/química , Luz Solar , Nanoestruturas/químicaRESUMO
Cardiovascular diseases (CVDs) are the world's leading cause of death, accounting for 32% of all fatalities. Although therapeutic agents are available for CVDs, however, most of them have significant limitations such as the time-dependency effect, hypotension, and bradycardia. To overcome the limitations of current pharmacological therapies, new molecular targets and pathways need to be identified and investigated to provide better treatment options for CVDs. Recent evidence suggested the involvement of pyruvate kinase M2 (PKM2) and targeting PKM2 by its modulators (inhibitors and activators) has shown promising results in several CVDs. PKM2 regulates gene activation in the context of apoptosis, mitosis, hypoxia, inflammation, and metabolic reprogramming. PKM2 modulators might have a significant impact on the molecular pathways involved in CVD pathogenesis. Therefore, PKM2 modulators can be one of the therapeutic options for CVDs. This review provides an insight into PKM2 involvement in various CVDs along with their therapeutic potential.