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1.
Biochem Pharmacol ; 225: 116284, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38750903

RESUMO

Chronic Kidney Disease (CKD) presents a significant global health challenge with limited treatment options. Nesfatin-1, an anorexigenic peptide, has demonstrated antioxidant, anti-inflammatory, and anti-apoptotic properties in various diseases. However, the role of nesfatin-1 in CKD remains unclear. This study investigates the potential renoprotective effects of nesfatin-1 in adenine-induced CKD mice and in NRK-52E renal epithelial cells. Male C57BL/6J mice and NRK-52E renal epithelial cells were administered adenine to induce CKD. Various aspects of renal function, histopathology, oxidative stress, inflammation, apoptosis, and renal interstitial fibrosis were assessed and downstream pathways were investigated. Adenine-fed mice exhibited reduced nesfatin-1 expression and increased markers of kidney damage, including elevated blood urea nitrogen (BUN), serum creatinine, and histological abnormalities, reactive oxygen species (ROS), inflammation, apoptosis, and fibrosis. Treatment with nesfatin-1 in adenine induced mice significantly reversed these changes. Nesfatin-1 also lowered calcium levels and the expression of inflammatory markers, including IL-1ß, IL-6, TNF-α, and Nf-kB. Furthermore, nesfatin-1 reduced the expression of apoptotic markers (Caspase-3, Caspase-1, Bax/Bcl2 ratio) and restored the balance of Bcl2 and MMP. Lastly, nesfatin-1 attenuated fibrotic markers (Tgf-ß, Smad2/3,4, type IV collagen, α-SMA) in both adenine-induced CKD mice and NRK-52E cells. In conclusion, our results suggest that nesfatin-1 may enhance kidney function in adenine-induced CKD mice and NRK-52E cells. The renoprotective effects of nesfatin-1 are likely associated with its antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic properties.


Assuntos
Adenina , Insuficiência Renal Crônica , Animais , Masculino , Camundongos , Ratos , Adenina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Camundongos Endogâmicos C57BL , Nucleobindinas , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia
2.
Artigo em Inglês | MEDLINE | ID: mdl-38566388

RESUMO

Diabetes is a medical condition associated with impaired glucose regulation caused either due to insufficient insulin production or resistance to insulin (Type 2 diabetes, gestational diabetes) or the absence of insulin through the selective killing of beta cells in the pancreas (Type 1 diabetes). Irregular insulin production leads to various health complications. To prevent such complications, patients must adhere to medical recommendations before availing of any advanced insulin therapy(ies), considered productive for the treatment. Natural insulin, although highly effective in controlling blood glucose levels, patients are often at risk of developing hypoglycemia and many other complications. This has led to the development of insulin analogs, the modified variants of natural insulin having a minimal risk of causing hypoglycemia. Besides the development of analogs, the mode of insulin delivery is also considered critical in achieving better glycemic control in diabetic patients. Until recently, various exogenous insulin delivery methods were practiced, but effective glycemic control without any associated risk and ease of delivery remains a subject of paramount concern. It countered attenuation or delayed onset of diabetes-associated complications without a permanent cure, raising an unmet demand for insulin formulations and delivery methods that offer stability, biocompatibility, reproducibility, precision dosing, non-immunogenicity, and safety. The current practice utilizes non-physiological delivery methods with less invasive administration routes, offering glycemic stability and therapeutic effectiveness. This review focuses on the recent advances made and future perspectives envisioned about newer insulin therapies and delivery methods that tend to improve the management of diabetes by inculcating ideas to reduce the disease's severity and improve the quality of life.

3.
Biochim Biophys Acta Mol Basis Dis ; 1870(4): 167110, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38462025

RESUMO

BACKGROUND: The aortic endothelium is crucial in preserving vascular tone through endothelium-derived vasodilators and vasoconstrictors. Dysfunction in the endothelium is an early indicator of cardiovascular diseases. Our study explores the therapeutic potential of a dual-acting peptide (DAP) to co-activate Mas and pGCA receptors and restore the balance between vasodilators and vasoconstrictors on endothelial dysfunction in DOCA-salt-induced hypertensive rats. METHODS: DOCA-salt was administered to male wistar rats to induce hypertension, and various parameters, including blood pressure (BP), water intake and body weight were monitored. DAP, Ang1-7, BNP, and losartan were administered to hypertensive rats for three weeks. Histological analysis and isometric tension studies were carried out to assess endothelial function. In addition to this, we used primary aortic endothelial cells for detailed mechanistic investigations. RESULTS: DOCA-salt administration significantly elevated systolic, diastolic, mean arterial BP, and water intake whereas, downregulated the gene expression of Mas and pGCA receptors. However, DAP co-administration attenuated BP increase, upregulated the gene expression of Mas and pGCA receptors, normalized serum and urinary parameters, and effectively reduced fibrosis, inflammation, and vascular calcification. Notably, DAP outperformed the standard drug, Losartan. Our findings indicate that DAP restores aortic function by balancing the NO and ET1-induced pathways. CONCLUSION: Co-activating Mas and pGCA receptors with DAP mitigates vascular damage and enhances endothelial function, emphasizing its potential to maintain a delicate balance between vasodilatory NO and vasoconstrictor ET1 in endothelial dysfunction.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Ratos , Masculino , Animais , Endotelina-1/metabolismo , Endotelina-1/farmacologia , Endotelina-1/uso terapêutico , Losartan/farmacologia , Losartan/uso terapêutico , Óxido Nítrico/metabolismo , Acetato de Desoxicorticosterona/efeitos adversos , Células Endoteliais/metabolismo , Vasodilatadores/efeitos adversos , Endotélio Vascular/metabolismo , Ratos Wistar , Vasoconstritores/efeitos adversos , Cloreto de Sódio na Dieta/efeitos adversos
4.
Ther Adv Cardiovasc Dis ; 17: 17539447231210170, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38069578

RESUMO

Diabetic cardiomyopathy (DCM) is characterized by structural and functional abnormalities in the myocardium affecting people with diabetes. Treatment of DCM focuses on glucose control, blood pressure management, lipid-lowering, and lifestyle changes. Due to limited therapeutic options, DCM remains a significant cause of morbidity and mortality in patients with diabetes, thus emphasizing the need to develop new therapeutic strategies. Ongoing research is aimed at understanding the underlying molecular mechanism(s) involved in the development and progression of DCM, including oxidative stress, inflammation, and metabolic dysregulation. The goal is to develope innovative pharmaceutical therapeutics, offering significant improvements in the clinical management of DCM. Some of these approaches include the effective targeting of impaired insulin signaling, cardiac stiffness, glucotoxicity, lipotoxicity, inflammation, oxidative stress, cardiac hypertrophy, and fibrosis. This review focuses on the latest developments in understanding the underlying causes of DCM and the therapeutic landscape of DCM treatment.


Assuntos
Diabetes Mellitus , Cardiomiopatias Diabéticas , Humanos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Miocárdio/metabolismo , Coração , Transdução de Sinais , Inflamação/tratamento farmacológico
5.
Mol Cell Biol ; 43(8): 401-425, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37439479

RESUMO

Replication fork arrest-induced DNA double strand breaks (DSBs) caused by lesions are effectively suppressed in cells due to the presence of a specialized mechanism, commonly referred to as DNA damage tolerance (DDT). In eukaryotic cells, DDT is facilitated through translesion DNA synthesis (TLS) carried out by a set of DNA polymerases known as TLS polymerases. Another parallel mechanism, referred to as homology-directed DDT, is error-free and involves either template switching or fork reversal. The significance of the DDT pathway is well established. Several diseases have been attributed to defects in the TLS pathway, caused either by mutations in the TLS polymerase genes or dysregulation. In the event of a replication fork encountering a DNA lesion, cells switch from high-fidelity replicative polymerases to low-fidelity TLS polymerases, which are associated with genomic instability linked with several human diseases including, cancer. The role of TLS polymerases in chemoresistance has been recognized in recent years. In addition to their roles in the DDT pathway, understanding noncanonical functions of TLS polymerases is also a key to unraveling their importance in maintaining genomic stability. Here we summarize the current understanding of TLS pathway in DDT and its implication for human health.


Assuntos
DDT , Reparo do DNA , Humanos , Replicação do DNA , DNA/genética , Dano ao DNA , Instabilidade Genômica
6.
J Cell Biochem ; 124(7): 943-960, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37210727

RESUMO

Cardiovascular diseases (CVDs) are associated with vascular smooth muscle cell (VSMC) and endothelial cell (EC) damage. Angiotensin1-7 (Ang1-7) and B-type natriuretic peptide (BNP) are responsible for vasodilation and regulation of blood flow. These protective effects of BNP are primarily mediated by the activation of sGCs/cGMP/cGKI pathway. Conversely, Ang1-7 inhibits Angiotensin II-induced contraction and oxidative stress via Mas receptor activation. Thus, the aim of the study was to determine the effect of co-activation of MasR and particulate guanylate cyclase receptor (pGCA) pathways by synthesized novel peptide (NP) in oxidative stress-induced VSMCs and ECs. MTT and Griess reagent assay kits were used for the standardization of the oxidative stress (H2 O2 ) induced model in VSMCs. The expression of targeted receptors in VSMC was done by RT-PCR and Western blot analysis. Protective effect of NP in VSMC and EC was determined by immunocytochemistry, FACS analysis, and Western blot analysis. Underlying mechanisms of EC-dependent VSMC relaxation were done by determining downstream mRNA gene expression and intracellular calcium imaging of cells. Synthesized NP significantly improved oxidative stress-induced injury in VSMCs. Remarkably, the actions of NP were superior to that of the Ang1-7 and BNP alone. Further, a mechanistic study in VSMC and EC suggested the involvement of upstream mediators of calcium inhibition for the therapeutic effect. NP is reported to possess vascular protective activities and is also involved in the improvement of endothelial damage. Moreover, it is highly effective than that of individual peptides BNP and Ang1-7 and therefore it may represent a promising strategy for CVDs.


Assuntos
Cálcio , Músculo Liso Vascular , Músculo Liso Vascular/metabolismo , Cálcio/metabolismo , Células Endoteliais/metabolismo , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo , Peptídeo Natriurético Encefálico/metabolismo , Células Cultivadas
7.
Eur J Pharmacol ; 949: 175720, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37054940

RESUMO

Sodium-glucose transport protein 2 (SGLT-2) inhibitors are approved antidiabetic drugs with a beneficial effect on reducing major adverse cardiac events and heart failure hospitalization. Among them, canagliflozin has the least selectivity toward SGLT-2 over the SGLT-1 isoform. Canagliflozin can inhibit SGLT-1 at therapeutic levels; however, the underlying molecular mechanism is not understood. This study aimed to evaluate the effect of canagliflozin on SGLT1 expression in an animal model of diabetic cardiomyopathy (DCM) and its associated effects. In vivo studies were carried out in the most clinically relevant high-fat diet and streptozotocin-induced type-2 diabetes model of diabetic cardiomyopathy, and in vitro studies were performed using cultured rat cardiomyocytes stimulated with high glucose and palmitic acid. DCM was induced in male Wistar rats for 8 weeks with or without 10 mg/kg canagliflozin treatment. At the end of the study, systemic and molecular characteristics were measured using immunofluorescence, quantitative RT‒PCR, immunoblotting, histology, and FACS analysis. SGLT-1 expression was upregulated in DCM hearts and was associated with fibrosis, apoptosis, and hypertrophy. Canagliflozin treatment attenuated these changes. The histological evaluation showed improved myocardial structure, and in vitro results revealed improved mitochondrial quality and biogenesis after canagliflozin treatment. In conclusion, canagliflozin protects the DCM heart by inhibiting myocardial SGLT-1 and associated hypertrophy, fibrosis, and apoptosis. Thus, developing novel pharmacological inhibitors targeting SGLT-1 could be a better strategy for treating DCM and associated cardiovascular complications.


Assuntos
Diabetes Mellitus Tipo 2 , Cardiomiopatias Diabéticas , Masculino , Ratos , Animais , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/etiologia , Ratos Wistar , Diabetes Mellitus Tipo 2/tratamento farmacológico , Miócitos Cardíacos , Mitocôndrias , Fibrose , Hipertrofia/patologia
8.
Peptides ; 165: 171013, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37105355

RESUMO

Nesfatin-1 is a potent polypeptide and plays a crucial role in many physiological functions. Nesfatin-1 levels are reported in both the central nervous system and peripheral organs. However, the expression of nesfatin-1 in the renal system under chronic oxidative stress-induced conditions and the direct effect of nesfatin-1 treatment on stress-induced pathological damage are not reported. Thus, the present study aimed to explore the role of nesfatin-1 in vitro in oxidative stress-induced renal epithelial cells. High glucose (HG) and H2O2 combination were used to induce oxidative stress (OS). MTT, crystal violet, and H and E staining were used to measure cell viability, cytotoxicity, and morphology. FACS analysis and confocal microscopy were used to measure OS and apoptosis. RT-PCR was done for gene expression analysis. Decreased nesfatin-1 expression was observed in renal epithelial cells induced with HG and H2O2 compared to an untreated control (0.16; p < 0.0001). Nesfatin-1 co-treatment with HG and H2O2 attenuated ROS, apoptosis, and fibrosis. SOD, Catalase, and Bcl-2 expression decreased (p < 0.0001) and Caspase-3 and TGF-ß1 expression increased in HG and H2O2-induced cells compared to control cells (p < 0.0001). Nesfatin-1 co-treatment attenuated these changes induced by HG and H2O2 (p < 0.0001). Nesfatin-1 expression was decreased in renal epithelial cells under stress-induced conditions. Moreover, nesfatin-1 co-treatment under stress-induced conditions protects the renal epithelial cells via inhibition of oxidative stress, apoptotic, and fibrotic signaling pathways.


Assuntos
Apoptose , Peróxido de Hidrogênio , Animais , Ratos , Células Epiteliais , Fibrose , Glucose/farmacologia , Glucose/metabolismo , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo
10.
Peptides ; 162: 170959, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36693526

RESUMO

Over-activation of the renin-angiotensin-aldosterone system (RAAS) is a leading cause of cardio-renal complications. Oxidative stress is one of the major contributing factors in the over-activation of RAAS. Angiotensin-converting enzyme2/Angiotensin1-7/MasR and natriuretic peptide/particulate guanylyl cyclase receptor-A pathways play a key role in cardiorenal disease protection. Even though individual activation of these pathways possesses cardiorenal protective effects. However, the dual activation of these pathways under stress conditions and the underlying mechanism has not been explored. The study aimed to investigate whether activation of these pathways by dual-acting peptide (DAP) shows a protective effect in-vitro in oxidative stress-induced renal epithelial cells. Oxidative stress was induced in renal epithelial NRK-52E cells with H2O2. Co-treatment with Ang 1-7, BNP, and DAP was given for 30 min. AT1, MasR, and pGCA expression were measured by RT-PCR. The markers of oxidative stress and apoptosis were measured by confocal microscopy and FACS analysis. A significant increase in AT1, renin, α-SMA, and NFk-ß expression and a significant decrease in MasR and pGCA expression was observed in H2O2-induced cells. DAP improved H2O2-induced pathological changes in NRK-52E cells. The effect of DAP was superior to that of Ang1-7 and BNP alone. Interestingly, MasR and pGCA inhibitors could block the effect of DAP in H2O2-induced cells. DAP shows superior anti-RAAS activity, and it is effective against H2O2-induced oxidative stress, apoptosis, fibrosis, and inflammation compared to Ang1-7 and BNP alone. The protective effect is mediated by the dual activation of MasR and pGCA.


Assuntos
Peróxido de Hidrogênio , Proteínas Proto-Oncogênicas , Proteínas Proto-Oncogênicas/metabolismo , Peróxido de Hidrogênio/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Estresse Oxidativo , Fragmentos de Peptídeos/farmacologia , Células Epiteliais/metabolismo , Angiotensina II/metabolismo
11.
Pain Manag ; 13(1): 61-69, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36515014

RESUMO

COVID-19, an infection caused by SARS-CoV-2, had a devastating impact on people's lives. The pandemic placed a heavy burden on healthcare systems and impacted the care of patients, including those with pain. This narrative review aims to highlight the challenges in managing pain and fever resulting from COVID-19 and pre-existing conditions, and to discuss the role of over the counter analgesics as a key part of the COVID-19 treatment regimen. As most patients with COVID-19 are being managed in the outpatient setting, lifestyle interventions and over the counter analgesics are readily available options to effectively treat pain and fever, which can help to decrease the burden on the healthcare system during the COVID-19 pandemic.


COVID-19 is an infection caused by SARS-CoV-2. The COVID-19 pandemic not only affects patient lives, but also heavily impacts healthcare systems. This review aims to discuss the available literature on how to manage pain from COVID-19 and encourage a consensus meeting for recommendations. As most patients with COVID-19 are being managed in the outpatient setting, lifestyle interventions and over the counter analgesics are readily available options to effectively treat pain and fever, which can help to decrease the demand on the healthcare system during the COVID-19 pandemic.


Assuntos
COVID-19 , Humanos , COVID-19/complicações , SARS-CoV-2 , Manejo da Dor/métodos , Pandemias , Tratamento Farmacológico da COVID-19 , Dor , Analgésicos/uso terapêutico
12.
Life Sci ; 305: 120762, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35787996

RESUMO

AIMS: Acute kidney injury (AKI) is a debilitating condition followed by sudden kidney damage or failure within hours or days of its occurrence. AKI is characterized by rapid increase in serum creatinine/BUN and decrease in urine output. Nesfatin-1 is an endogenous peptide reported to possess anorexic, antioxidant and anti-apoptotic properties. Although few clinical studies have shown altered nesfatin-1 levels in hemodialysis patients, however, there are no reports investigating the distribution and expression pattern of nesfatin-1 in AKI. MATERIALS AND METHODS: Nesfatin-1 expression was determined in different disease induced models of AKI by immunoblotting, immunofluorescence and RT-PCR. Gene markers of oxidative stress and inflammation were determined by RT-PCR. The expression of different markers of AKI was measured by assay kits and RT-PCR analysis. KEY FINDINGS: There was a significant increase in serum levels of creatinine and BUN in AKI rats followed by significant increase in KIM-1 in the kidneys. Significant decrease in nesfatin-1 expression along with increased expression of IL-1ß, TNF-α and decreased expression of SOD and catalase was observed in doxorubicin and cisplatin induced AKI rats. However, SOD and catalase expression were upregulated in glycerol induced AKI rats. Moreover, in vitro treatment of renal NRK-52E epithelial cells with nesfatin-1 reversed the changes induced by doxorubicin. SIGNIFICANCE: Our study reports for the first time, nesfatin-1 expression is decreased in kidneys of different models of AKI induced rats as well as cultured NRK-52E renal epithelial cells. Further studies are required to understand the possible molecular mechanism and therapeutic potential of nesfatin-1 in acute kidney injury.


Assuntos
Injúria Renal Aguda , Apoptose , Nucleobindinas/genética , Injúria Renal Aguda/metabolismo , Animais , Catalase/metabolismo , Células Cultivadas , Creatinina , Regulação para Baixo , Doxorrubicina/efeitos adversos , Rim/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Superóxido Dismutase/metabolismo
13.
Int J Mol Sci ; 23(14)2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35887150

RESUMO

Most living organisms have in their genome a sizable proportion of DNA sequences capable of mobilization; these sequences are commonly referred to as transposons, transposable elements (TEs), or jumping genes. Although long thought to have no biological significance, advances in DNA sequencing and analytical technologies have enabled precise characterization of TEs and confirmed their ubiquitous presence across all forms of life. These findings have ignited intense debates over their biological significance. The available evidence now supports the notion that TEs exert major influence over many biological aspects of organismal life. Transposable elements contribute significantly to the evolution of the genome by giving rise to genetic variations in both active and passive modes. Due to their intrinsic nature of mobility within the genome, TEs primarily cause gene disruption and large-scale genomic alterations including inversions, deletions, and duplications. Besides genomic instability, growing evidence also points to many physiologically important functions of TEs, such as gene regulation through cis-acting control elements and modulation of the transcriptome through epigenetic control. In this review, we discuss the latest evidence demonstrating the impact of TEs on genome stability and the underling mechanisms, including those developed to mitigate the deleterious impact of TEs on genomic stability and human health. We have also highlighted the potential therapeutic application of TEs.


Assuntos
Elementos de DNA Transponíveis , Instabilidade Genômica , Elementos de DNA Transponíveis/genética , Evolução Molecular , Genômica , Humanos , Sequências Reguladoras de Ácido Nucleico , Transcriptoma
14.
ACS Pharmacol Transl Sci ; 5(4): 216-225, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35434529

RESUMO

Sodium-dependent glucose cotransporter 2 inhibitors (SGLT2) are recently approved drugs for the treatment of diabetes that regulate blood glucose levels by inhibiting reabsorption of glucose and sodium in the proximal tubules of the kidney. SGLT2 inhibitors have also shown cardiovascular (CV) benefits in diabetic patients. However, the therapeutic efficacy of SGLT2 inhibitors with respect to CV disease needs further investigation. Thus, the aim of the present study was to examine the effects of SGLT2 inhibitors, canagliflozin (CANA) and dapagliflozin (DAPA) in vitro under glucolipotoxic condition by treating cultured cardiomyocytes (H9C2) with high glucose (HG) and high lipid, palmitic acid (PA), to investigate whether inhibition of sodium glucose cotransporter could prevent any harmful effects of glucolipotoxicity in these cells. SGLT1 expression was measured by immunofluorescence staining and quantitative polymerase chain reaction. Oxidative stress and apoptosis were measured by flow cytometry. Hypertrophy was measured by hematoxylin and eosin (H&E) and crystal violet staining. A significant increase in SGLT1 expression was observed in HG- and PA-treated cardiomyocytes. Also, a significant increase in reactive oxygen species generation and apoptosis was observed in HG+PA-treated cultured cardiomyocytes. HG- and PA-treated cardiomyocytes developed significant structural alterations. All these effects of HG and PA were attenuated by CANA and DAPA. In conclusion, our study demonstrates upregulation of SGLT1 induces oxidative stress and apoptosis in cultured cardiomyocytes. Thus, inhibition of SGLT1 may be used as a possible approach for the treatment of CVD in diabetic patients.

15.
Curr Med Res Opin ; 38(5): 811-825, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35253560

RESUMO

Acute pain is among the most common reasons that people consult primary care physicians, who must weigh benefits versus risks of analgesics use for each patient. Paracetamol (acetaminophen) is a first-choice analgesic for many adults with mild to moderate acute pain, is generally well tolerated at recommended doses (≤4 g/day) in healthy adults and may be preferable to non-steroidal anti-inflammatory drugs that are associated with undesirable gastrointestinal, renal, and cardiovascular effects. Although paracetamol is widely used, many patients and physicians still have questions about its suitability and dosing, especially for older people or adults with underlying comorbidities, for whom there are limited clinical data or evidence-based guidelines. Inappropriate use may increase the risks of both overdosing and inadequate analgesia. To address knowledge deficits and augment existing guidance in salient areas of uncertainty, we have researched, reviewed, and collated published evidence and expert opinion relevant to the acute use of paracetamol by adults with liver, kidney, or cardiovascular diseases, gastrointestinal disorders, asthma, or/and who are older. A concern is hepatotoxicity, but this is rare among adults who use paracetamol as directed, including people with cirrhotic liver disease. Putative epidemiologic associations of paracetamol use with kidney or cardiovascular disease, hypertension, gastrointestinal disorders, and asthma largely reflect confounding biases and are of doubtful relevance to short-term use (<14 days). Paracetamol is a suitable first-line analgesic for mild to moderate acute pain in many adults with liver, kidney or cardiovascular disease, gastrointestinal disorders, asthma, and/or who are older. No evidence supports routine dose reduction for older people. Rather, dosing for adults who are older and/or have decompensated cirrhosis, advanced kidney failure, or analgesic-induced asthma that is known to be cross-sensitive to paracetamol, should be individualized in consultation with their physician, who may recommend a lower effective dose appropriate to the circumstances.


Assuntos
Dor Aguda , Analgésicos não Narcóticos , Asma , Doenças Cardiovasculares , Gastroenteropatias , Acetaminofen/efeitos adversos , Dor Aguda/tratamento farmacológico , Adulto , Idoso , Analgésicos , Analgésicos não Narcóticos/efeitos adversos , Asma/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/tratamento farmacológico , Humanos , Rim , Fígado
16.
NPJ Vaccines ; 7(1): 31, 2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35236842

RESUMO

COVID-19 vaccines are effective and important to control the ongoing pandemic, but vaccine reactogenicity may contribute to poor uptake. Analgesics or antipyretic medications are often used to alleviate vaccine side effects, but their effect on immunogenicity remains uncertain. Few studies have assessed the effect of analgesics/antipyretics on vaccine immunogenicity and reactogenicity. Some studies revealed changes in certain immune response parameters post-vaccination when analgesics/antipyretics were used either prophylactically or therapeutically. Still, there is no evidence that these changes impact vaccine efficacy. Specific data on the impact of analgesic/antipyretic medications on immunogenicity of COVID-19 vaccines are limited. However, available data from clinical trials of licensed vaccines, along with recommendations from public health bodies around the world, should provide reassurance to both healthcare professionals and vaccine recipients that short-term use of analgesics/antipyretics at non-prescription doses is unlikely to affect vaccine-induced immunity.

17.
AAPS PharmSciTech ; 23(2): 70, 2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35132496

RESUMO

Oral cancer is one of the most common malignancies with an increased rate of incidence. 5-Fluorouracil (5FU) is an effective chemotherapeutic indicated for oral cancer treatment. Etodolac (Et), a cyclooxygenase-2 inhibitor, can be used as an adjuvant agent to sensitize cancer cells to chemotherapy. The aim of this work was to prepare and characterize 5FU and Et dual drug-loaded transfersomes to treat oral cancer. Transfersomes were prepared by thin-film hydration method and characterized for the average particle size and zeta-potential using dynamic light scattering and scanning electron microscopy techniques. The prepared transfersomes were further characterized for their drug loading, entrapment efficiencies using amicon centrifuge tubes and drug release behavior using cellulose membrane. The synergistic activity of dual drug-loaded transfersomes was studied in FaDu oral cancer cells. Results showed that the average particle size, polydispersity index, and zeta potential were 91±6.4 nm, 0.28±0.03, and (-)46.9±9.5 mV, respectively, for 5FU- and Et (1:1)-loaded transfersomes. The highest encapsulation efficiency achieved was 36.9±3.8% and 79.8±6.4% for 5FU and Et (1:1), respectively. Growth inhibition studies in FaDu cells using different concentrations of 5FU and Et showed a combination index of 0.36, indicating a synergistic effect. The FaDu cell uptake of drug-loaded transfersomes was significantly (p<0.05) greater than that of free drugs. The transfersome hydrogel made of HPMC (2% w/w) showed similar flux, lag time, and permeation coefficient as that of drug-loaded transfersomes across excised porcine buccal tissue. In conclusion, 5FU and Et transfersome hydrogel can be developed for localized delivery to treat oral cancer.


Assuntos
Etodolac , Neoplasias Bucais , Administração Cutânea , Animais , Portadores de Fármacos , Fluoruracila , Hidrogéis , Lipossomos , Neoplasias Bucais/tratamento farmacológico , Tamanho da Partícula , Suínos
18.
IEEE Trans Nanobioscience ; 21(1): 97-104, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34170829

RESUMO

Herein, a continuous-flow driven microfluidic device has been designed and fabricated using the CO2 laser ablation method for polymerase chain reaction (PCR). The device consists of a polymethyl methacrylate (PMMA) microfluidic channel with 30 serpentine thermal cycles, an arduino board, two custom-made cartridge heaters, and thermocouple sensors. The portable thermal management system, with aluminium blocks placed on a wooden substrate, working on the PID controller principle, is low-cost, battery-powered, automated, integrated, and IoT-enabled. The device with dimensions 80×72×36 mm3 (L × W × H) has a temperature accuracy of ±0.2 °C. The IoT module enables accessing and storage of real-time temperature values directly onto the smartphone through ThingSpeak analytics. It was developed to achieve desirable accurate temperature at two thermal zones, denaturation and annealing (95 °C and 60 °C) on the microfluidic thermal management platform. A PCR mixture of [Formula: see text] was infused into the serpentine-based microchannel using a syringe pump. Amplification of DNA template with 594-base pair (bp) fragment of the rat GAPDH gene was successfully performed on the miniaturized thermal management system. The total time required for a complete PCR reaction was 32 min at an optimum flow rate of [Formula: see text]/min. The amplified sample of the target DNA obtained from the PCR microchannel was then separated by agarose gel electrophoresis and was further analyzed using a gel-doc system. Finally, the obtained results were compared to the conventional PCR instrument showing excellent performance.


Assuntos
Dispositivos Lab-On-A-Chip , Técnicas Analíticas Microfluídicas , Animais , DNA/genética , Microfluídica , Reação em Cadeia da Polimerase , Ratos
19.
J Cancer Res Ther ; 17(6): 1547-1551, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34916393

RESUMO

BACKGROUND: The medicinal properties of Syzygium sp., especially the antidiabetic property, date back to the ancient times. However, in the recent past, extracts from different parts of the Syzygium sp. have demonstrated promising anticancer activities in diverse cancer types, and now, attempts are being made to identify the active phytochemicals. AIMS AND OBJECTIVES: In this study, we intended to test the anticancer properties of phytochemicals extracted from the fruit of Syzygium cumini plant in ovarian cancer cells. MATERIALS AND METHODS: A total of nine phytochemicals extracted from the S. cumini fruits using chloroform were tested for their anticancer activity in the ovarian cancer cell line PA-1. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium assay was performed to calculate the 50% inhibition (IC50) concentration and cell cytotoxicity values. Cell scratch assay was performed to assess the proliferation inhibition activity of the phytochemicals. Cisplatin was used as positive control. RESULTS: Out of the nine phytochemicals tested, quercetin (QC), gallic acid (GA), and oleanolic acid (OA) were found active. QC and GA were most effective with more than 90% cell cytotoxicity at 2.5 µ g/ml and above concentrations and OA moderately effective up to 5 µg/ml serial concentrations. Cell proliferation was significantly inhibited by QC and GA and moderately but significantly by OA. CONCLUSION: Our data demonstrate the anticancer activity of QC, GA, and OA phytochemicals, which is consistent with the previous reports. However, this is the first report showing the anticancer activity of these phytochemicals derived from S. cumini in the ovarian cancer cells. These data suggest that there is a potential to develop these phytochemicals as anticancer therapeutic agents either as monotherapeutic agents or in combination with commonly used chemotherapeutic agents, which needs to be explored.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Syzygium/química , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Frutas/química , Humanos , Neoplasias Ovarianas/patologia , Ratos
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