RESUMO
Background: Diabetes is a degenerative disease associated with metabolic disorders. The majority of people have type 2 diabetes mellitus (DM) insulin resistance due to an unhealthy lifestyle. The development of DM treatment is also growing, one of which is using conditioned medium. Aim: This study aims to determine the effect of Bovine umbilical mesenchymal stem cell-conditioned medium (BUMSC-CM) on nicotinamide (NA) and streptozotocin (STZ) induced rats as an animal model of DM. Methods: The study began with the in vitro docking of Cholecalciferol with aldolase reductase and glucokinase. In the in vivo study, animal models were divided into five groups: group A (negative control), group B (diabetic rats), group C (NA+STZ+Metformin), group D (NA+STZ+ BUMSC-CM 0.2 ml/kg BW), and group E (NA+STZ+ BUMSC-CM 0.5 ml/kg BW). Blood sugar levels were checked, and BUMSC-CM was administered by intramuscular injection at four-day intervals for a duration of 16 days. Blood sugar levels were also sampled, and GLUT4 histochemical and immunohistochemical staining was performed. Results: The results showed that Cholecalciferol can bind to aldolase reductase ASP43 and TYR48 and bind to glucokinase at TYR214 with hydrogen bonds. BUMSC-CM administration was able to reduce blood sugar well. In addition, BUMSC-CM also helped repair the tissue structure of the pancreas damaged by inflammation from STZ administration. Conclusion: This study can be concluded that the administration of BUMSC-CM can be an alternative cell-free therapy for patients with DM.
Assuntos
Diabetes Mellitus Experimental , Transportador de Glucose Tipo 4 , Células-Tronco Mesenquimais , Niacinamida , Estreptozocina , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Niacinamida/farmacologia , Niacinamida/administração & dosagem , Ratos , Células-Tronco Mesenquimais/efeitos dos fármacos , Bovinos , Meios de Cultivo Condicionados/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos WistarRESUMO
INTRODUCTION: Obesity is a chronic noncommunicable disease characterized by excessive body fat that can have negative health consequences. Obesity is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. It is characterized by a discrepancy between caloric intake and expenditure. Obesity increases the risk of acquiring major chronic diseases, including heart disease, stroke, cancer, and Type 2 diabetes mellitus (T2DM). Currently, the inhibition of pancreatic lipases (PL) is a promising pharmacological therapy for obesity and weight management. In this study, the inhibition of pancreatic lipase by Cannabis sativa (C. sativa) plant extract and cannabinoids was investigated. METHODS: The inhibitory effect was assessed using p-nitrophenyl butyrate (pNPB), and the results were obtained by calculating the percentage relative activity and assessed using one-way analysis of variance (ANOVA). Kinetic studies and spectroscopy techniques were used to evaluate the mode of inhibition. Diet-induced; and diabetic rat models were studied to evaluate the direct effects of C. sativa extract on PL activity. RESULTS: Kinetic analyses showed that the plant extracts inhibited pancreatic lipase, with tetrahydrocannabinol (THC) and cannabinol (CBN) being the potential cause of the inhibition noted for the C. sativa plant extract. CBN and THC inhibited the pancreatic lipase activity in a competitive manner, with the lowest residual enzyme activity of 52â¯% observed at a 10⯵g/mL concentration of CBN and 39â¯% inhibition at a 25⯵g/mL concentration of THC. Circular dichroism (CD) spectroscopy revealed that the inhibitors caused a change in the enzyme's secondary structure. At low concentrations, THC showed potential for synergistic inhibition with orlistat. C.sativa treatment in an in vivo rat model confirmed its inhibitory effects on pancreatic lipase activity. CONCLUSION: The findings in this study provided insight into the use of cannabinoids as pancreatic lipase inhibitors and the possibility of using these compounds to develop new pharmacological treatments for obesity.
Assuntos
Canabinoides , Cannabis , Lipase , Obesidade , Pâncreas , Extratos Vegetais , Ratos Wistar , Animais , Cannabis/química , Lipase/antagonistas & inibidores , Lipase/metabolismo , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Canabinoides/farmacologia , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Masculino , Ratos , Extratos Vegetais/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/enzimologia , Dronabinol/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Dieta Hiperlipídica/efeitos adversosRESUMO
In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of the tumor mass. Pancreatitis, characterized by the increased infiltration of macrophages into the pancreas, is a known risk factor for pancreatic cancer. The NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor regulates responses to oxidative stress and can promote cancer and chemoresistance. NRF2 also attenuates inflammation through the regulation of macrophage-specific genes. Heme oxygenase 1 (HO-1) is expressed by anti-inflammatory macrophages to degrade heme, and its expression is dependent on NRF2 translocation to the nucleus. In macrophages stimulated with conditioned media from pancreatic cancer cells, HO-1 protein levels increased, which correlated with higher NRF2 expression in the nuclear fraction. Significant differences in macrophage infiltration and HO-1 expression were detected in LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice and wildtype mice with pancreatitis. Since epigenetic modulation is a mechanism used by tumors to regulate the TME, using small molecules as epigenetic modulators to activate immune recognition is therapeutically desirable. When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.
Assuntos
Heme Oxigenase-1 , Macrófagos , Fator 2 Relacionado a NF-E2 , Neoplasias Pancreáticas , Fatores de Transcrição , Animais , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/genética , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/efeitos dos fármacos , Humanos , Pancreatite/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/genética , Camundongos Knockout , Microambiente Tumoral/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Proteínas que Contêm Bromodomínio , Proteínas de Membrana , Proteínas NuclearesRESUMO
Oleuropein (OLP) is a naturally occurring phenolic compound in olive plant with antioxidant and anti-inflammatory potential and can possibly be used in treating pancreatic injuries. This investigation aimed to follow the molecular mechanism behind the potential therapeutic effect of OLP against pancreatic injury persuaded by ischemia-reperfusion (I/R). Pancreatic I/R injury was induced by splenic artery occlusion for 60 min followed by reperfusion. Oral administration of OLP (10 and 20 mg/kg) for 2 days significantly alleviated I/R-persuaded oxidative damage and inflammatory responses in pancreatic tissue as indicated by the decreased malondialdehyde (MDA) content and increased glutathione peroxidase (GPx) activity, accompanied by the suppression of myeloperoxidase (MPO) activity and reduced levels of interleukin-1beta (IL-1ß), nuclear factor kappa B (NF-κB), and tumor necrosis factor alpha (TNF-α) in pancreatic tissues. Furthermore, OLP treatment markedly restored the serum levels of amylase, trypsinogen-activated peptide (TAP), and lipase, with concurrent improvement in pancreatic histopathological alterations. Moreover, treatment with OLP regulated the pancreatic expression of inducible nitric oxide synthase (iNOS) and high-mobility group box 1 (HMGB1) relative to rats of the pancreatic IR group. Thus, OLP treatment significantly alleviates the I/R-induced pancreatic injury by inhibiting oxidative stress and inflammation in rats through downregulation of HMGB1 and its downstream NF-κB signaling pathway.
Assuntos
Proteína HMGB1 , Glucosídeos Iridoides , Iridoides , NF-kappa B , Estresse Oxidativo , Pâncreas , Traumatismo por Reperfusão , Transdução de Sinais , Animais , Glucosídeos Iridoides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteína HMGB1/metabolismo , NF-kappa B/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Ratos , Iridoides/farmacologia , Iridoides/uso terapêutico , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Masculino , Transdução de Sinais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Ratos Sprague-Dawley , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
Severe acute pancreatitis (SAP) is an inflammatory disease with varying severity, ranging from mild local inflammation to severe systemic disease, with a high incidence rate and mortality. Current drug treatments are not ideal. Therefore, safer and more effective therapeutic drugs are urgently needed. 7α,14ß-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione DGA, a diterpenoid compound derivatized from glaucocalyxin A, exhibits anti-inflammatory activity. In this study, we demonstrated the therapeutic potential of DGA against SAP and elucidated the underlying mechanisms. Treatment with DGA markedly (1) inhibited death of RAW264.7 and J774a.1 cells induced by Nigericin and lipopolysaccharide, (2) alleviated edema, acinar cell vacuolation, necrosis, and inflammatory cell infiltration of pancreatic tissue in mice, and (3) inhibited the activity of serum lipase and the secretion of inflammatory factor IL-1ß. DGA significantly reduced the protein expression of IL-1ß and NLRP3 and inhibited the phosphorylation of NF-κB. However, DGA exhibited no inhibitory effect on the expression of caspase-1, gasdermin D (GSDMD), NF-κB, TNF-α, or apoptosis-associated speck-like protein (ASC) and on the cleavage of caspase-1 or GSDMD. Molecular docking simulation confirmed that DGA can bind to TLR4 and IL-1 receptor. In conclusion, DGA may effectively alleviate the symptoms of SAP in mice and macrophages by inhibiting the binding of TLR4 and IL-1 receptor to their ligands; therefore, DGA is a promising drug candidate for the treatment of patients with SAP.
Assuntos
Macrófagos , Pancreatite , Piroptose , Animais , Piroptose/efeitos dos fármacos , Camundongos , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Pancreatite/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Células RAW 264.7 , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Camundongos Endogâmicos C57BL , Interleucina-1beta/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Receptor 4 Toll-Like/metabolismo , NF-kappa B/metabolismo , Lipopolissacarídeos , Simulação de Acoplamento Molecular , Linhagem Celular , Lipase/metabolismoRESUMO
Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully understood and causal treatment options are not available. Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato-protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato-protective effect better than each drug alone. Thus, the current study examines the pancreato-protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild-type (WT) and Hpa over-expressing (Hpa-Tg) mice. Cerulein-induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa-Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti-Hpa drug combinations constitute a novel therapy for this common orphan disease.
Assuntos
Glucuronidase , Pancreatite , Animais , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Camundongos , Glucuronidase/metabolismo , Glucuronidase/antagonistas & inibidores , Trealose/farmacologia , Trealose/uso terapêutico , Ceruletídeo , Aspirina/farmacologia , Aspirina/uso terapêutico , Modelos Animais de Doenças , Doença Aguda , Autofagia/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/enzimologia , Masculino , Camundongos Transgênicos , Lipase/metabolismo , Lipase/antagonistas & inibidores , Amilases/sangue , Camundongos Endogâmicos C57BL , SaponinasRESUMO
Herbs have been used as medicines since antiquity, and it has been discovered that the human body responds well to herbal remedies. Research on the effect of butin was conducted in the current study in the alloxan-induced diabetic rat paradigm. A total of 30 Wistar rats were randomly assigned into the following groups (n = 6): I-Normal; II-Alloxan-induced (50 mg/kg); III-Alloxan + butin 25 mg/kg; IV-Alloxan + butin 50 mg/kg; V-Butin per se 50 mg/kg. Various diabetic parameters (blood glucose, insulin, HbA1c), lipid profile, inflammatory (TNF-α, IL-1ß, IL-6 and NF-κB), antioxidant enzymes (CAT, SOD and GSH), oxidative stress indicators (MDA), apoptosis marker (caspase-3), hepatic markers (ALT and AST), and histopathological changes were assessed. Additionally, molecular docking and dynamics were performed to evaluate the interaction of butin with target proteins. Butin treatment, at both doses, significantly restored biochemical parameters and preserved pancreatic histopathology in diabetic rats. It effectively modulated blood parameters, lipid profiles, inflammatory markers, apoptosis, antioxidant enzyme activity, oxidative stress, and hepatic markers. Molecular docking revealed that butin binds to proteins such as caspase-3 (1NME), NF-κB (1SVC), and serum insulin (4IBM) with binding affinities of - 7.4, - 6.5, and - 8.2 kcal/mol, respectively. Molecular dynamics simulations further suggested that butin induces significant conformational changes in these proteins. Butin exhibits potential effects against alloxan-induced diabetic rats by restoring biochemical balance, reducing inflammation, and protecting pancreatic tissue. Its binding to key proteins involved in apoptosis and inflammation highlights its therapeutic potential in diabetes management.
Assuntos
Aloxano , Diabetes Mellitus Experimental , Simulação de Acoplamento Molecular , Ratos Wistar , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Ratos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Glicemia/metabolismo , Pâncreas/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Apoptose/efeitos dos fármacos , Insulina/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Simulação de Dinâmica MolecularRESUMO
Pharmacological studies proved that Commelina diffusa Burm.f. performs various biological activities. Nevertheless, the scientific evidence supporting the hypoglycemic activities of this medicinal plant is insufficient. Thus, this study aims to assess the acute toxicity and the antidiabetic activity of the ethyl acetate fraction of Commelina diffusa (CD.EAF) in type 2 diabetic mice model induced by a high-fat diet and streptozotocin injection. The oral acute toxicity assessment was conducted following Lorke's method. The in vivo study was conducted by feeding Swiss male mice with a high-fat diet for 8 weeks and giving them a single intraperitoneal injection of streptozotocin at 100mg/kg. When the experimental mice model was successfully induced, the CD.EAF at 100mg/kg/day and 300mg/kg/day doses were orally administered to animals for 14 days. After the treatment period, the repeated daily administration of the CD.EAF at both tested doses exposed significant antihyperglycemic activities in comparison with the untreated diabetic group (p<0.05). However, it did not affect the serum lipid levels of mice. Besides, there were significant ameliorations in the histopathological images of the liver and pancreas in mice treated with the CD.EAF. Our findings suggested that the CD.EAF might be a potential agent for drug development to prevent and treat type 2 diabetes.
Assuntos
Acetatos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Hipoglicemiantes , Extratos Vegetais , Estreptozocina , Animais , Masculino , Hipoglicemiantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Camundongos , Extratos Vegetais/farmacologia , Acetatos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Testes de Toxicidade AgudaRESUMO
The unsustainable use of manmade chemicals poses significant threats to biodiversity and human health. Emerging evidence highlights the potential of certain chemicals to cause transgenerational impacts on metabolic health. Here, we investigate male transmitted epigenetic transgenerational effects of the anti-androgenic herbicide linuron in the pancreas of Xenopus tropicalis frogs, and their association with metabolic phenotypes. Reduced representation bisulfite sequencing (RRBS) was used to assess genome-wide DNA methylation patterns in the pancreas of adult male F2 generation ancestrally exposed to environmentally relevant linuron levels (44 ± 4.7 µg/L). We identified 1117 differentially methylated regions (DMRs) distributed across the X. tropicalis genome, revealing potential regulatory mechanisms underlying metabolic disturbances. DMRs were identified in genes crucial for pancreatic function, including calcium signalling (clstn2, cacna1d and cadps2), genes associated with type 2 diabetes (tcf7l2 and adcy5) and a biomarker for pancreatic ductal adenocarcinoma (plec). Correlation analysis revealed associations between DNA methylation levels in these genes and metabolic phenotypes, indicating epigenetic regulation of glucose metabolism. Moreover, differential methylation in genes related to histone modifications suggests alterations in the epigenetic machinery. These findings underscore the long-term consequences of environmental contamination on pancreatic function and raise concerns about the health risks associated with transgenerational effects of pesticides.
Assuntos
Metilação de DNA , Epigênese Genética , Pâncreas , Fenótipo , Xenopus , Animais , Metilação de DNA/efeitos dos fármacos , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Epigênese Genética/efeitos dos fármacos , Linurona/toxicidade , Herbicidas/toxicidade , Praguicidas/toxicidadeRESUMO
OBJECTIVES: To determine the metabolic effects of tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF) in vivo . DESIGN AND METHODS: Male Wistar rats ( Rattus novergicus , 250-300âg body weight) were divided into three groups ( n â=â8) and orally treated daily with 1.0âml distilled water (group 1), TAF (0.42âmg/kg) (group 2), or TDF (5.0âmg/kg) (group 3), respectively, for 56âdays. Glucose tolerance tests were done before the animals were sacrificed by halothane overdose, and blood was collected by cardiac puncture for the analysis of plasma lipids, electrolytes, and insulin. The kidney and pancreatic tissues were excised and homogenized to measure oxidative stress. Compartmentation of TAF and TDF was determined in NRK-52 and peripheral blood mononuclear cells (PBMCs). RESULTS: There were no significant differences in weight gain among controls, TAF- or TDF-treated rats. TAF-treated rats had significantly increased fasting blood glucose (FBG), fasting plasma insulin (FPI), insulin resistance, impaired glucose tolerance, and dyslipidemia compared to control or TDF-treated rats, respectively. There was increased lipid peroxidation in the pancreas of TAF-treated compared to TDF-treated or control animals, respectively. TDF- treated rats presented with symptoms of Fanconi syndrome compared to TAF-treated or control animals, respectively. Kidney homogenates from TDF-treated animals had significantly reduced antioxidant enzyme activity compared to TAF-treated animals or controls, respectively. Intracellular concentrations of TAF were significantly higher than TDF in both NRK-52E cells and PBMC, respectively. CONCLUSIONS: TAF treatment is weight-neutral and causes dysglycemia, and dyslipidemia but not Fanconi syndrome compared to TDF.
Assuntos
Adenina , Dislipidemias , Ratos Wistar , Tenofovir , Animais , Tenofovir/análogos & derivados , Masculino , Dislipidemias/induzido quimicamente , Adenina/análogos & derivados , Adenina/efeitos adversos , Adenina/farmacologia , Ratos , Alanina , Fármacos Anti-HIV , Teste de Tolerância a Glucose , Glicemia/análise , Rim/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here, we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a 1-day post-endoscopic retrograde cholangiopancreatography (ERCP) and a 2-day severe cerulein induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development.NEW & NOTEWORTHY Renalase is a secretory protein. The prosurvival and anti-inflammatory effects of the whole molecule are contained in a 20 aa renalase site (RP220). Systemic treatment with peptides containing this renalase site reduced the severity of post-endoscopic retrograde cholangiopancreatography (ERCP) and severe cerulein pancreatitis in mouse models.
Assuntos
Ceruletídeo , Camundongos Endogâmicos C57BL , Pancreatite , Animais , Pancreatite/prevenção & controle , Pancreatite/patologia , Masculino , Camundongos , Feminino , Modelos Animais de Doenças , Índice de Gravidade de Doença , Peptídeos/farmacologia , Pâncreas/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Anti-Inflamatórios/farmacologia , Quimases/metabolismo , MonoaminoxidaseRESUMO
Diabetic nephropathy (DN) is a progressive kidney disorder that develops as a complication of diabetes due to long-term exposure to elevated blood glucose levels (BGLs). In this case, an intervention of therapeutic moieties is needed to target the specific elements involved in diabetes to prevent/delay the deterioration of kidney function. Therefore, the present study focused on designing and evaluating a potent nano-formulation of a combination of C-peptide (CPep) and the anti-diabetic drug lisofylline (LSF) to prevent streptozotocin (STZ)-induced DN. As a strategic intervention, an LSF-oleic acid prodrug (LSF-OA) was initially synthesized and further encapsulated in an in-house-synthesized cationic polymer [(mPEG-b-P(CB-{g-DMDP}-co-LA)); mPLM] to prepare polymeric nano-complexes of CPep via electrostatic interaction, possessing a size of 218.6 ± 14.4 nm and zeta potential of +5.2 mV together with stability for 30 days at 25 °C. mPLM-LSF-OA-CPep nanoparticles demonstrated hemocompatibility with RBCs and exhibited potent anti-oxidant activity by reducing nitrite levels, inducing the release of anti-oxidant GSH and protecting metabolically stressed rat kidneys and murine insulinoma cells from apoptosis. In vivo pharmacokinetics depicted an increase in t½ and mean residence time in rats, which further improved the BGL and renal conditions and reduced plasma IL-6 and TNF-α levels in the STZ-induced DN animal model when treated with mPLM-LSF-OA-CPep compared to free LSF and CPep. Moreover, an increase in the plasma insulin level and detection of proliferative marker cells in pancreatic islets suggested the regeneration of ß-cells in diabetic animals.
Assuntos
Peptídeo C , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Rim , Nanopartículas , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/metabolismo , Ratos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Peptídeo C/sangue , Peptídeo C/química , Nanopartículas/química , Camundongos , Pâncreas/patologia , Pâncreas/metabolismo , Pâncreas/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Polímeros/química , Polímeros/farmacologia , Estreptozocina , Ratos Sprague-Dawley , Pentoxifilina/análogos & derivadosRESUMO
Caffeine, a controversial substance, was once known to be addictive and harmful. In recent years, new effects of caffeine on the human body have been confirmed. Recent research over the past few decades has shown the potential of caffeine in treating pancreas-related diseases. This review aims to analyze the known and possible mechanisms of caffeine on pancreatic diseases and provides an overview of the current research status regarding the correlation between caffeine and pancreatic disease, while enhancing our understanding of their relationship.
Assuntos
Cafeína , Pancreatopatias , Humanos , Cafeína/farmacologia , Pancreatopatias/tratamento farmacológico , Animais , Pâncreas/efeitos dos fármacosRESUMO
Inhibition of pancreatic lipase (PL) is a strategy to prevent obesity. The inhibitory effects of Flos Sophorae Immaturus (FSI) extract and its main flavonoid components, rutin and quercetin, on PL were investigated. The contents of rutin and quercetin in FSI extract were 44.10 ± 1.33 % and 6.07 ± 1.62 %, respectively. The IC50 values of FSI extract, rutin and quercetin on PL were 322, 258 and 71 µg/mL, respectively. Rutin and quercetin inhibited PL in a reversible and noncompetitive manner. The combination of rutin and quercetin exhibited synergistic inhibitory effects at low concentration. The binding of rutin/quercetin with PL caused the fluorescence quenching of protein. Fluorescence titration showed the binding affinity of quercetin with PL protein was stronger than that of rutin. Circular dichroism analysis showed the binding changed the secondary structure of PL with an increase in random coil and a decrease in α-Helix and ß-Sheet. Molecular docking revealed that rutin and quercetin could interact with the amino acid residues around the catalytic site through multiple secondary interactions. In vivo studies showed that FSI extract can reduce fat absorption and promote fecal fat excretion through inhibition of PL activity, and the effects were mainly due to rutin and quercetin.
Assuntos
Flavonoides , Lipase , Simulação de Acoplamento Molecular , Pâncreas , Extratos Vegetais , Quercetina , Rutina , Lipase/antagonistas & inibidores , Lipase/metabolismo , Lipase/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Quercetina/farmacologia , Quercetina/química , Pâncreas/enzimologia , Pâncreas/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/química , Rutina/farmacologia , Rutina/química , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Masculino , Sophora/químicaRESUMO
OBJECTIVE: It was targeted to assess the efficacy of certolizumab on pancreas and target organs via biochemical parameters and histopathologic scores in experimental acute pancreatitis (AP). MATERIALS AND METHODS: Forty male Sprague Dawley rats were divided into the following 5 equal groups: group 1 (sham group), group 2 (AP group), group 3 (AP + low-dose certolizumab group), group 4 (AP + high-dose certolizumab group), and group 5 (placebo group). Rats in all groups were sacrificed 24 hours after the last injection and amylase, tumor necrosis factor α, transforming growth factor ß, interleukin 1ß, malondialdehyde, superoxide dismutase, and glutathione peroxidase levels were studied in blood samples. Histopathological investigation of both the pancreas and target organs (lungs, liver, heart, kidneys) was performed by a pathologist blind to the groups. In silico analysis were also accomplished. RESULTS: The biochemical results in the certolizumab treatment groups were identified to be significantly favorable compared to the AP group (P < 0.001). The difference between the high-dose group (group 4) and low-dose treatment group (group 3) was found to be significant in terms of biochemical parameters and histopathological scores (P < 0.001). In terms of the effect of certolizumab treatment on the target organs (especially on lung tissue), the differences between the low-dose treatment group (group 3) and high-dose treatment group (group 4) with the AP group (group 2) were significant. CONCLUSIONS: Certolizumab has favorable protective effects on pancreas and target organs in AP. It may be a beneficial agent for AP treatment and may prevent target organ damage.
Assuntos
Amilases , Pulmão , Pâncreas , Pancreatite , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa , Animais , Masculino , Pancreatite/prevenção & controle , Pancreatite/induzido quimicamente , Pancreatite/patologia , Pancreatite/tratamento farmacológico , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/metabolismo , Amilases/sangue , Doença Aguda , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/sangue , Certolizumab Pegol/farmacologia , Malondialdeído/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Superóxido Dismutase/metabolismo , Glutationa Peroxidase/metabolismo , Miocárdio/patologia , Miocárdio/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ratos , Modelos Animais de Doenças , Estresse Oxidativo/efeitos dos fármacosRESUMO
In recent years, the worldwide epidemic of metabolic diseases, namely obesity, metabolic syndrome, diabetes and metabolic-associated fatty liver disease (MAFLD) has been strongly associated with constant exposure to endocrine-disruptive chemicals (EDCs), in particular, the ones able to disrupt various metabolic pathways. EDCs have a negative impact on several human tissues/systems, including metabolically active organs, such as the liver and pancreas. Among their deleterious effects, EDCs induce mitochondrial dysfunction and oxidative stress, which are also the major pathophysiological mechanisms underlying metabolic diseases. In this narrative review, we delve into the current literature on EDC toxicity effects on the liver and pancreatic tissues in terms of impaired mitochondrial function and redox homeostasis.
Assuntos
Disruptores Endócrinos , Fígado , Mitocôndrias , Estresse Oxidativo , Pâncreas , Humanos , Estresse Oxidativo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Disruptores Endócrinos/toxicidade , Animais , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologiaRESUMO
Diabetes mellitus, as a chronic metabolic disorder, significantly impacts the pancreas and among other organs, affects duodenal function. Emerging evidence suggests that probiotics can exert beneficial effects on gut health and metabolism. In our previous research, we evaluated the probiotic Lactobacillus paraplantarum BGCG11 primarily for its protective properties against diabetic rats' damaged liver and kidneys. In this work, we further examined the effects of probiotic strain BGCG11 on the function of the duodenum and pancreas in diabetic rats. We explored the potential mechanisms underlying the probiotic's effects, focusing on general indicators of diabetes, the architecture and morphology of pancreatic islets, duodenal integrity (measuring the transfer of fluid and serum zonulin level), and the modulation of gut microbiota composition. Our findings reveal the protective and regulatory roles of L. paraplantarum BGCG11 in mitigating diabetes-induced pancreatic and duodenal dysfunction regardless of its application time (pre- or post-treatment), highlighting its therapeutic potential in managing diabetes-related gastrointestinal complications.
Assuntos
Diabetes Mellitus Experimental , Duodeno , Microbioma Gastrointestinal , Lactobacillus , Pâncreas , Probióticos , Animais , Probióticos/farmacologia , Duodeno/microbiologia , Duodeno/metabolismo , Ratos , Diabetes Mellitus Experimental/terapia , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/metabolismo , Pâncreas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacosRESUMO
Polygonatum sibiricum polysaccharide (PSP) was extracted and purified from raw material obtained from P. sibiricum. The structural features of PSP were investigated by Congo red, circular dichroism spectrum, high-performance gel permeation chromatography, scanning electron microscope, atomic force microscope, ultraviolet spectroscopy, and Fourier transform infrared spectroscopy analysis. In vitro simulations were conducted to investigate the kinetics of PSP enzyme inhibition. Moreover, a type II diabetes mouse model (T2DM) with streptozotocin-induced insulin resistance was established, and the indexes of lipid quadruple, insulin resistance index, oral glucose tolerance (OGTT), organ index, and pancreatic morphology of model mice were measured. The results showed that PSP mainly consists of monosaccharides, such as mannose, glucose, galactose, xylose, and arabinose. It also has a ß-glycosidic bond of a pyranose ring and an irregular reticulated aggregated structure with a triple helix. In vitro enzyme inhibition assays revealed that PSP acts as a reversible competitive inhibitor of α-glucosidase and α-amylase. Furthermore, PSP was found to reduce insulin resistance index, increase OGTT and serum insulin levels, decrease free fatty acid content to improve lipid metabolism, and lower glycated serum protein content to enhance glucose metabolism in T2DM mice, thereby leading to a reduction in blood glucose concentration. Additionally, PSP exhibited reparative effects on the damaged liver tissue cells and pancreatic tissue in T2DM mice. The experiment results provide a preliminary basis for the therapeutic mechanism of PSP about type II diabetes and a theoretical reference for application in food and pharmaceutical development.
Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Resistência à Insulina , Polygonatum , Polissacarídeos , Animais , Polygonatum/química , Polissacarídeos/farmacologia , Polissacarídeos/química , Camundongos , Hipoglicemiantes/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Espectroscopia de Infravermelho com Transformada de Fourier/métodosRESUMO
Type 2 diabetes (T2D) is a serious health problem, and its prevalence is expected to increase worldwide in the years ahead. Cruciferous vegetables such as Brassica oleracea var. capitata L. (green cabbage) and Raphanus sativus L. (radish) have therapeutic properties that can be used to support the treatment of T2D. This study evaluated the effect of B. oleracea (BAE) and R. sativus (RAE) aqueous extracts on zoometric parameters, glycemic profiles, and pancreas and liver in prediabetic rats induced by a high-sucrose diet (HSD). BAE and RAE were administered to male HSD-induced Wistar rats (n = 35) at 5 and 10 mg/kg doses for 5 weeks. Zoometric and biochemical changes were measured, and then the pancreas and liver histological preparations were analyzed to observe the protective effect. BAE decreased feed intake and weight gain. Both extracts decreased fasting glucose and insulin levels compared with control (not treated), although not significantly (P > .05). The extracts significantly (P < .05) reduced homeostatic model assessment for insulin resistance, homeostasis model assessment of ß-cell function, and glucose intolerance, similar to metformin control. In addition, minor damage occurred in the pancreas and liver. The results indicated that BAE and RAE decreased weight gain, improved glucose regulation, and protected the pancreas and liver in HSD rats. Therefore, they have multiple therapeutical properties and may be helpful in the prevention of T2D.