The effect of serum triglyceride levels and different lipid-lowering methods on the prognosis of hypertriglyceridemic acute pancreatitis: a single-center 12-year retrospective study by propensity score matching.

AIM: To investigate the impact of triglyceride on hypertriglyceridemic acute pancreatitis (HTG-AP) and different lipid-lowering methods on triglyceride-lowering efficiency and HTG-AP. METHODS: The patients with HTG-AP from January 2012 to December 2023 in Civil Aviation General Hospital were analyzed, retrospectively. Patients were divided and compared according to whether their triglycerides were below 5.56 mmol/L at 48 and 72 h of admission. The patients were divided into control group, insulin group, and low molecular weight heparin (LMWH)+bezafibrate group based on the different methods of lipid-lowering. Propensity score matching (PSM) was employed to balance the baseline characteristics. RESULTS: There was no correlation between the severity of HTG-AP and the triglyceride at admission. The incidence of severity, local complications, and persistent organ failure (POF) were significantly decreased in patients with 48-h and 72-h triglyceride attainment. Following PSM, the incidence of infectious pancreatic necrosis (IPN) (3.3% vs. 13.3%) was significantly reduced in insulin group compared with control group (p < .05). Compared with control group, LMWH + bezafibrate group had higher lipid reduction efficiency, and the incidence of IPN (0.9% vs. 10.1%) and POF (8.3% vs. 19.3%) was significantly decreased (p < .05). There was no significant difference in the efficiency of lipid-lowering, complications, and POF between LMWH + bezafibrate group and insulin group (p > .05). CONCLUSION: The severity of HTG-AP is not associated with the triglyceride levels at admission. However, rapid reduction of triglyceride levels can lower the incidence of local complications and respiratory failure. Compared with conservative treatment, insulin and LMWH + bezafibrate can both reduce the incidence of IPN in patients with HTG-AP.

Treatment in primary biliary cholangitis: Beyond ursodeoxycholic acid.

Primary biliary cholangitis (PBC) is a rare cholestatic immune-mediated liver disease. The clinical course varies from mild to severe, with a substantial group of patients developing cirrhosis within a decade. These patients are at risk of hepatocellular carcinoma, decompensation and liver failure. First line Ursodeoxycholic acid (UDCA) treatment improves the cholestatic surrogate markers, and was recently associated with a favorable survival free of liver transplantation, even in case of an incomplete biochemical response. However, despite adequate UDCA therapy, patients remain at risk of liver disease progression. Therefore, on-treatment multifactor-based risk stratification is necessary to identify patients in need of additional therapy. This requires a personalized approach; especially as recent studies suggest that complete biochemical normalization as most stringent response criterion might be preferred in selected patients to optimize their outcome. Today, stricter biochemical goals might actually be reachable with the addition of farnesoid X receptor or peroxisome proliferator-activated receptor agonists, or, in highly-selected cases, use of corticosteroids. Randomized controlled trials showed improvements in the key biochemical surrogate markers with the addition of these drugs, which have also been associated with improved clinical outcome. Considering this evolving PBC landscape, with more versatile treatment options and treatment goals, this review recapitulates the recent insight in UDCA therapy, the selection of patients with a residual risk of liver disease progression and the results of the currently available second line treatment options.

PIEZO1 as a new target for hyperglycemic stress-induced neuropathic injury: The potential therapeutic role of bezafibrate.

Hyperglycemic stress can directly lead to neuronal damage. The mechanosensitive ion channel PIEZO1 can be activated in response to hyperglycemia, but its role in hyperglycemic neurotoxicity is unclear. The role of PIEZO1 in hyperglycemic neurotoxicity was explored by constructing a hyperglycemic mouse model and a high-glucose HT22 cell model. The results showed that PIEZO1 was significantly upregulated in response to high glucose stress. In vitro experiments have shown that high glucose stress induces changes in neuronal cell morphology and membrane tension, a key mechanism for PIEZO1 activation. In addition, high glucose stress upregulates serum/glucocorticoid-regulated kinase-1 (SGK1) and activates PIEZO1 through the Ca2+ pool and store-operated calcium entry (SOCE). PIEZO1-mediated Ca2+ influx further enhances SGK1 and SOCE, inducing intracellular Ca2+ peaks in neurons. PIEZO1 mediated intracellular Ca2+ elevation leads to calcium/calmodulin-dependent protein kinase 2α (CaMK2α) overactivation, which promotes oxidative stress and apoptosis signalling through p-CaMK2α/ERK/CREB and ox-CaMK2α/MAPK p38/NFκB p65 pathways, subsequently inducing synaptic damage and cognitive impairment in mice. The intron miR-107 of pantothenic kinase 1 (PANK1) is highly expressed in the brain and has been found to target PIEZO1 and SGK1. The PANK1 receptor is activated by peroxisome proliferator-activated receptor α (PPARα), an activator known to upregulate miR-107 levels in the brain. The clinically used lipid-lowering drug bezafibrate, a known PPARα activator, may upregulate miR-107 through the PPARɑ/PANK1 pathway, thereby inhibiting PIEZO1 and improving hyperglycemia-induced neuronal cell damage. This study provides a new idea for the pathogenesis and drug treatment of hyperglycemic neurotoxicity and diabetes-related cognitive dysfunction.

Bezafibrate mitigates oxidized-low density lipoprotein (ox-LDL)-induced the attachment of monocytes to endothelial cells: An implication in atherosclerosis.

BACKGROUND: Oxidized forms of low-density lipoproteins (ox-LDL)-associated endothelial dysfunction and subsequent monocyte adhesion play an important role in the development of atherosclerosis (AS). Bezafibrate (BEZ) is a peroxisome proliferator-activated receptor (pan-PPAR) agonist licensed as a hypolipidemic drug. However, the effects of BEZ on endothelial dysfunction are less reported. OBJECTIVES: In this study, we aim to investigate the protective effects of BEZ on ox-LDL-challenged vascular endothelial cells to evaluate its potential value in treating AS. METHODS: Human aortic endothelial cells (HAECs) and THP-1 cells were used to establish an In Vitro AS model. Cell Counting Kit-8 (CCK-8) assay, Real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) were used to test the data. RESULTS: As expected, treatment with BEZ suppressed the expression of vascular endothelial growth factor A (VEGF-A), tissue factor (TF), Interleukin 12 (IL-12), tumor necrosis factor (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). BEZ was also found to inhibit ox-LDL-induced expression of the endothelial adhesion molecules vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HAECs. Correspondingly, BEZ prevented attachment of THP-1 monocytes to ox-LDL-incubated HAECs. Mechanically, BEZ was found to prevent NF-κB activation by reducing the levels of nuclear NF-κB p65 and inhibiting luciferase activity of NF-κB. CONCLUSION: Our study revealed the pharmacological function of BEZ in protecting endothelial dysfunction against ox-LDL, which may provide valuable insight for the clinical application of BEZ.

Bezafibrate alleviates diabetes-induced spermatogenesis dysfunction by inhibiting inflammation and oxidative stress.

The metabolic disorders caused by diabetes can lead to various complications, including male spermatogenesis dysfunction. Exploring effective therapeutics that attenuate diabetes mellitus (DM)-induced male subfertility is of great importance. Pharmaceuticals targeting PPARα activation such as bezafibrate have been regarded as an important strategy for patients with diabetes. In this study, we use streptozocin (STZ) injection to establish a type 1 DM mice model and use bezafibrate to treat DM mice and evaluate the effects of bezafibrate on the spermatogenic function of the DM male mice. Bezafibrate treatment exhibited protective effects on DM-induced spermatogenesis deficiency, as reflected by increased testis weight, improved histological morphology of testis, elevated sperm parameters, increased serum testosterone concentration as well as increased mRNA levels of steroidogenesis enzymes. Meanwhile, testicular cell apoptosis, inflammation accumulation and oxidative stress status were also shown to be alleviated by bezafibrate compared with the DM group. In vivo and in vitro studies, PPARα specific inhibitor and PPARα knockout mice were further used to investigate the role of PPARα in the protective effects of bezafibrate on DM-induced spermatogenesis dysfunction. Our results indicated that the protection of bezafibrate on DM-induced spermatogenesis deficiency was abrogated by PPARα inhibition or deletion. Our study suggested that bezafibrate administration could ameliorate DM-induced spermatogenesis dysfunction and may represent a novel practical strategy for male infertility.

Bezafibrate protects blood-brain barrier (BBB) integrity against traumatic brain injury mediated by AMPK.

Bezafibrate (BEZ) has displayed a wide range of neuroprotective effects in different types of neurological diseases. However, its pharmacological function in traumatic brain injury (TBI) is still unknown. In the current study, a TBI model was constructed in mice to examine the potential beneficial roles of BEZ. After TBI, mice were daily dieted with BEZ or vehicle solution. The motor function, learning and memory, brain edema, vascular inflammatory factors, the integrity of the blood-brain barrier (BBB), and the expression of the tight junction zona occludens 1 (ZO-1) were assessed. The findings demonstrate that after TBI, BEZ treatment significantly promoted the recovery of motor function and cognitive function deficits. Moreover, BEZ attenuated brain edema by reducing the levels of brain water content. We also found that administration of BEZ alleviated cerebral vascular pro-inflammation by suppressing the expression of ICAM-1, VCAM-1, and E-selectin. Notably, BEZ improved the impaired BBB integrity in TBI mice by restoring the expression of the tight junction (TJ) protein ZO-1. Further in vitro experiments show that treatment with BEZ prevented the aggravation of endothelial permeability and restored the reduction of trans-epithelial electrical resistance (TEER) as well as the expression of ZO-1 in TBI-exposed brain bEnd.3 cells. Mechanistically, we prove that the protective effects of BEZ are mediated by AMPK. Based on these findings, we conclude that BEZ improves TBI-induced BBB injury and it might be considered for the treatment or management of TBI.

Evaluating the safety and efficacy of seladelpar for adults with primary biliary cholangitis.

INTRODUCTION: Seladelpar (MBX-8025) is a once-daily administered highly specific PPAR-δ agonist in Phase 3 and extension trials for use in patients with primary biliary cholangitis (PBC). AREAS COVERED: This review provides background on current treatment options for PBC, and summarizes clinical trial data regarding the safety and effectiveness of seladelpar within the context of these treatments. EXPERT OPINION: Clinical trials results demonstrate the safety and tolerability of seladelpar use for PBC, including in patients with cirrhosis. The primary composite endpoint (ALP <1.67 times ULN, decrease ≥ 15% from baseline, and TB ≤ULN) was met in 61.7% of the patients treated with seladelpar and in 20% receiving placebo (p < 0.001). Moreover, pruritus - a cardinal and often intractable symptom of PBC - was improved with seladelpar treatment, as were overall quality of life measurements. Improvements in markers of inflammation were likewise observed. These biochemical and clinical findings therefore represent landmark developments in PBC treatment and offer a therapeutic option for PBC.

Critical shortfalls in the management of PBC: Results of a UK-wide, population-based evaluation of care delivery.

Background & Aims: Guidelines for the management of primary biliary cholangitis (PBC) were published by the British Society of Gastroenterology in 2018. In this study, we assessed adherence to these guidelines in the UK National Health Service (NHS). Methods: All NHS acute trusts were invited to contribute data between 1 January 2021 and 31 March 2022, assessing clinical care delivered to patients with PBC in the UK. Results: We obtained data for 8,968 patients with PBC and identified substantial gaps in care across all guideline domains. Ursodeoxycholic acid (UDCA) was used as first-line treatment in 88% of patients (n = 7,864) but was under-dosed in one-third (n = 1,964). Twenty percent of patients who were UDCA-untreated (202/998) and 50% of patients with inadequate UDCA response (1,074/2,102) received second-line treatment. More than one-third of patients were not assessed for fatigue (43%; n = 3,885) or pruritus (38%; n = 3,415) in the previous 2 years. Fifty percent of all patients with evidence of hepatic decompensation were discussed with a liver transplant centre (222/443). Appropriate use of second-line treatment and referral for liver transplantation was significantly better in specialist PBC treatment centres compared with non-specialist centres (p <0.001). Conclusions: Poor adherence to guidelines exists across all domains of PBC care in the NHS. Although specialist PBC treatment centres had greater adherence to guidelines, no single centre met all quality standards. Nationwide improvement in the delivery of PBC-related healthcare is required. Impact and implications: This population-based evaluation of primary biliary cholangitis, spanning four nations of the UK, highlights critical shortfalls in care delivery when measured across all guideline domains. These include the use of liver biopsy in diagnosis; referral practice for second-line treatment and/or liver transplant assessment; and the evaluation of symptoms, extrahepatic manifestations, and complications of cirrhosis. The authors therefore propose implementation of a dedicated primary biliary cholangitis care bundle that aims to minimise heterogeneity in clinical practice and maximise adherence to key guideline standards.

ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis.

Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC50. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.

BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

Impacto del tratamiento con bezafibrato en pacientes con hiperfibrinogenemia e infarto agudo del miocardio con elevación del ST / Impact of bezafibrate treatment in patients with hyperfibrinogenemia and ST-elevation acute myocardial infarction: a randomized clinical trial

Introducción: La hiperfibrinogenemia se considera predictora de eventos cardiovasculares en sujetos sanos y pacientes con cardiopatía isquémica. Como medida de prevención primaria, el bezafibrato disminuye el fibrinógeno sanguíneo y los eventos cardiovasculares, pero su efecto en el síndrome coronario agudo aún no se conoce. Material y métodos: Ensayo clínico, aleatorizado, controlado con tratamiento convencional. Se incluyeron pacientes con infarto agudo del miocardio con elevación del segmento ST y concentraciones de fibrinógeno > 500 mg/dl a las 72 horas de evolución. Se asignaron a recibir 400 mg de bezafibrato (grupo I) o tratamiento convencional (grupo II). Punto primario de evaluación: concentraciones de fibrinógeno; puntos secundarios: recurrencia de angina o infarto, falla ventricular izquierda y puntos finales combinados durante la estancia hospitalaria. Resultados: Se incluyeron 25 pacientes por grupo. Las concentraciones de fibrinógeno al egreso hospitalario fueron significativamente menores en el grupo I (532.42 ± 129.6 versus 889 ± 127.32 mg/dl del grupo II, p < 0.0001). Los puntos secundarios se presentaron con mayor frecuencia en el grupo II que en el grupo I: angina (56 versus 4%, riesgo relativo 0.071 [0.010-0.503], p < 0.0001), falla ventricular (24 versus 4%, riesgo relativo 0.167 [0.022-1.286], p = 0.049) y puntos finales combinados (76 versus 8%, riesgo relativo 0.105 [0.027- 0.405], p < 0.001). Conclusiones: El tratamiento con bezafibrato fue seguro y logró reducir el fibrinógeno en pacientes con infarto agudo. Esta reducción se asoció con menor frecuencia de eventos cardiovasculares a corto plazo.

BACKGROUND: Hyperfibrinogenemia is a predictor of cardiovascular events in healthy subjects and in patients with chronic ischemic heart disease. Bezafibrate decreases fibrinogen levels and also the incidence of major cardiovascular events in primary prevention, but its effects in acute coronary syndrome are unknown. METHODS: This is a randomized, controlled clinical trial with conventional therapy. We included patients with Acute ST Elevation Myocardial Infarction (STEAMI) and fibrinogen concentration >500 mg/dl at 72 h of evolution. We randomized subjects into two groups: bezafibrate 400 mg (group I) and conventional therapy (group II). Primary end point was decrease of fibrinogen concentrations. Secondary end points were recurrence of angina or infarction, left ventricular failure and combined end points during hospitalization. RESULTS: We included 25 patients in each group. Fibrinogen concentrations were lower at hospital discharge in Group I than in Group II (532.42 +/- 129.6 vs. 889 +/- 127.32 mg/dl in group II, p <0.0001). Secondary end points were more frequent in Group II than in Group I: angina (56% vs. 4%, RR 0.071 [0.010-0.503], p <0.0001), left ventricular failure (24% vs. 4%, RR 0.167 [0.022-1.286], p = 0.049) and combined end points (76% vs. 8%, RR 0.105 [0.027-0.405], p <0.001). CONCLUSIONS: Bezafibrate treatment was a safe treatment and reduced fibrinogen levels in patients with STEAMI and hyperfibrinogenemia. In the short term, this reduction was associated with a lower incidence of major cardiovascular events.

Reduções dos níveis sangüíneos das frações lipídicas induzidas por sinvastatina e bezafibrato. Estudo multicêntrico Brasileiro / Atherorgenic Lipid Fraction Plasma Level Reductions Induced by Treatment with Simvastatin and Bezafibrate. Brazilian Multicenter Study

PURPOSE-To compare the effects of simvastatin and bezafibrate on the lipid profile to attain the objectives proposed by National Cholesterol Education Program (NCEP). METHODS--One hundred twenty six hypercholesterolemic patients (69 females and 57 men, 56.0 +/- 10.0 years old), after selection and placebo period (4 weeks) were maintained on lipid-lowering diet and were randomly assigned in a double-blind fashion to receive for 12 weeks, bezafibrate (B, 200mg t.i.d. - BG(n = 66)) or simvastatin (S, 10-40mg q.p.m. - SG(n = 60)). During the study, 28 patients (SG0) received S 10mg; in 14 patients (SG1) dosage was titrated to 20mg and in 18 cases (SG2) to 40mg. Clinical examination, lipid profile and safety determinations, and adverse effects were assessed in different periods of the study. RESULTS--Mean profile analysis showed different behaviour of BG, SG0, SG1 and SG2 through time for TC, TG, LDL-C and VLDL-C. Mean reductions of TC and LDL-C were more marked in SG (30.3 and 40.9) than in BG (18.8 and 24.8). BG showed greater increase of TG (33.7) and HDL-C (25.9) than did SG (16.3 and 7.7 respectively). Reduction greater than 30 (optimal responses) and between 20 and 29 (good responses) were more frequent in SG and LDL-C. BG showed greater frequency of good and optimal responses for TG reduction and HDL-C increase. NCEP goals were achieved in 75.4 of SG and 46.9 of BG (p = 0.001). No clinical or laboratorial adverse experiences were reported in any treatment groups. CONCLUSION--Simvastatin was more effective in the reduction of plasma levels of atherogenic lipid fractions (TC and LDL-C) and this treatment allowed earlier achievement of the goals proposed by NCEP in a greater number of patients

Objetivo - Comparar os efeitos da administração de sinvastatina e bezafibrato sobre o perfil lipídico sangüíneo para alcançar as proposições do Programa Nacional de Educação sobre Colesterol (NCEP) do Instituto Nacional de Saúde dos Estados Unidos. Métodos - Cento e vinte e seis hipercolesterolêmicos primários (69 mulheres e 57 homens, de 56,0±10,0 anos), após período de seleção e 4 semanas de placebo, foram alocados de modo cego e randomizado, para receber, durante 12 semanas, mantendo a orientação dietética, 200mg 3 vezes ao dia de bezafibrato (GB, n=66) e 10 a 40mg, à noite, de sinvastatina (GS, n=60). Em GS, durante o estudo, 28 pacientes foram mantidos com 10mg (GS0); em 14 (GS1), a dose foi aumentada para 20mg e em 18 (GS2) para 40mg Exames clínicos, determinações de variáveis do perfil lipídico sangüíneo, exames laboratoriais de controle e verificação de efeitos adversos foram realizados em diferentes períodos da investigação. Resultados - A análise do perfil de médias mostrou diferença de comportamento de GB, GS0, GS1 e GS2 ao longo do tempo para a colesterolemia total (CT), trigliceridemia (TG) e frações LDL-C e VLDL-C. Reduções médias de CT e LDL-C foram mais acentuadas em GS (30,3 e 40,9%) que em GB (18,8 e 24,8%). Em GB ocorreu maior redução de TG (33,7%) e aumento de HDLC (25,9%) que em GS (respectivamente 16,3 e 7,7%). Reduções superiores a 30% (resposta ótima) e entre 20-29% (resposta boa) foram mais freqüentes em GS para CT e LDL-C. GB teve maior freqüência de respostas boas e ótimas para a redução de TG e elevação de HDLC. Os objetivos do NCEP foram significantemente mais alcançados em GS (75,4%) do que em GB (46,9°/). Não ocorreram significativas reações adversas clínicas e/ou laboratoriais em GS e GB. Conclusão - A sinvastatina mostrou-se mais eficaz na redução dos níveis das frações aterogênicas (CT e LDL-C) e permitiu alcançar mais precocemente e em maior número de indivíduos os objetivos propostos pelo NCEP