Lipase

The feed energy derived from fat remains relatively low because young poultry have limited fat digestibility and inefficient lipid metabolism. This study aimed to evaluate the effectiveness of emulsifiers in regulating lipid metabolism and increasing lipase activity in poultry. A quantitative review of 57 studies (2015-2025) revealed that emulsifier supplementation significantly upregulated genes associated with lipogenesis, including diacylglycerol O-acyltransferase 2 (DGAT2), and increased lipolysis through the upregulation of perilipin 1 (PLN1). It also increased the activities of lipoprotein lipase and total lipase. Kyoto Encyclopaedia of Genes and Genomes (KEGG) mapping also suggested that fatty acid biosynthesis (gga00061), β-oxidation (gga00071), the PPAR signalling pathway (gga03320), cholesterol metabolism (hsa04979), and the regulation of lipolysis (gga04923) in adipocyte regulation pathways were synergistically activated. Taken together, these pathways suggest that emulsifiers improve lipid turnover, oxidative metabolism and lipoprotein formation in broiler chickens. In summary, emulsifiers modulate lipid metabolism at the molecular level, which offers mechanistic support for improving energy utilization and may also aid in developing precision nutrition strategies in poultry.

BACKGROUND: Age-related decline in digestive function increases malnutrition risk. Supplementing meals with digestive enzymes may improve macronutrient digestion and bioavailability in adults reaching older ages. OBJECTIVES: To assess postprandial plasma nutrient concentrations after co-ingestion of a mixed meal and a mixture of 6 enzyme preparations (ENZ), including proteases, lipase, amylase, and glucoamylase. METHODS: Thirty middle-aged and older adults (56 ± 11 y; 18 females, 12 males) ingested chicken, peas, potatoes, and butter (435 kcal; 34 g protein, 51 g carbohydrate, 11 g fat) with either ENZ or placebo (PLA) in a randomized crossover fashion. Blood samples were collected at baseline and throughout a 0-5 h postprandial period for measurement of plasma amino acid, insulin, glucose, and nonesterified fatty acid (NEFA) concentrations. Clustering of postprandial amino acid responses was conducted in MFuzz, and logistic regression for response groups was conducted in JMP 18.2.0 (JMP Statistical Discovery LLC). RESULTS: Plasma amino acid concentrations were not statistically different between treatments (PLA compared with ENZ) over the postprandial period (all P > 0.05). Leucine time to maximum concentration was significantly faster (P = 0.047) with ENZ (121.2 ± 55.9 min) compared with PLA (141.0 ± 49.2 min). Postprandial plasma glucose concentrations (P = 0.04) and total NEFA (P = 0.001) were higher with ENZ compared with PLA. Three distinct response patterns (clusters) were detected within and across all postprandial amino acid categories. Differences in habitual macronutrient intake and interactions between sex, lean mass, and BMI distinguished participants with an earlier time to maximum postprandial leucine concentration when consuming ENZ compared with PLA from those with stable responses. CONCLUSIONS: Multienzyme supplementation improved macronutrient digestion of a mixed meal in middle-aged and older adults. For plasma amino acids, this benefit was most pronounced in adults with lower BMI and higher lean mass, and the effect was sex-dependent. This study was registered at clinicaltrials.gov as NCT05211440.

BACKGROUND: Metabolic-dysfunction associated steatohepatitis (MASH) arises from sustained triglyceride overload of the intestine-liver axis, yet current therapies rarely coordinate intestinal lipid entry with hepatic triglyceride disposal. Here we identify a phenolic-acid fraction as a dual-compartment metabolic modulator that couples intestinal lipase inhibition to CPT1α-PPARα-dependent hepatic β-oxidation across species. METHODS: Across species, we investigated the kinetics and metabolic actions of a phenolic fraction (PhAM) using recombinant lipase systems, epithelial transport assays, hepatocyte models, pharmacokinetics, diet-induced metabolic disease paradigms, quantitative histopathology, and a 24-week randomized placebo-controlled clinical trial. RESULTS: PhAM selectively suppresses pancreatic and intestinal lipases non-competitively, lowering V_max with minimal K_m change, resembling some features of orlistat, but via a distinct, non-covalent mechanism. In Caco-2 monolayers and ex vivo loops, it reduces apical-to-basolateral fatty-acid flux, depletes intracellular triglycerides, and limits luminal-to-plasma lipid transfer. PhAM is orally bioavailable, with measurable plasma exposure and prolonged intestinal residence. Under high-fat feeding, it increases fecal fat loss, attenuates post-lipid-load triglyceride excursions, and lowers hepatic triglycerides without altering ApoB secretion. Its triglyceride-lowering effect requires CPT1α-dependent mitochondrial import and PPARα activation, elevates β-hydroxybutyrate, and induces oxidative genes while sparing lipogenesis. In chronic MASH, PhAM reduces steatosis, ballooning, inflammation, and metabolic-dysfunction associated steatotic liver disease (MASLD) Activity Score. A 24-week clinical subgroup, defined by ultrasound and transaminase enrichment, showed dose-responsive improvements in ultrasonographic steatosis and metabolic biomarkers. CONCLUSION: Collectively, these findings define PhAM as a phenolic-acid-based agent that aligns intestinal lipid restriction with hepatic oxidative unloading, offering a mechanistically coherent framework for potentially addressing steatotic liver disease-associated metaboli

Comment in JAMA Oncol. 2026 Mar 1;12(3):241-242. doi: 10.1001/jamaoncol.2025.5663. IMPORTANCE: Programmed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear. OBJECTIVE: To evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023. INTERVENTION: Patients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m2, every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression. MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: The analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) mont

BACKGROUND: Dietary interventions are key for managing metabolic dysfunction-associated steatotic liver disease (MASLD), yet optimal diets and the role of PNPLA3 in modulating response to diet remain unclear. We evaluated the efficacy of a Mediterranean diet (MD) versus a low-fat diet (LFD) on hepatic fat and fibrosis, assessing interactions with PNPLA3 genotype. METHODS: Two hundred fifty adults with MASLD with BMI ≥25 kg/m2 were randomized to a 12-week moderately hypocaloric MD or LFD intervention. Individuals with excess alcohol intake and other etiologies of steatosis were excluded. Subjects were genotyped for PNLPA3 single-nucleotide polymorphism. Anthropometric measures, blood tests, and liver assessments [controlled attenuation parameter (CAP) and liver stiffness measurement (LSM)] were conducted at baseline and follow-up. Essential food items were provided, and adherence was tracked using validated questionnaires. The primary outcome was CAP, analyzed using linear mixed models adjusted for age and metabolic syndrome. RESULTS: Both diets significantly reduced CAP, LSM, and body weight at follow-up, with no significant differences between groups. The mean difference between MD and LFD was -0.13 dB/m for CAP (p=0.976, 95% CI: -8.54, 8.28), -0.19 kPa for LSM (p=0.355, 95% CI: -0.58, 0.21), and 3.01 kg for weight (p=0.159, 95% CI: -7.21, 1.19). PNPLA3 genotype did not significantly interact with diet for CAP, LSM, or weight (p=0.286, p=0.464, p=0.622, respectively). CONCLUSIONS: Weight reduction achieved by MD and LFD is similarly efficient in steatosis and fibrosis reduction, while PNPLA3 genotype does not affect the response to diet. Further studies investigating the impact of diet and nutrigenetics on liver-related outcomes are warranted.

BackgroundTraditional Thai herbal medicine represents an alternative and complementary approach for managing hyperlipidemia, according to its low toxicity and advantageous benefits. However, there is limited clinical data for Thai herbal medicine formulations for hyperlipidemia.ObjectivesThe present study aimed to evaluate the biological and clinical efficacy of Thai herbal formulation for lowering blood lipids in patients with borderline hyperlipidemia.Materials and methodsThe chemical profile, in vitro antioxidant activity, pancreatic lipase inhibition, and cytotoxicity tests were evaluated in the aqueous and ethanol extracts of Thai herbal formulation. The clinical efficacy and safety of Thai herbal formulation for reducing blood lipids were assessed in patients with borderline hyperlipidemia during a 12-week period.ResultsThe main chemical constituents of Thai herbal formulation, including (+)-chebulic acid, 4-glucogallic acid, gallic acid, ellagic acid, piscidic acid, and 6-gingerol, demonstrated anti-oxidant and pancreatic lipase inhibitory effects. In cytotoxicity testing, the aqueous extracts exhibited no inhibitory effect on L929 cells and Vero cells (IC50 values above 80 μg/mL), whereas the ethanol extracts presented IC50 values of 18.59 ± 0.58 µg/mL in Vero cells and 39.86 ± 0.02 µg/mL in L929 cells. The clinical investigation revealed that the Thai herbal formulation significantly decreased total cholesterol and low-density lipoprotein levels (P < 0.05), and additionally reduced triglycerides and elevated high-density lipoprotein cholesterol, in comparison to the control group after 12 weeks, thereby demonstrating its efficacy in hyperlipidemia management.ConclusionThe findings indicated that the Thai herbal formulation exhibited potential as a herbal therapeutic approach for borderline hyperlipidemia management.

This study aimed to evaluate the effects of phytosterols (PSs), alone or in combination with phospholipids (PLs), on dyslipidemia and oxidative stress, using both a high-fat diet-induced rat model and a randomized controlled trial in individuals with borderline hypercholesterolemia. In the animal study, Sprague-Dawley rats were divided into five groups (control, model, PS, PL, and PS+PL) and treated for 8 weeks. The PS+PL combination significantly reduced body weight, liver index, and serum glutathione peroxidase activity, while improving hepatic and adipose morphology. In the human trial, 82 participants were randomized into PS, PS+PL, or placebo groups and treated for 2 months in a triple-blind, parallel-design trial. Both PS and PS+PL groups showed significant reductions in total cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, reactive oxygen species, and lipid peroxidation, along with improvements in antioxidant enzyme and lipase activities. The PS+PL group showed additional effects, including reduced apolipoprotein B and lactate dehydrogenase levels, demonstrating superior efficacy compared to PS alone. In conclusion, PSs, particularly when combined with PLs, effectively improve cholesterol profile and oxidative stress parameters. These findings highlight the potential translational benefits of PS+PL as a functional dietary intervention for managing borderline hypercholesterolemia. © 2025 Wiley‐VCH GmbH.

BACKGROUND/AIMS: To assess the safety and efficacy of early oral refeeding (ERF) versus delayed refeeding (DRF) in patients with mild post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). METHODS: Eligible patients were randomly assigned in a 1:1 ratio to the ERF or DRF group. Eligible patients were randomly assigned in a 1:1 ratio to the ERF or DRF group. In the ERF group, feeding began 24 hours after the diagnosis of PEP; in the DRF group, feeding commenced once normal bowel sounds returned and pain had decreased to a visual analog scale score of <2. The diet was advanced from clear fluids to soft foods according to patient tolerance. Refeeding was temporarily halted if the visual analog scale score reached ≥5 points or if intake was refused due to pain. Resumption required normal amylase/lipase levels, pain relief, and bowel movement restoration. Discharge criteria included patient well-being >24 hours post-diet. The primary outcome was PEP hospitalization duration, and secondary outcomes were the incidence of severe acute pancreatitis, readmission rate (<30 days), and PEP-related mortality rate. RESULTS: A total of 80 patients (40 in each ERF and DRF group) were enrolled across nine referral centers. Baseline characteristics, procedural parameters and initial PEP severity were not significantly different between the two groups. Four ERF and three DRF patients had refeeding interruptions. ERF significantly reduced PEP hospitalization duration compared to DRF (2.93±1.59 days vs 3.78±1.97 days: relative risk, 0.75; 95% confidence interval, 0.59 to 0.97; p=0.026). Rates of severe acute pancreatitis, readmission, and mortality/morbidity related to PEP were similar between the two groups. CONCLUSIONS: ERF effectively shortens hospitalization in mild PEP patients without increasing safety risks (ClinicalTrials.gov identifier NCT04750044).

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) prevents malnutrition in people with exocrine pancreatic insufficiency, including those with cystic fibrosis (CF). We developed a lipase that is stable against proteolysis and at the pH of the fed stomach, so it can be taken during a meal to promote mixing of enzyme and substrate. We designed a dose-ranging study of ANG003, a microbial PERT combining this lipase with low pH-stable protease and amylase, also of microbial origin. METHODS: This was a multicenter, randomized evaluation of ANG003 in subjects with CF, studied once without PERT and again after randomization to a single dose level of four possible combinations of lipase, protease, and amylase. We developed blood-based substrate absorption challenge tests employing DHA+EPA, whey and potato starch to determine dose-response to each of these enzymes, respectively. RESULTS: ANG003 improved DHA+EPA absorption with a statistically significant increase with 80 mg and 120 mg lipase doses compared to 20 mg (p = 0.03; p = 0.004). The absorption of total fats followed a similar pattern to DHA+EPA. There was a significant increase in absorbed amino acid equivalents, reflecting proteolysis, over no PERT in the highest (75 mg) dose of protease (p = 0.03). In subjects without diabetes, glucose was slightly lower while c-peptide levels remained unchanged with all amylase doses. Adverse events were mild and transient. No serious adverse events occurred. CONCLUSIONS: ANG003 lipase significantly improves DHA+EPA and total fat absorption in a dose dependent manner. Results for ANG003 protease and amylase activity suggest that doses lower than those in current porcine-derived PERTs may be efficacious.

BACKGROUND: Sarcomas are frequently infiltrated with immunosuppressive myeloid cells. Vimseltinib is an inhibitor of the colony-stimulating factor 1 receptor kinase and has been shown to decrease tumor-infiltrating myeloid cells in preclinical models. We hypothesized that vimseltinib combined with the Programmed death-ligand 1 (PD-L1) inhibitor avelumab would be safe, tolerable, and clinically effective in patients with advanced sarcoma. METHODS: This was a phase I study of vimseltinib plus avelumab in patients with unresectable or metastatic sarcoma. The study used a standard 3 + 3 dose-escalation design, followed by dose expansion in patients with select histological subtypes. Vimseltinib was administered daily by mouth in 28-day cycles; avelumab was administered intravenously every 2 weeks. The primary objectives of the dose-escalation and dose-expansion phases were to determine the recommended phase II dose and to estimate the best objective response rate by RECIST version 1.1. RESULTS: Thirteen patients were treated in the dose-escalation phase, and 19 patients were treated in the dose-expansion phase. The most common treatment-related adverse events were asymptomatic increases in serum levels of amylase, lipase, creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase. One of six patients treated at the highest dose level had a dose-limiting toxicity (grade 4 increase in aspartate aminotransferase). The highest dose level was determined to be the recommended phase II dose. There were no objective responses. The median progression-free survival of patients treated at the recommended phase II dose was 1.55 months (95% confidence interval 1.25-1.78 months). Flow cytometric analysis of peripheral blood mononuclear cells revealed a decrease in myeloid-derived suppressor cells and regulatory T cells after treatment. RNA sequencing of paired tumor samples revealed an increase in tumor-infiltrating T cells and a decrease in macrophages after treatment. CONCLUSIONS: Vimseltinib plus avelumab was generally safe and well tolerated. This combination had minimal clinical efficacy in our population of heavily pretreated patients with sarcoma.

The angiopoietin-like protein 3/8 complex (ANGPTL3/8) inhibits lipoprotein lipase (LPL) activity, primarily in oxidative tissues, and does so more potently than ANGPTL3, making ANPTL3/8 an attractive target for treating dyslipidemia. This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia to assess the primary outcome of safety and the secondary outcomes of pharmacokinetics and pharmacodynamics of ascending doses of LY3475766, a human monoclonal antibody that specifically blocks ANGPTL3/8-mediated inhibition of LPL activity. Participants received a single dose of LY3475766 or placebo. LY3475766 was well tolerated with no severe adverse events or adverse event-related discontinuations. Compared with placebo, LY3475766 dose-dependently reduced the concentration of triglycerides (-70%), remnant cholesterol (-86%), low-density lipoprotein cholesterol (-32%), non-high-density lipoprotein cholesterol (non-HDL-C) (-35%) and apolipoprotein B (-29%) while increasing HDL-C (+27%). LY3475766 thus significantly reduced atherogenic lipoprotein levels while increasing HDL-C levels; however, the effects on cardiovascular risk remain to be established. ClinicalTrials.gov registration: NCT04052594 . © 2025. The Author(s).

Feline infectious peritonitis virus (FIPV) poses a significant threat to cats worldwide. Besides the limited development of antiviral drugs that mainly target virus proteins, concerns about resistance to mutant strains - similar to those seen in human and other mammalian viruses - remain high. Therefore, addressing these challenges involves developing innovative antiviral therapies, such as host-directed treatments that target host cell processes essential for viral replication. FIPV infection induced distinctive dynamics of lipid droplet (LD) remodelling, characterized by an increase in LD abundance from early to mid-infection, followed by a subsequent decline. Phosphorylated hormone-sensitive lipase, a key mediator of LD hydrolysis and fatty-acid release, became activated after the mid-infection phase, potentially contributing to elevated intracellular fatty-acid availability during late infection. Notably, atglistatin (DABPU-DM) and its derivatives robustly suppressed FIPV replication in Crandell-Rees feline kidney (CRFK) and feline macrophage Fcwf-4 cells, coincident with preservation of LD integrity and inhibition of LD breakdown. Among these compounds, DABPU-DE had the best selectivity index (686.0±35.2) against FIPV, with a higher half-maximal cytotoxic concentration (274.4±3.6 µM) and a lower half-maximal inhibitory concentration (0.4±0.02 µM). Moreover, combining DABPU-DE (0.18 µM) with remdesivir (1.35 µM), a viral RNA-dependent RNA polymerase inhibitor, showed a very strong synergistic effect (CI=0.09 and Bliss synergy score=14.46±1.80) in inhibiting FIPV replication in CRFK cells, even at lower doses than either drug alone. In conclusion, DABPU-DE is a promising antiviral candidate for FIPV, and its synergistic effect with remdesivir warrants further research in cats infected with FIPV.

OBJECTIVE: To explore the effects and mechanism of co-exposure of water disinfection byproducts (DBPs) dibromo-1,4-benzoquinone (DBBQ) and dichloro-1,4-benzoquinone (DCBQ) on liver lipid metabolism in mice. METHODS: ICR mice were randomly distributed into control group, DBBQ group, DCBQ group and combined group (DCBQ + DBBQ). The mice received intragastric administration once a day for four weeks. After exposure, serum and liver tissues were collected to determine indexes related to lipid metabolism. RESULTS: The serum cholesterol (TC) and triglyceride (TG) levels in exposure groups were significantly increased, with a much higher level in co-exposure group. Histopathological observation showed that the liver structures were disordered and the lipid droplets were significantly increased in exposure groups. Liver TC levels were significantly increased in DCBQ group, while the liver TG levels were significantly increased in DBBQ group, and both levels in co-exposure group were higher than those in DCBQ or DBBQ group. The liver levels of hormone sensitive lipase (HSL) and lecithin cholesterol acyltransferase (LCAT) in exposure groups were significantly decreased, and the levels in co-exposure group were lower than DCBQ or DBBQ group. The mRNA expression of AMPK decreased, while the mRNA expression of SREBP-1c and FAS increased in both DCBQ and DBBQ group, with a lower mRNA expression of AMPK and a higher mRNA expression of SREBP-1C and FAS in co-exposure group. CONCLUSION: Co-exposure of DBBQ and DCBQ can lead to lipid metabolism disorders in mice, demonstrating a synergistic effect, which may bemediated through AMPK/SREBP-1c/FAS signaling pathway. Our data highlight the importance of understanding the combined effects of water DBPs.

Recently, essential oils (EOs) have garnered attention for their biological properties as a source of natural compounds with anticancer and antioxidant effects. Artemisia herba alba grows commonly on the dry steppes of the Mediterranean regions in Northern Africa, Western Asia, and Southwestern Europe. This species is native to Palestine and the western region of Jordan, known as Sheeh. It is employed by the Bedouins for the remedy of many diseases. Recently, essential oils (EOs) have been booming with a growing interest in their use as palliative treatments to conventional medicine due to their biological qualities. The objective of this study is to identify the chemical composition of EO extracted from the dry leaves of A. herba alba and to evaluate their in vitro antioxidant, anticancer, and α-amylase and lipase inhibitory activity. The EO was extracted via hydrodistillation and examined using gas chromatography-mass (GC-MS) spectrometry to determine its chemical composition. The primary components included 1,8-cineole (28.67%), followed by trans-thujone (24.00%), cis-thujone (17.69%), camphor (12.76%), and concluding with terpinen-4-ol (8.34%). Biologically, the EO performed high antioxidant activity against 1,1-diphenyl-2-picrylhydrzyl (DPPH) with 22.17 ± 1.11 µg/mL and modest lipase and α-amylase activity. The EO displayed significant anticancer properties against B16F10 and MCF-7 with IC50 values of 12.39 and 13.60 µg/mL, respectively. A 1:1 combination of Artemisia herba alba and Teucrium polium EOs improved the anticancer activities against B16F10 and MCF-7 cell lines, with IC50 values of 6.184 and 9.427, respectively. Adding 25-50 µg/mL to Taxol (10 ng) caused a remarkable increase in the inhibition of cancer cells. This enhancement in cancer cell inhibition suggests a potential synergistic effect between the essential oil and Taxol, warranting further investigation into their combinatory use in therapeutic applications. Future studies may explore the underlying mechanisms of this synergy to optimize treatment strategies for cancer patients. © 2025. The Author(s).

In this study, Alangium salvifolium and Ocimum sanctum extracts were investigated for their antioxidant, antidiabetic and hypolipidemic activities individually and in combined form. HPLC, LC-MS and UPLC phytochemicals profiling identified phenolics and flavonoids as major bioactives. Antioxidant assays showed significant DPPH and ABTS radical scavenging activities, with the combined formulation (1:1 ratio) 91.2 and 89.6% inhibition was achieved respectively. Antidiabetic activities were first investigated in vitro with the ability of the combination to inhibit both α-amylase (IC50 = 38.4 µg/mL) and α-glucosidase (IC50 = 45.2 µg/mL) having the strongest inhibitory effects. The hypolipidemic activity included inhibition of lipid peroxidation (78.5%); pancreatic lipase inhibition (70.2%). The bioactives were further molecular docked to find strong binding affinities with PPARγ, DPP-IV, and HMG-CoA reductase. Results were confirmed statistically different (p < 0.05) between treated and control groups. These results suggest that the extracts can exhibit synergy as natural therapeutics in diabetes and lipid disorders.

BACKGROUND: Bladder cancer (BCa) remains clinically challenging due to high recurrence rates. As an endocannabinoid, 2-arachidonoylglycerol (2-AG) plays a pivotal role in regulating numerous physiological and pathological processes, including tumorigenesis. The maintenance of its levels in the biological system is essential for 2-AG to exert its biological functions. Therefore, inhibitors targeting the 2-AG metabolic enzyme, such as monoacylglycerol lipase (MGLL), are considered promising for clinical application. METHODS: The cell viability assay, colony formation, cell migration, and invasion assay were used to demonstrate 2-AG's anti-proliferative and anti-metastatic effects in BCa cells, inversely correlated with MGLL expression. MGLL overexpression or knockdown confirmed its regulatory role in 2-AG efficacy. Transcriptomics identified LKB1 as a potential 2-AG target. From a medicinal-food compound library, the MGLL activity assay was used to discover Cistanoside F (CF) as a potent MGLL inhibitor. RESULTS: The in vitro experiments confirmed 2-AG's selective anti-proliferative and anti-metastatic effects in BCa cells, while MGLL attenuates the anti-tumor effect of 2-AG in BCa cells via metabolizing 2-AG into AA. In mechanism, 2-AG activated the LKB1-AMPKα-mTOR axis to suppress BCa progression. At non-cytotoxic concentrations (4-8 nM), CF enhanced 2-AG's effects in BCa cells by sustaining endogenous 2-AG levels through MGLL suppression. In vivo, CF synergized with 2-AG to significantly inhibit tumor growth and lung metastasis compared to 2-AG monotherapy. CONCLUSION: These findings establish CF as a novel MGLL-targeting adjuvant that amplifies 2-AG's anti-BCa efficacy via LKB1 pathway activation, providing dual therapeutic strategies: MGLL inhibition for 2-AG potentiation and LKB1 modulation for pathway-directed therapy.

Ulcerative colitis (UC) is a chronic, relapsing nonspecific intestinal inflammatory disease. It is difficult for a single drug to treat UC effectively and maintain long-term efficacy. There is an urgent need to find new drugs and treatment strategies. MAGL11 is a new kind of single acylglycerol lipase (MAGL) inhibitor. Icaritin (Y003) is the major metabolite of icariin in vivo. Several studies have confirmed the role of MAGL inhibitors and icariin in anti-inflammatory and regulation of intestinal stability. Therefore, this study adopted a new strategy of combining MAGL inhibitor with Icaritin to further explore the role and mechanism of drugs in the treatment of UC. Enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin staining (HE), immunohistochemical (IHC) and Western blot were used to detect the synergistic protective effects of MAGL11 and Y003 on intestinal pathological injury, intestinal mucosal permeability and inflammation in UC mice. 16S rDNA sequencing was used to detect the synergistic effect of MAGL11 and Y003 on gut microbiota. The effects of MAGL11 and Y003 combined therapy on serum and fecal metabolism of UC mice were analyzed by untargeted metabolomics. Proteomics method was applied to investigate the molecular mechanisms underlying MAGL11 and Y003 synergy in the treatment of UC. The results showed that MAGL11 and Y003 could synergistically improve the clinical symptoms, reduce intestinal inflammation and pathological damage, and improve intestinal mucosal permeability in UC mice. The mechanism study found that MAGL11 and Y003 could synergistically inhibit Toll-like receptors 4 (TLR4) / Myeloid differentiation primary response gene (Myd88)/Nuclear factor kappa-B (NF-κB) pathway and further regulate gut microbiota imbalance and metabolic disorders to treat UC. Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors. Paredes-Ruiz KJ(1)(2), Chavira-Ramos K(1)(2), Galvan-Arzate S(3), Rangel-López E(1), Karasu Ç(4), Túnez I(5), Skalny AV(6)(7), Ke T(8), Aschner M(8), Orozco-Morales M(9), Colín-Gonz

9. Neurotox Res. 2023 Dec;41(6):514-525. doi: 10.1007/s12640-023-00661-4. Epub 2023 Jul 17. Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors.

Sapindus saponins extracted from Sapindus mukorossi Gaertn. have been reported to exert antibacterial activity against Cutibacterium acnes (C. acnes). However, there are no reports about their potentials against its biofilm, which is a major contributor to the antibiotic resistance of C. acnes. This study aimed to investigate the synergistic antibiofilm activity and action of the combination of Sapindoside A and B (SAB) against C. acnes. SAB with sub-MICs significantly inhibited the early-formed and mature biofilm of C. acnes and decreased the adhesion and cell surface hydrophobicity (p < 0.05). Also, SAB greatly reduced the production of exopolysaccharide and lipase (p < 0.05), and the binding mode of SAB and lipase was predicted by molecular docking, via hydrogen bonds and hydrophobic interactions. Biofilm observed with electron microscopies further confirmed the high antibiofilm activity of SAB against C. acnes. Furthermore, a significant down-regulation of biofilm biosynthesis-associated genes was observed. The combination index explained the synergistic effects of SAB leading to the above results, and the contribution of SA was greater than that of SB. The current results showed that SAB had synergistic antibiofilm activity against C. acnes, and the Sapindoside A played a major role, indicating that SAB could be a natural antiacne additive against C. acnes biofilm-associated infections.

Off-target drug release and insufficient drug delivery are the main obstacles for effective anticancer chemotherapy. Prodrug-based self-assembled nanoparticles bioactivated under tumor-specific conditions are one of the effective strategies to achieve on-demand drug release and effective tumor accumulation. Herein, stimuli-activable prodrugs are designed yielding smart tumor delivery by combination of the triglyceride-mimic (TG-mimetic) prodrug structure and disulfide bond. Surprisingly, these prodrugs can self-assemble into uniform nanoparticles (NPs) with a high drug loading (over 40%) and accumulate in tumor sites specifically. The super hydrophobic TG structure can act as a gate that senses lipase to selectively control over NP dissociation and affect the glutathione-triggered prodrug activation. In addition, the impacts of the double bonds in the prodrug NPs on parent drug release and the following cytotoxicity, pharmacokinetics, and antitumor efficiency are further demonstrated. Our findings highlight the promising potential of TG-mimetic structure-gated prodrug nanoparticles for tumor-specific drug delivery.

INTRODUCTION: Acute pancreatitis associated with Pazopanib has been reported in the literature. Bitter Melon (Momordica Charantia) is traditionally used as a folk medicine in many regions. In this report, we describe a 65-year-old patient with a diagnosis of renal cell carcinoma, admitted to the hospital with symptoms of acute pancreatitis at the 8th year of pazopanib treatment. CASE REPORT: The patient diagnosed with renal cell carcinoma was admitted to the hospital with the complaint of abdominal pain, nausea, and vomiting in the 8th year of Pazopanib treatment. It was noticed from the patient's history that he had received Bitter Melon extract for 4 days prior to the beginning of his complaints (100-150 ml/day). Levels of serum amylase and lipase were measured as 9163 U/L and 14,206 U/L, respectively. MANAGEMENT & OUTCOME: Pazopanib drug was held. The patient was treated for acute pancreatitis. Pazopanib treatment was started again after the clinical condition of the patient had improved and levels of serum amylase and lipase had returned to normal levels. Levels of serum amylase and lipase did not increase again after re-administration of pazopanib treatment. DISCUSSION: It is thought that Bitter Melon extract and pazopanib interaction might have led to acute pancreatitis. To the best of our knowledge, this case is the first to highlight the interaction of Bitter Melon extract with pazopanib. The Drug Interaction Probability Scale indicates that there is a probable association between bitter melon and acute pancreatitis.

AIM: We conducted a multicentre, randomized phase 3 trial in China to evaluate the efficacy and safety of cofrogliptin (HSK7653), a novel long-acting dipeptidyl peptidase-4 inhibitor, in patients with drug-naïve type 2 diabetes (T2D). MATERIALS AND METHODS: Patients with inadequately controlled T2D were randomly assigned (1:1:1) to cofrogliptin 10 mg, cofrogliptin 25 mg or placebo, taken orally once every 2 weeks for a 24-week double-blind period. Eligible patients then received cofrogliptin 25 mg in a 28-week open-label extension. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. RESULTS: In total, 475 patients (median age: 54.0 years) were randomized and received at least one dose of cofrogliptin 10 mg (n = 158), cofrogliptin 25 mg (n = 158) or placebo (n = 159); 401 patients entered the open-label extension. At week 24, the least-squares (LS) mean difference (95% confidence interval [CI]) in HbA1c versus placebo was -0.63% (-0.81, -0.46) with cofrogliptin 10 mg and -0.59% (-0.77, -0.42) with cofrogliptin 25 mg (both p < 0.0001). The LS mean (standard error) change in HbA1c from baseline was maintained at the end of the study in patients given open-label cofrogliptin 25 mg for an additional 28 weeks: cofrogliptin 10 mg: -0.86% (0.07); cofrogliptin 25 mg: -0.74% (0.07); placebo: -0.89% (0.07). Over the entire study, common adverse events were hyperuricaemia, hyperlipidaemia, hypertriglyceridaemia, increased lipase, upper respiratory tract infection and urinary tract infection. Hypoglycaemic events did not significantly differ between groups. CONCLUSIONS: Cofrogliptin provided glycaemic control over 52 weeks and was generally well tolerated in patients with T2D. CLINICAL TRIAL REGISTRATION: Registered on Clinicaltrials.gov with the registration number NCT04556851 (https://clinicaltrials.gov/study/NCT04556851). © 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

AIM: To evaluate the efficacy and safety of retagliptin in Chinese patients with type 2 diabetes (T2D) inadequately controlled with metformin. MATERIALS AND METHODS: This multicentre, phase 3 trial consisted of a 16-week, randomized, double-blind, placebo-controlled period, where patients with HbA1c levels between 7.5% and 11.0% were randomized to receive either once-daily (QD) retagliptin 100 mg (n = 87) or placebo (n = 87), both as an add-on to metformin. The primary endpoint was the change in HbA1c from baseline to week 16. RESULTS: At week 16, the least squares mean change in HbA1c from baseline, compared with placebo, was -0.82% (95% CI, -1.05% to -0.58%) for the retagliptin 100 mg QD group (P < .0001) per treatment policy estimand. Significantly higher proportions of patients in the retagliptin 100 mg QD group achieved HbA1c levels of less than 6.5% (11.5%) and less than 7.0% (26.4%) compared with those receiving placebo (0% and 4.6%; P = .0016 and P < .0001, respectively) at week 16. Retagliptin 100 mg QD also lowered fasting plasma glucose and 2-hour postprandial plasma glucose levels. The incidence of adverse events (AEs) during the treatment period was similar between the two groups. However, slightly higher proportions of increased lipase and increased amylase in the retagliptin 100 mg QD group were observed. No patients discontinued treatment permanently because of AEs, and no episodes of severe hypoglycaemia were reported. CONCLUSIONS: Retagliptin 100 mg QD as an add-on therapy to metformin offers a new therapeutic option for treating Chinese patients with T2D inadequately controlled by metformin alone, and is generally well tolerated. © 2024 John Wiley & Sons Ltd.

BACKGROUND: Sapanisertib is a potent ATP-competitive, dual inhibitor of mTORC1/2. Ziv-aflibercept is a recombinant fusion protein comprising human VEGF receptor extracellular domains fused to human immunoglobulin G1. HIF-1α inhibition in combination with anti-angiogenic therapy is a promising anti-tumor strategy. This Phase 1 dose-escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv-aflibercept in advanced solid tumors. METHODS: Fifty-five patients with heavily pre-treated advanced metastatic solid tumors resistant or refractory to standard treatment received treatment on a range of dose levels. RESULTS: Fifty-five patients were enrolled and treated across a range of dose levels. Forty were female (73%), median age was 62 (range: 21-79), and ECOG PS was 0 (9, 16%) or 1 (46, 84%). Most common tumor types included ovarian (8), colorectal (8), sarcoma (8), breast (3), cervical (4), and endometrial (4). Median number of prior lines of therapy was 4 (range 2-11). Sapanisertib 4 mg orally 3 days on and 4 days off plus 3 mg/kg ziv-aflibercept IV every 2 weeks on a 28-day cycle was defined as the maximum tolerated dose. Most frequent treatment-related grade ≥2 adverse events included hypertension, fatigue, anorexia, hypertriglyceridemia, diarrhea, nausea, mucositis, and serum lipase increase. There were no grade 5 events. In patients with evaluable disease (n = 50), 37 patients (74%) achieved stable disease (SD) as best response, two patients (4%) achieved a confirmed partial response (PR); disease control rate (DCR) (CR + SD + PR) was 78%. CONCLUSION: The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies. © 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

PURPOSE: Acne vulgaris is a common skin disease accompanied by chronic inflammation in the pilosebaceous follicles, resulting from excessive Cutibacterium acnes. This study aimed to investigate the inhibition of biofilm formation by C. acnes ATCC 6919 using heat-treated Pediococcus acidilactici LM1013 (HT-LM1013), previously isolated from the Korean traditional fermented alcoholic beverage-makgeolli, and its application as a leave-on-type product for patients with acne vulgaris. METHODS: HT-LM1013 was prepared by Lactomason and homogenized using a high-pressure homogenizer. The minimum inhibitory concentration (MIC), tricarboxylic acid (TCA) cycle, and lipase activity were evaluated for C. acnes inhibition. Inhibition of biofilm formation was demonstrated using a crystal violet solution. Damaged C. acnes was observed using field-emission scanning electron microscopy (FE-SEM). Clinical trials were performed using a leave-on-type product containing HT-LM1013. RESULTS: HT-LM1013 inhibited the TCA cycle (36.80%) and lipase activity using palmitate (31.89%), stearate (36.91%), and oleate (30.86%) as substrates at 1 × MIC (p < 0.01). After treatment with HT-LM1013, concave and elongated shapes of C. acnes were observed by FE-SEM. In addition, HT-LM1013 inhibited biofilm formation by 71.75% at 1 × MIC (p < 0.001) and removed 73.35% of mature biofilms (p < 0.01). In the clinical trial, the leave-on-type product decreased the number of closed comedones from 14.04 to 10.22, open comedones from 7.22 to 4.39%, and sebum content to 76.23% at week 4 (p < 0.01). The satisfaction score of the participants was recorded 3.83 on a five-point scale. CONCLUSION: HT-LM1013 is potent for the treatment of acne vulgaris. © 2023 LactoMason. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.

BACKGROUND: The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk muscle-invasive urothelial carcinoma. However, the efficacy and safety of adjuvant nivolumab in Japanese patients with muscle-invasive urothelial carcinoma have not been clarified. METHODS: Patients with muscle-invasive urothelial carcinoma were randomized to adjuvant nivolumab 240 mg or placebo (every 2 weeks via intravenous infusion) up to 120 days after radical surgery in CheckMate 274. RESULTS: Of 49 patients in the Japanese subgroup, 27 and 22 patients were randomized to nivolumab and placebo, respectively. Eleven and 8 patients, respectively, had tumor PD-L1 expression level of 1% or more. The median disease-free survival times in the nivolumab and placebo groups were 29.67 months (95% confidence interval 7.79-not reached) and 9.72 months (95% confidence interval 4.73-not reached), respectively (hazard ratio 0.77, 95% confidence interval 0.35-1.69). The corresponding values in patients with tumor PD-L1 expression level of 1% or more were 29.67 months (95% confidence interval 2.63-not reached) and 25.95 months (95% confidence interval 5.59-not reached) (hazard ratio 1.10, 95% confidence interval 0.31-3.92), respectively. Treatment-related adverse events of Grade 3-4 occurred in 25.9 and 13.6% of patients in the nivolumab and placebo groups, respectively. The most common treatment-related adverse events in the nivolumab group were lipase increased, amylase increased and diarrhea. The changes in quality of life scores from baseline over time were similar in both groups. CONCLUSIONS: The efficacy and safety results in the Japanese subgroup were consistent with the overall population of CheckMate 274. © The Author(s) 2022. Published by Oxford University Press.

A 7-week feeding trial was conducted to evaluate the combined effects of propionic acid (PA, 5 or 10 g/kg) and a multi-strain Bacillus spp. (Bacillus subtilis IS02 (accession no. JN856456) and B. licheniformis IBRC-M 11,319) (1.7 × 107 CFU/g) probiotic in a plant protein source (PP)-rich diet (∼70% of dietary protein derived from PP sources) on performance of Asian sea bass (Lates calcarifer) fry (initial body weight 2.97 ± 0.11 g). In this regard, six isoproteic (∼48%) diets were formulated as follows: a control (without supplementation of the additives); probiotic (only contained Bacillus spp. mixture); 5 g PA/kg diet; 10 g PA/kg diet; probiotic + 5 g PA/kg diet, and probiotic + 10 g PA/kg diet. Specific growth rate in fish fed with 10 g PA/kg (2.84 ± 0.1%) and diets contained blends of probiotic and PA (2.76 ± 0.19% in probiotic + 5 g PA, and 2.79 ± 0.04% in probiotic + 10 g PA) was better than in the control (2.45 ± 0.1%) (P < 0.05). Feed conversion ratio in fish fed with 10 g PA/kg (0.92 ± 0.12) and diets contained blends of probiotic and PA (0.94 ± 0.06 in probiotic + 5 g PA and 0.91 ± 0.02 in probiotic + 10 g PA) was better than in the control (1.24 ± 0.08) (P < 0.05). Digestive enzymes including α-amylase, total alkaline proteases, and bile salt dependent lipase activities improved in fish fed diets contained additives. The activity of glutathione-S-transferase and glutathione reductase enhanced in the liver of fish fed diets contained additives. The relative abundance of lysozyme, interleukin 1β, and insulin-like growth factor-1 genes mRNA transcript showed multifold increase in the liver of fish fed with the 10 g PA/kg and diets contained blends of probiotic and PA (P < 0.05). By considering the above mentioned results, supplementing a PP-rich diet with 10 g PA/kg diet or combination of PA and a mixture of Bacillus spp. probiotic recommended for L. calcarifer. © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

In the present study, we demonstrated that borage (Borago officinalis L.) seed oil subjected to immobilized lipase pretreatment are enriched with linoleic acid (LNA, 18:2n-6), γ-linolenic acid (GLA, 18:3n-6), and oleic acid (OLA, 18:1n-9). We further showed that lipase-treated borage oil (LT-BOL) regulates the activity and degradation of tyrosinase, an important enzyme implicated in the synthesis of melanin in murine melanocytes, B16F10. LT-BOL and its free fatty acid components reduced the levels of melanin and tyrosinase in melanocytes with GLA exerting similar or stronger effects compared with LNA and OLA. The brightening efficacy of LT-BOL on melanin metabolism in humans was tested by an 8-week, double-blind, randomized clinical trial, which enrolled 21 Korean female adults (mean age 48.57 ± 3.28). Visual evaluation showed that cream containing 1% LT-BOL significantly decreased (p < 0.05) melasma on the treated skin area after 6 and 8 weeks. The analysis of the skin brightness using Chromameter CR-400 confirmed that the brightness of the treated area was significantly increased (p < 0.01) after 4, 6, and 8 weeks. Together, our results suggest that LT-BOL may be suitable as a natural skin whitening cosmeceutical product. © 2020 AOCS.

BACKGROUND: We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. METHODS: In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov, NCT01982955, and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. FINDINGS: From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were

BACKGROUND: Orlistat is a potent lipase inhibitor utilized as a preventive agent for obesity and fat absorption control. Existing literature presents conflicting findings regarding its impact on lipid parameters. METHODS: This systematic review followed the PRISMA guidelines and was registered in PROSPERO (ID: CRD42024550889). A comprehensive search of PubMed, Scopus, Web of Science, and Cochrane Register of Controlled Trials was conducted for studies published before January 19, 2025. Eligible studies included randomized controlled trials (RCTs) evaluating orlistat in adults (≥ 18 years) with dyslipidemia. Furthermore, the Grading of Recommendations, Assessment, Development, and Evaluations assessment tool was employed to analyze the certainty of evidence or each outcome. RESULTS: A total number of 1369 participants, with 682 in treatment and 687 in control categories, were included in our study. Orlistat reduced body mass index (BMI) (SMD [95% CI]: -0.30 [-0.58, -0.03], p value (heterogeneity) = 0.026), and also it was associated with a decrease in high-density lipoprotein cholesterol (SMD (95% CI): -0.31 [-0.48, -0.13], p value (heterogeneity) = 0.436). Changes in waist circumference (WC) and triglycerides (TGs) did not reach statistical significance in the primary analysis (WC: SMD [95% CI] -0.1562 [-0.3138; 0.0015], I 2 = 0.0%, p-value (heterogeneity) = 0.7572; TG: SMD [95% CI] -0.1668 [-0.7979; 0.4642], I 2 = 97.7% p value (heterogeneity) < 0.0001); however, after publication-bias adjustment using the trim-and-fill sensitivity analysis, meaningful reductions were discovered for WC (SMD (%95CI): -0.1712 [-0.3248; -0.0176], I 2 = 0.0%, p value (heterogeneity) = 0.7696) and TG (SMD (%95CI): -0.8900 [-1.6619; -0.1181], I 2 = 97.9%, p value (heterogeneity) < 0.0001). The secondary analysis demonstrated that follow-up duration accounted for 30% of TG heterogeneity, suggesting a small but significant decline in orlistat's TG-lowering effect over time (slope: -0.1239; 95% CI: -0.2355, -0.0123; p value = 0.0295). No significant changes were observed in other parameters of the study. Besides, gastrointestinal issues were the most frequently reported adverse events a