GP Treatment Research Articles

Structural characterization of the glucan from Gastrodia elata Blume and its ameliorative effect on DSS-induced colitis in mice

The polysaccharide glucan was extracted from Gastrodia elata Blume, and its structural characterizations and beneficial effects against acute dextran sulfate sodium (DSS)-induced ulcerative colitis were investigated. The results showed that a polysaccharide GP with a molecular weight of 811.0 kDa was isolated from G. elata Blume. It had a backbone of α-D-1,4-linked glucan with branches of α-d-glucose linked to the C-6 position. GP exhibited protective effects against DSS-induced ulcerative colitis, and reflected in ameliorating weight loss and pathological damages in mice, increasing colon length, inhibiting the expression of inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), decreasing the levels of inflammatory related proteins NLRP3 and ASC, and elevating the anti-inflammatory cytokine interleukin-10 (IL-10) level in mouse colon tissues. GP supplementation also reinforced the intestinal barrier by promoting the expression of ZO-1, Occludin, and MUC2 of colon tissues, and positively regulated intestinal microbiota. Thus, GP treatment possessed a significant improvement in ulcerative colitis in mice, and it was expected to be developed as a functional food.

Gentiopicroside and swertiamarin induce non-selective oxidative stress-mediated cytotoxic effects in human peripheral blood mononuclear cells

Gentiopicroside (Gp) and swertiamarin (Sm), secoiridoid glycosides commonly found in plants of the Gentianaceae family, differ in one functional group. They exhibit promising cytotoxic effects in cancer cell lines and overall protective outcomes, marking them as promising molecules for developing novel pharmaceuticals. To investigate potential variations in cellular sensitivity to compounds of similar molecular structures, we analyzed the mode of Gp and Sm induced cell death in human peripheral blood mononuclear cells (PBMCs) after 48 h of treatment. The lowest tested concentration that significantly reduces cell viability, 50 μM, was applied. Oxidative stress parameters were estimated by measuring the levels of prooxidative/antioxidative balance, lipid peroxidation products, and 8-oxo-7,8-dihydro-2-deoxyguanosine, while gene expression of DNA repair enzymes was evaluated by employing quantitative real-time PCR. Cellular morphology was analyzed by fluorescent microscopy, and immunoblot analysis of apoptosis and necroptosis-related proteins was used to assess the type of cell death induced by the treatments. The discriminatory impact of Gp/Sm treatments on apoptosis and necroptosis-induced cell death was evaluated by monitoring the cell survival in co-treatment with specific cell death inhibitors. Obtained results show greater cytotoxicity of Gp than Sm suggesting that variations in the molecular structures of the tested compounds can substantially affect their biological effects. Gp/Sm co-treatment with apoptosis and necroptosis inhibitors revealed a distinct, albeit non-specific mechanism of PBMCs cell death. Although the therapeutic may not directly cause a specific type of cell death, its extent can be pivotal in assessing the safety of therapeutic application and developing phytopharmaceuticals with improved features. Since phytopharmaceuticals affect all exposed cells, identification of cytotoxic mechanisms on PBMCs after Gp and Sm treatment is important for addressing the formulation and dosage of potential phytopharmaceuticals.

Integrated skin metabolomics and network pharmacology to explore the mechanisms of Goupi Plaster for treating knee osteoarthritis

Background and aimGoupi Plaster (GP) is topical traditional Chinese medicine preparation. It has been used to treat Knee Osteoarthritis (KOA) in clinical practice of traditional Chinese medicine (TCM). However, the mechanisms of GP relieve KOA are poorly understood. Experimental procedureRabbit models of KOA were established and treated with GP. Knee cartilage pathology was analyzed using hematoxylin and eosin staining, while plasma levels of inflammatory factors (interleukin (IL)-4, IL-6, and IL-17) and skin neurotransmitters (calcitonin gene-related peptide (CGRP), substance P (SP), and5-hydroxytryptamine (5-HT)) were measured by enzyme linked immunosorbent assay. Metabolomics based on GC-TOF-MS analysis screened for skin biomarkers as well as relevant pathways. Network pharmacology screened for relevant skin targets as well as relevant pathways, and finally, MetScape software was utilized to integrate the results of metabolomics and network pharmacology to screen for key skin targets, key metabolites, and key pathways for GP treatment of KOA. Results and conclusionGP administration substantially repaired cartilage surface breaks in KOA and led to relatively intact cartilage structure and normal cell morphology. GP decreased plasma levels of IL-6 and IL-17 and skin levels of CGRP, SP and 5-HT while increased plasma IL-4. GP administration normalized the levels of 15 metabolites which were changed in KOA. Network pharmacology analysis identified 181 targets. Finally, 3 key targets, 5 key metabolites and 3 related pathways were identified, which suggested that GP improved skin barrier function and skin permeability by regulating skin lipid metabolism. GP treatment also regulated skin amino acid levels and subsequently affected neurotransmitters and signaling molecules. In addition, the purinergic signaling pathway was also involved in the treatment of GP against KOA.In conclusion, GP treatment is associated with changes in skin lipid metabolism, neurotransmitters, and the purinergic signaling pathway.

Targeting altered calcium homeostasis and uncoupling protein-2 promotes sensitivity in drug-resistant breast cancer cells.

Metastatic breast cancer has the highest mortality rate among women owing to its poor clinical outcomes. Metastatic tumors pose challenges for treatment through conventional surgery or radiotherapy because of their diverse organ localization and resistance to various cytotoxic agents. Chemoresistance is a significant obstacle to effective breast cancer treatment owing to cancer's heterogeneous nature. Abnormalities in intracellular calcium signaling, coupled with altered mitochondrial metabolism, play a significant role in facilitating drug resistance and contribute to therapy resistance. Uncoupling protein-2 (UCP2) is considered as a marker of chemoresistance and is believed to play a major role in promoting metabolic shifts and tumor metastasis. In this context, it is imperative to understand the roles of altered calcium signaling and metabolic switching in the development of chemotherapeutic resistance. This study investigates the roles of UCP2 and intracellular calcium signaling (Ca2+ ) in promoting chemoresistance against cisplatin. Additionally, we explored the effectiveness of combining genipin (GP, a compound that reverses UCP2-mediated chemoresistance) and thapsigargin (TG, a calcium signaling modulator) in treating highly metastatic breast cancers. Our findings indicate that both aberrant Ca2+ signaling and metabolic shifts in cancer cells contribute to developing drug-resistant phenotypes, and the combination treatment of GP and TG significantly enhances drug sensitivity in these cells. Collectively, our study underscores the potential of these drug combinations as an effective approach to overcome drug resistance in chemoresistant cancers.

Hormesis of glyphosate on ferulic acid metabolism and antifungal volatile production in rice root biocontrol endophyte Burkholderia cepacia LS-044

Glyphosate (GP, N-phosphonomethyl glycine) is one of the most popular organophosphate herbicides widely used in agricultural practices worldwide. There have been extensive reports on the biohazard attributes and hormetic impacts of GP on plant and animal systems. However, the effects of GP on plant growth-promoting microbes and its ecological relevance remain unknown. Here, we show that GP does exert a hormetic impact on Burkholderia cepacia LS-044, a rice (Oryza sativa ssp. japonica cv. Tainung 71) root endophytic isolate. We used increasing doses of ferulic acid (FA, 1–25 mM) and GP (0.5–5 mM) to test the growth and antifungal volatile production in LS-044 by electrochemical, liquid chromatographic, gas chromatographic and spectrophotometric means. GP treatment at a low dose (0.5 mM) increased FA utilization and significantly (P < 0.0001) enhanced antifungal volatile activity in LS-044. Although FA (1 mM) was rapidly utilized by LS-044, no chromatographically detectable utilization of GP was observed at tested doses (0.5–5 mM). LS-044 emitted predominant amounts of tropone in addition to moderate-to-minor amounts of diverse ketones and/or their derivatives (acetone, acetophenone, 2-butanone, 1-propanone, 1-(2-furanyl-ethanone, 1-phenyl-1-propanone and 1-(3-pyridinyl)-1-propanone), d-menthol, 2-methoxy-3-(1-methylethyl)-pyrazine, dimethyl disulfide, pyridine and ammonium carbamate when grown under GP supplement. GP hormesis on LS-044 induced phenotypic variations in O. sativa ssp. japonica cv. Tainan 11 as evident through seed germination assay. Genes involved in the transformation of FA, and a key gene encoding 5-enolpyruvylshikimate 3-phosphate synthase (EPSPS) with Gly-94 and Tyr-95 residues localized at active site most likely rendering EPSPS sensitivity to GP, were detected in LS-044. This is the first report on the GP hormesis influencing morphological and metabolic aspects including volatile emission in a biocontrol bacterium that could modulate rice plant phenotype.

349 How a Service Evaluation Carried Out by Junior Doctors Helped the Post Pandemic Management of Lumps and Bumps

Abstract Aim The GI surgery department deals with many clinical conditions including lumps and bumps that affect the torso, posterior neck, groin, buttock, perianal and perineal areas. Over the pandemic it was noted that there were many referrals for ‘lumps and bumps’ at a time where theatre capacity and staffing was limited. To create a referral pathway to assess patients for suitability for referral and treatment in the secondary care setting/ to determine which lesions were suitable for treatment in the community. Method A review of 374 cases of lumps and bumps referred between 2019 and 2021. Various patient factors were taken in to account, as well as the size and type of lesion to determine whether it could be managed in the community under local anaesthetic. Results Of the total cases, 45% were deemed to be suitable for treatment in community. Of all lesion types, epidermoid cysts were most suitable for GP treatment. Patients were travelling long distances to reach the hospital and we were treating patients outside our catchment area. We also found that the average waiting time from referral until treatment for lesions managed in community was nearly 9 times shorter than when managed in the hospital setting. Conclusions A new referral pathway was created for all of South East London to reduce the number of lumps and bumps referred. This ultimately allowed for increased theatre capacity for more complex cases, ensured faster treatment and reduced travel distances for patients.

Gynostemma pentaphyllum Makino extract induces hair growth and exhibits an anti-graying effect via multiple mechanisms.

In traditional Asian medicine, Gynostemma pentaphyllum Makino leaf extract (Gp) is used to treat aging, metabolic syndrome, diabetes, and neurodegenerative diseases. Hair loss and hair-graying are common phenomena that haunt everyone. However, whether Gp activities on inhibition of hair loss and getting gray have been rarely studied. Study the Gp activity and mechanism by in vivo and in vitro experiments to explore its application on hair health. In the present study, we determined the effects of Gp on the expression of hair growth-related genes and proliferation of human dermal papilla cells (hDPCs). Furthermore, Gp was topically applied to the hair-shaved skin of male C57BL/6 mice, and the histological profile of the skin was studied. Because emotional stress may lead to melanocyte disappearance, norepinephrine-exposed mice B16 melanocytes were treated with Gp to elucidate the anti-hair graying capacity of Gp in response to this stress type. Gp stimulated the proliferation of hDPCs and the Wnt signaling pathways associated with hair growth; furthermore, the expression of the hair loss-related gene transforming growth factor-β1 was suppressed. Gp treatment significantly increased the size of hair follicles in the treated mice and stimulated them. Moreover, Gp not only increased melanin synthesis but also tyrosinase activity in B16 cells. Quantitative real-time polymerase chain reaction revealed that Gp increased melanin synthesis by increasing the expression of tyrosine-related protein-1, tyrosine-related protein-2, tyrosinase, and microphthalmia-associated transcription factor. Our study provides preclinical evidence regarding the potential of Gp as a promising hair growth and anti-graying agent.

Learning from Errors: Qualitative Analysis of Expert Reports on Malpractice in Family Medicine

Expert committees of the German medical associations provide a free and out-of-court evaluation of putative cases of medical malpractice. They prepare reports that contain valuable information on process steps that precede the actual treatment error. The aim of the present study was to identify and systematically categorize individual process steps in the expert reports and thus to lay the foundations for the understanding of malpractice evaluation processes. In this study, ten randomly selected and anonymized expert reports of the Expert Committee for Questions of Medical Liability of the District Medical Association of South Württemberg with identified GP treatment errors were evaluated, using the method of qualitative content analysis. In an iterative process, central elements of expert reports were classified into a deductively and inductively built category system. Six main categories with associated subcategories were identified: 1) structural aspects of the report, 2) doctor-patient communication, 3) medical course, 4) patient's experience, 5) action by the GP team, and 6) coordinative role in the health care system. The category system showed sufficient reliability with repeated use. This study offers an opportunity to learn from errors. The proposed system allows to structure the complexity of expert reports on GP malpractice and may thus serve as a tool in various contexts. In particular, it facilitates the preparation and comparative analysis of reports in a structured way. It could also be used in health care research as well as in education and training.

Addressing current challenges in optimization of lipid management following an ACS event: Outcomes of the ACS EuroPath III initiative.

Low-density lipoprotein cholesterol (LDL-C) lowering is key to reduce atherosclerotic disease progression and recurrent events for patients after acute coronary syndrome (ACS). However, LDL-C management for post-ACS patients remains challenging in clinical practice. The ACS EuroPath III project was designed to optimize LDL-C management in post-ACS patients by promoting guideline implementation and translating existing evidence into effective actions. Three surveys targeting cardiologists (n = 555), general practitioners (GPs; n = 445), and patients (n = 662) were conducted in Europe, with the aim of capturing information on patient characteristics and treatment during acute phase, discharge and follow-up. GPs' and patients' opinions on key treatment aspects were also collected. Based on survey results, international experts and clinicians identified areas of improvement and generated prototype solutions. Participants voted to select the most feasible and replicable proposals for co-development and implementation. Five key areas of improvement were identified: (1) inappropriate treatment prescribed at discharge; (2) lack of lipid guidance in the discharge letter; (3) inadequate lipid-lowering therapy (LLT) optimization; (4) gaps in guideline knowledge and lack of referral practices for GPs; (5) patients' concerns about lipid management. Proposed solutions for these focus areas included development of a treatment algorithm for the acute phase, a standardized GP discharge letter, an assessment tool for LLT efficacy at follow-up, an education plan for GPs/patients and a patient engagement discharge kit. The standardized GP discharge letter and treatment algorithm have been selected as the highest priority solutions for development. These initiatives have the potential to improve adherence to guidelines and patient management after ACS.

Effect of implementation of mental health services within primary care on GP detection and treatment of mental disorders in Israel

BackgroundPsychiatric morbidity is frequent in primary care, but a substantial proportion of these psychiatric problems appear to be neither recognized nor adequately treated by GPs. There exists a number of models of introduction of mental health services (MHS) into primary care, but little data are available on their effect on GPs’ detection or management of mental disorders. The study aimed to measure the effect of referring patients to a psychiatrist within primary care (Shifted OutPatient model—SOP) or consultation of psychiatrists by the GPs (Psychiatric Community Consultation Liaison—PCCL) on the detection and treatment of mental disorders by GPs.MethodsIn six primary care clinics in Israel (three “SOP clinics” and three “PCCL clinics”), GP detection of mental disorders and treatment of GP-detected cases were evaluated before and after provision of 1-year MHS, according to GP questionnaires on a sample of primary care consecutive attenders whose psychological distress was determined according to the GHQ12 and psychiatric disorders according to the Composite International Diagnostic Interview.ResultsAfter model implementation, a significant reduction in detection of mental disorders was found in SOP clinics, while no significant change was found in PCCL clinics. No significant change in detection of distress was found in any clinic. An increase in referrals to MHS for GP-diagnosed depression and anxiety cases, a reduction in GP counselling for GP-detected cases and those with diagnosed anxiety, an increased prescription of antidepressants and a reduced prescription of antipsychotics were found in SOP clinics. In PCCL clinics, no significant changes in GP management were observed except an increase in referral of GP-diagnosed depression cases to MHS.ConclusionsMHS models did not improve GP detection of mental disorders or distress, but possibly improved referral case mix. The SOP model might have a deskilling influence on GPs, resulting from less involvement in treatment, with decrease of detection and counselling. This should be taken into consideration when planning to increase referrals to a psychiatrist within primary care settings. Lack of positive effect of the PCCL model might be overcome by more intensive programs incorporating educational components.

Аналіз клінічної ефективності комплексної терапії генералізованого пародонтиту у хворих на подагру

Resume. Gout is a common disease, the basis of which is a violation of purine metabolism with an increased concentration of uric acid in the blood, excessive deposition of uric acid salts in the tissues of the musculoskeletal system and internal organs, with the subsequent development of inflammatory and, later, destructive and sclerotic changes in them . One of the relevant interdisciplinary problems is comorbidity in gout, which is closely related to cardiovascular pathology, chronic kidney disease, and metabolic syndrome, which includes diabetes, obesity, hypertension, and dyslipidemia. In connection with the steady trend towards a significant "rejuvenation" of patients with gout, considerable interdisciplinary scientific interest is caused by the search for relationships between gout and periodontal pathology. The aim of the study was to analyze the clinical effectiveness of complex pathogenetic treatment of generalized periodontitis in patients with gout. For the complex treatment of generalized periodontitis, 70 patients with gout were divided into 2 groups: the main group of patients was treated according to the developed pathogenetic scheme, the control group (35 humans) used traditional methods. The complex treatment of generalized periodontitis in patients with gout involved a combination of various therapeutic approaches and included professional oral hygiene and drug therapy. In the subjects of the main group, who used the developed pathogenetically directed scheme for the treatment of generalized periodontitis, a significant improvement in the state of the periodontal tissues was observed: the elimination of the inflammatory process and bleeding gums, a decrease in the depth of the periodontal pockets during all periods of observation. In the patients of the control group , who were treated with generally accepted methods, a noticeable improvement in the periodontal status was observed only after 1 month. In the long term of observation, there was a gradual progression of the pathological process in the periodontium, which testified to the insufficient effectiveness of the treatment of GP. Key words: gout, generalized periodontitis, treatment, clinical effectiveness.

314 Steer Production Performance and Enteric gas Emissions Associated with Free-Choice Mineral Supplement Infused with Varying Levels of Garlic Powder

Abstract The addition of phytogenics such as garlic powder into beef mineral supplements is motivated by the potential for increased mineral intake and associated insectifugal outcomes. This 3-yr study compared feed and mineral intake and performance in crossbred beef steers that received free-choice mineral supplements infused with or without garlic powder (5% inclusion). The study design was a randomized complete block design where each steer (n=180) was randomly assigned to either a 5%GP or 0%GP treatment group, balancing for breed composition and initial body weight. Different garlic brands (5%GPLO, 5%GPSE, and 5%GPWL) were also assessed during the third year of study. Individual feed and mineral supplement intakes were monitored using automatic feeding units from different bunks ad libitum. Enteric gas fluxes (CH4, CO2, O2, and H2) were also measured with an automated head-chamber emission monitoring system. Over 3 yr, there was no difference (P &amp;gt; 0.05) in dry matter intake, average daily gain, and gain to feed ratio between 5%GP and 0%GP groups, but supplement intake was greater (P &amp;lt; 0.05) for 5%GP (206 gd-1) compared with 0%GP (152 gd-1) treatment. Comparing all brands in third year showed differences in mineral consumption where 5%GPLO (223 gd-1) had greatest (P &amp;lt; 0.0001) supplement intake, but there was no difference (P &amp;gt; 0.05) among 5%GPSE (133 gd-1), 5%GPWL (103 gd-1) and 0%GP (145 gd-1). Enteric gas fluxes did not differ between 5%GPLO and 0%GP for CH4 (129 gd-1, 119 gd-1; P = 0.69), CO2 (7912 gd-1, 7351 gd-1; P = 0.31), O2 (5394 gd-1, 4816 gd-1; P = 0.15) and H2 (0.84 gd-1, 0.67 gd-1; P = 0.42). Results suggest that infusing garlic at 5% increased supplement intake in feedlot cattle but had no effect on growth or enteric gas fluxes. Differences in the brands evaluated here may be related to the shelf/storage age of the products and the bioactive compound profiles.

Hypouricemic Effect of Submerged Culture of Ganoderma lucidum in Potassium Oxonate-Induced Hyperuricemic Rats.

Hyperuricemia is a disease caused by a high level of uric acid in the blood. It is an important factor for gout and may be linked to renal and hepatic failure. The objective of this study was to investigate the hypouricemic effects of submerged culture of Ganoderma lucidum. The lyophilized powder of mycelium (GM) and extracellular polysaccharides (GP) of the G. lucidum submerged culture were prepared. The contents of hypouricemic components, including phenolics and flavonoids, in GM (34.33 ± 0.41 mg/g and 0.32 ± 0.01 mg/g) were higher than that in GP (20.52 ± 1.49 mg/g and not detected). The hypouricemic effect of GM and GP was evaluated in potassium oxonate (PO)-injected rats. The average food intake (23.3 ± 1.2 g/day) and body weight (355.7 ± 28.0 g) were decreased, and the serum level of uric acid (5.56 ± 0.41 mg/dL) was increased in PO-injected rats. However, allopurinol (10 mg/kg b.w.) or GM treatment (200 or 400 mg/kg b.w) improved food intake (26.3 ± 2.7 g/day) and reduced the level of uric acid (4.45 ± 0.46 mg/dL). In parallel, the activity of hepatic xanthine oxidase (XOD) was downregulated from 841.29 ± 299.58 μU/mg protein to 540.80 ± 199.20 μU/mg protein. Moreover, GM and GP (200 or 400 mg/kg b.w) alleviated the level of blood urea nitrogen (BUN) from 30.49 ± 4.71 to 21.16 ± 4.25 mg/dL. GP treatment also diminished the level of alanine transaminase (ALT) from 52.63 ± 18.82 to 27.35 ±6.82 U/L. These results clearly demonstrated the hypouricemic effect of submerged G. lucidum culture and their potential against hyperuricemia-associated renal and hepatic damage. GM was more potent to alleviate hyperuricemia, and GP was more potent to improve renal and hepatic function.

Opportunities to improve nitrogen use efficiency in an intensive vegetable system without compromising yield

Intensive vegetable cropping systems rely heavily on nitrogen (N) inputs from multiple synthetic and organic fertilizer applications. The majority of applied N is lost to the environment through numerous pathways, including as nitrous oxide (N2 O). A field trial was conducted to examine the opportunities to reduce N input in an intensive vegetable system without compromising yield. Treatments applied were control (no N), manure (M, 408kg N ha-1 from chicken manure), grower practice (GP, 408kg N ha-1 from chicken manure + 195kg N ha-1 from fertilizer), and 2/3 GP (two-thirds of the total N input in GP), all with and without 3,4-dimethylpyrazole phosphate (DMPP). Nitrogen recovery in the GP treatment was determined using 15 N-labeled fertilizer. Using only manure significantly lowered celery (Apium graveolens L.) yield and apparent N use efficiency (ANUE) compared with GP. Reducing N input by one-third did not affect yield or ANUE. Use of DMPP increased ANUE despite no yield improvement. More than 50% of the applied N in the GP treatment was lost to the environment, with almost 10kg N ha-1 emitted as N2 O over the season, which was 67 times more than from the control. Reducing the N input by one-third or using manure only reduced N2 O emissions by more than 70% relative to GP. This study shows that there is a clear opportunity to reduce N input and N2 O emissions in high-fertilizer-input vegetable systems without compromising vegetable yield.

Parathyroid hormone ameliorates osteogenesis of human bone marrow mesenchymal stem cells against glucolipotoxicity through p38 MAPK signaling.

Diabetes mellitus (DM)-induced glucolipotoxicity is a factor strongly contributing to alveolar bone deficiency. Parathyroid hormone (PTH) has been identified as a main systemic mediator to balance physiological calcium in bone. This study aimed to uncover PTH's potential role in ameliorating the osteogenic capacity of human bone marrow mesenchymal stem cells (HBMSCs) against glucolipotoxicity. Optimal PTH concentrations and high glucose and palmitic acid (GP) were administered to cells, followed by alkaline phosphatase (ALP) staining and ALP activity assay. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and Immunoblot were carried out for assessing mRNA and protein amounts, respectively. Cell counting kit-8 (CCK-8) and flow cytometry were performed for quantitating cell proliferation. Osteogenesis and oxidative stress were determined, and the involvement of mitogen-activated protein kinase (MAPK) signaling was further verified. About 1-50 mmol/ml GP significantly inhibited the osteogenic differentiation of HBMSCs. 10-9 mol/L PTH was found to be the optimal concentration for HBMSC induction. PTH had no effects on HBMSC proliferation, with or without GP treatment. PTH reversed inadequate osteogenesis and excessive oxidative stress in GP-treated HBMSCs. Mechanistically, PTH activated p38 MAPK signaling, while inhibiting p38 MAPK-suppressed PTH's beneficial impacts on HBMSCs. Collectively, PTH promotes osteogenic differentiation in HBMSCs against glucolipotoxicity via p38 MAPK signaling.

Gypenoside inhibits ox-LDL uptake and foam cell formation through enhancing Sirt1-FOXO1 mediated autophagy flux restoration

BackgroundGypenoside (GP) is the major bioactive constituent of G. pentaphyllum, a traditional Chinese medicine. It has been reported that GP can affect autophagy and lipid metabolism in cultured cells. We hypothesize that GP can inhibit foam cell formation in cultured macrophages through autophagy modulation. MethodsTHP1 cells were cultured and treated with oxidized low-density lipoprotein (ox-LDL), followed by GP treatment at different concentrations. The autophagy flux was evaluated using western blot and confocal microscope analyses. The ox-LDL uptake and foam cell formation abilities were measured. ResultsWe found that ox-LDL impaired the autophagy flux in the cultured macrophages, indicated by a significant reduction of LC3-II and autophagosome puncta quantification, as well as an accumulation of p62 proteins. GP treatment, however, dose-dependently restored the autophagy flux impaired by ox-LDL and reduced the ox-LDL uptake and foam cell transformation from THP1 cells, which can be alleviated, or exacerbated, by modulation of autophagy status using autophagy enhancer or inhibitor. Coimmunoprecipitation assays showed that GP up-regulated Srit1 and FOXO1 expression and enhanced their direct interaction, and thus contributed to the regulation of autophagy. ConclusionGP inhibits ox-LDL uptake and foam cell formation through enhancing Sirt1-FOXO1 mediated autophagy flux restoration, suggesting this compound has therapeutic potential for atherosclerosis.

Polyphenol-induced improvements in glucose metabolism are associated with bile acid signaling to intestinal farnesoid X receptor.

IntroductionBile acid (BA) biotransformation by gut bacteria impacts BA profile and signaling to nuclear receptors, such as the farnesoid X receptor (FXR) regulating glucose metabolism. Altered BA-FXR signaling was therefore investigated as a potential mechanism linking polyphenol-induced gut bacterial changes and improved glucose metabolism.Research design and methodsDiabetic db/db were fed low-fat diet (LFD) or LFD supplemented with a proanthocyanidin-rich extract of grape polyphenols (LFD-GP) for 4 weeks. Metabolic phenotypes, serum BAs, gut microbiota composition, and gene expression markers relevant to gut barrier and glucose metabolism were assessed. Gut organoids were used to investigate effects of individual BAs on ileal FXR activity.ResultsCompared with LFD-fed controls, GP supplemented db/db mice showed improved glucose metabolism, decreased relative abundance of gut bacteria associated with production of secondary BAs (SBAs), and depleted serum levels of SBAs taurohyodeoxycholic acid (THDCA), ω-muricholic acid (ωMCA), and tauro-ω-muricholic acid (TωMCA). Serum levels of primary BAs (PBAs) increased, consistent with higher gene expression of PBA synthesis enzyme Cyp7a1. GP-induced BA changes associated with FXR inhibition as evidenced by reduced expression of FXR-responsive genes Shp, Fgf15, and Fabp6 in ileum tissue as well as hepatic Shp, which negatively regulates PBA synthesis. GP treatment did not affect expression of hepatic Fxr or expression of Abcb11, Slc51b, and Obp2a genes controlling BA transport. Ceramide biosynthesis genes Smpd3, Sptlc2, and Cers4 were decreased in liver and intestine suggesting lower tissue ceramides levels may contribute to improved glucose metabolism. THDCA, ωMCA, and TωMCA behaved as FXR agonists in ileal organoid experiments; therefore, their depletion in serum of GP-supplemented db/db and wild type (WT) mice was consistent with FXR inhibition.ConclusionThese data suggest that by altering the gut microbiota, GPs modify BA-FXR signaling pathways to promote glucoregulation.

General practice patients starting treatment for substance use problems: observations from two data sources across levels of care

BackgroundIn Belgium, the incidence of treatment episodes for substance use problems is monitored by the Network of Sentinel General Practices (SGP), and at higher, specialist care levels by the Treatment Demand Indicator (TDI) surveillance. Using both data sources, we examine 1) how patients starting specialist treatment for substance use problems on referral by their GP compare to those that were referred by non-GP caregivers; 2) how patients starting GP treatment for substance use problems without receiving concurrent specialist treatment compare to those who did.MethodsBoth surveillances are based on the TDI protocol for reporting data to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) on individuals starting treatment as a result of their substance use. Data from 2016 and 2017 were examined using 95% confidence intervals and multivariate logistic regression.ResultsAccording to TDI-data (n = 16,543), determinants of being referred by a GP (versus by a non-GP caregiver) for specialist treatment were age ≥ median (OR 1.25; 95% CI 1.13–1.38), education ≥ secondary level (OR 1.27; 95% CI 1.15–1.41), recent employment (OR 1.71; 1.56–1.88), recent stable accommodation (3.62; 95% CI 3.08–4.26), first treatment episode (OR 1.72; 95% CI 1.57–1.87), recent daily primary substance use (OR 1.46; 95% CI 1.33–1.59) and mono substance use (OR 1.23; 95% CI 1.04–1.48). Type of substance use was a significant determinant with higher odds of using pharmaceuticals (and alcohol) (OR 1.24; 95% CI 1.04–1.48), and lower odds of using cannabis only/primarily (OR 0.73; 95% CI 0.62–0.86), with reference to street drugs minus cannabis only/primarily. According to SGP data (n = 314), determinants of starting GP treatment without concurrent specialist treatment were recent employment (OR 2.58; 95% CI 1.36–4.91), first treatment episode (OR 2.78; 95% CI 1.39–5.55) and living in the Brussels or Walloon region (OR 1.97; 95% CI 1.06–3.66).ConclusionsThis study provides a useful insight into the general practice population treated for substance use problems. It shows that both surveillances consistently found a relatively favourable profile of general practice patients with substance use problems.

Antioxidant stress as an indicative marker of diagnosis and vector verification of treatment of generalized parodontitis with anorexia nervosa

Purpose of the study. To study the balance of fatty acid spectrum of oral lipids as a marker of oxidant-antioxidant stress in patients with generalized parodontitis with anorexia nervosa.&#x0D; Materials and methods. The study metabolic disorders of fatty acids oral fluid was conducted in 28 patients with GP, primary-I, I–II degree, chronic course associated with anorexia nervosa, (average age 26 ± 3,8) – the main group (M). The comparison group (C) included 23 patients with GP, primary-I, I–II degree, chronic course with no eating disorders. The control group consisted of 25 healthy individuals of the same age category. Patients' oral fluid was used as the object of study. In the spectrum of fatty acids of lipids of the oral fluid, the 9 most informative fatty acids were identified: myristic C 14:0,&#x0D; pentodecane C 15:0, palmitic C 16:0, margarine C 17:0, stearic C 18:0, oleic C 18:1, linoleum C 18:2, linolen C 18:3, arachidone C 20:4. Quantification of the spectrum of lipid fatty acids was performed by the method of normalization of planes and determined the proportion of acids in percents.&#x0D; Results. The fatty acid content of the oral fluid of patients in the main group was significantly different from the control parameters. 12% in patients with anorexia nervosa significantly increased the amount of saturated fatty acids by increasing the content of palmitic acid (C 16 0) and reducing stearic acid (C 18:0) by 2 times compared with control.&#x0D; It was established that the sum of unsaturated fatty acids was reduced by 2 times due to polyunsaturated fatty acids, and this level was significantly reduced by 2 times in comparison with control group due to 3 times reduction of linoleum fatty acid (C 18:2), linolenic fatty acid (C 18:3) 2-fold and unreliable increase in arachidone fatty acid (C 20:4), in comparison with the control, which in our opinion, reflects disturbance of the oxidant-antioxidant balance and is a marker of stress as an indicator of endogenous intoxication in patients with GP and anorexia nervosa.&#x0D; In patients with generalized parodontitis of primary-I, I–II degree, chronic course of anorexia nervosa in the oral fluid there was a significant violation of lipid metabolism – increase in the content of palmitic fatty acid (C 16:0) and decrease in the content of linoleic fatty acid (C 18:2).&#x0D; Conclusions. The revealed features of the course of GP in patients with anorexia nervosa indicate the need for additional treatment and prophylactic measures in this group of patients. Disorders of the fatty acid spectrum of the oral fluid in these patients were necessitate the inclusion in the traditional scheme of treatment of GP aimed at correcting the processes of antioxidant protection, which increase the effectiveness of therapeutic and prophylactic effects.

Short-term outcomes of double versus single pyloromyotomy at peroral endoscopic pyloromyotomy in the treatment of gastroparesis (with video)

The prevalence of gastroparesis (Gp), a chronic debilitating disorder, and resulting hospitalizations are increasing. Gastric peroral endoscopic pyloromyotomy (POP or GPOEM) is a novel technique in the treatment of refractory Gp. Despite the initial promising results of GPOEM, one-third of patients do not exhibit any clinical response. Furthermore, loss of clinical response was reported in several studies. No response or loss of response after GPOEM may be related to inadequate myotomy. The aim of our study is to examine whether double pyloromyotomy at GPOEM is superior to single pyloromyotomy. A retrospective case-controlled study of patients who underwent GPOEM for refractory Gp at our tertiary care institution between June 2015 and March 2018 was performed. Because the follow-up time for the single myotomy group was much longer than that of the double myotomy group, we matched the length of follow-up for the single myotomy group to that of the double myotomy group. The outcomes were measured by the changes in the Gastroparesis Cardinal Symptom Index (GCSI) before and 3 to 6 months after the procedure. Adverse events and other procedural and clinical parameters were also compared. Ninety patients underwent GPOEM (55 single and 35 double pyloromyotomy). The mean age was 47 ± 14 years, and the mean duration of symptoms was 5.3 ± 4.4 years. The average GCSI score was 3.8 before the GPOEM, and the average GCSI score 6 months after procedure was 1.8. Thirty-seven of 55 (67%) patients who underwent single pyloromyotomy achieved clinical response compared with 30 of 35 (86%) patients who underwent double pyloromyotomy. There were no significant differences for procedure time, postoperative pain, or length of hospital stay between the 2 groups. There was no difference in adverse events in the 2 pyloromyotomy groups. Double pyloromyotomy is a safe and feasible technique during GPOEM. Clinical success was higher in patients undergoing double pyloromyotomy compared with single pyloromyotomy in this nonrandomized, short-term follow-up study. Long-term studies are needed to further confirm our results.