Reductions of food intake and body weight in diet-induced obese rats following chronic treatment with a monomeric peptide multiagonist.

INTRODUCTION: While therapies based on endogenous gut peptides such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been compelling therapeutic agents for obesity and type 2 diabetes (T2D), only a few have achieved long-term weight loss and all have shown significant side-effects, including nausea/malaise and gastrointestinal ailments. OBJECTIVE: As the pathophysiology of obesity is driven by dysregulation of multiple, inter-related, pathways, we tested a novel peptide targeting multiple receptors of complementary neurocircuits regulating the controls of energy balance. METHODS: Response to daily injections of GEP44, a GLP-1R and neuropeptide Y1R and Y2R receptor (Y1R/Y2R) triple agonist was tested vs. the GLP-1R agonist liraglutide (LIRA) in diet-induced obese (DIO) male and female rats. Glucose tolerance tests after intraperitoneal injection of glucose (IPGTT) were performed at baseline and after 14-d of treatment in GEP44 treated rats. Other metabolic parameters were assessed in blood at the end of a 28-d intervention. RESULTS: Upon conclusion at 28-d, body weight reduction compared to vehicle was -15.6%/-11.9% in response to GEP44, vs. -9.7%/-5.1% after LIRA, males, and females, respectively. Significant reductions of cumulative food intake occurred over 28-d in female rats treated with GEP44 (-30%; p < 0.0001), vs. LIRA (-10%), and in male rats GEP44 (-39%; p < 0.0001), vs. LIRA (-20%; p = 0.003). In IPGTTs, a similar stimulation glucose induced insulin secretion was noted in rats treated with GEP44 and LIRA. CONCLUSION: The strong reductions of body weight in response to long-term applications of the triple agonist GEP44 confirms the therapeutic potential of targeting multiple receptors for achieving more robust and potentially more sustained improvement of energy balance.

What are the effects of pharmacological, non-invasive brain stimulation and psychological interventions, and their combination, in the treatment of post-stroke depression? A Cochrane Review summary with commentary.

BACKGROUND: Post-stroke depression (PSD) is a prevalent condition that can significantly influence the recovery process. OBJECTIVE: To assess the effects of pharmacological, non-invasive brain stimulation and psychological interventions, and their combination on PSD. METHODS: A summary of the Cochrane Review by Allida et al. (2023), with comments from a rehabilitation perspective. RESULTS: Sixty-one studies with 5831 participants were included in the Cochrane Review. Very low-certainty evidence indicated favorable treatment effects of pharmacological interventions, psychological therapies, and the combination of pharmacological intervention and non-invasive brain stimulation on PSD. Pharmacological intervention has resulted in increased side effects associated with the central nervous system and gastrointestinal system, with very low-certainty evidence. CONCLUSION: Evidence for the effectiveness of pharmacological, psychological, and combination therapies for the management of PSD is uncertain, as the quality of the evidence has been assessed as very low. Therefore, further studies with improved methods should investigate pharmacological and non-pharmacological interventions for the treatment of depression in stroke survivors.

A proof of concept phase II study with the PDE-4 inhibitor roflumilast in patients with mild cognitive impairment or mild Alzheimer's disease dementia (ROMEMA): study protocol of a double-blind, randomized, placebo-controlled, between-subjects trial.

BACKGROUND: Research into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer's disease (AD) dementia. METHODS: The study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 µg roflumilast, and 100 µg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants' performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants. DISCUSSION: The outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders. TRIAL REGISTRATION: The Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL ) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1 ) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020.

Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly defined as non-alcoholic fatty liver disease (NAFLD), is a disorder marked by the excessive deposition of lipids in the liver, giving rise to a spectrum of liver pathologies encompassing steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. Despite the alarming increase in its prevalence, the US Food and Drug Administration has yet to approve effective pharmacological therapeutics for clinical use. MASLD is characterized by the accretion of lipids within the hepatic system, arising from a disarray in lipid provision (whether through the absorption of circulating lipids or de novo lipogenesis) and lipid elimination (via free fatty acid oxidation or the secretion of triglyceride-rich lipoproteins). This disarray leads to the accumulation of lipotoxic substances, cellular pressure, damage, and fibrosis. Indeed, the regulation of the lipid metabolism pathway is intricate and multifaceted, involving a myriad of factors, such as membrane transport proteins, metabolic enzymes, and transcription factors. Here, we will review the existing literature on the key process of lipid metabolism in MASLD to understand the latest progress in this molecular mechanism. Notably, de novo lipogenesis and the roles of its two main transcription factors and other key metabolic enzymes are highlighted. Furthermore, we will delve into the realm of drug research, examining the recent progress made in understanding lipid metabolism in MASLD. Additionally, we will outline prospective avenues for future drug research on MASLD based on our unique perspectives.

[Setting up, running and evaluating NMIs as part of the "ageing well" project]. / Mise en place, déroulement et évaluation des INM dans le cadre du projet "Bien vieillir".

Non-drug interventions (NDIs) are recommended as a first-line treatment in gerontology to address the psychological and behavioral symptoms of dementia. This article illustrates the NMIs implemented, how they are carried out and how they are evaluated as part of the Bien vieillir project at Nice University Hospital.

Treatment of hypothalamic obesity in people with hypothalamic injury: new drugs are on the horizon.

Hypothalamic obesity (HO) is a complex and rare disorder affecting multiple regulatory pathways of energy intake and expenditure in the brain as well as the regulation of the autonomic nervous system and peripheral hormonal signaling. It can be related to monogenic obesity syndromes which often affect the central leptin-melanocortin pathways or due to injury of the hypothalamus from pituitary and hypothalamic tumors, such as craniopharyngioma, surgery, trauma, or radiation to the hypothalamus. Traditional treatments of obesity, such as lifestyle intervention and specific diets, are still a therapeutic cornerstone, but often fail to result in meaningful and sustained reduction of body mass index. This review will give an update on pharmacotherapies of HO related to hypothalamic injury. Recent obesity drug developments are promising for successful obesity intervention outcomes.

Preventive effects of 13 different drugs on colorectal cancer: a network meta-analysis.

Introduction: The aim of the study was to evaluate the preventive effect of 13 drugs on colorectal cancer (CRC) and guide the clinical application of these drugs. Material and methods: PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure were searched for randomized controlled trials (RCTs) and cohort studies. The Cochrane bias risk assessment tool and the Newcastle-Ottawa Scale quality evaluation tool were used to evaluate the quality of the included RCTs and cohort studies. The funnel plot was used to analyze publication bias. A network meta-analysis of the extracted data was conducted using Stata16.0 software. Results: A total of 57 studies (34 RCTs and 23 cohort studies) involving 82719 participants were included. The network meta-analysis revealed that the quality of the included studies was good; the funnel plot showed no obvious publication bias. The network meta-analysis showed that the preventive effect of 13 drugs on CRC was better than that of the placebo. Allopurinol (SUCRA: 97.2%) was found to have the best effect, followed by berberine (SUCRA: 89.9%), non-aspirin NSAIDs (SUCRA: 84.5%), statins (SUCRA: 66.5%), metformin (SUCRA: 66.3%), calcium (SUCRA: 48.9%), mesalazine (SUCRA: 44.5%), ursodeoxycholic acid (SUCRA: 42.6%), vitamin D (SUCRA: 41.4%), mercaptopurine (SUCRA: 39.4%), aspirin (SUCRA: 30.4%), folic acid (SUCRA: 24.9%), and eicosapentaenoic acid (SUCRA: 16.3%). Conclusions: The preventive effect of allopurinol on CRC was better than that of the other 13 drugs. These results can help doctors and patients understand the preventative effects of these drugs more intuitively and provide an evidence-based basis for the clinical application of these drugs.

Effects of non-drug interventions on anxiety and depression in patients with heart failure: A systematic review based on Bayesian network meta-analysis.

BACKGROUND: To discuss the effect of non-drug interventions on anxiety and depression in patients with heart failure (HF) through Bayesian network meta-analysis. METHODS: Relevant literature was searched from PubMed, Web of Science, Embase and Medline from database establishment to October 2022 by a computer. Next, a screening was performed on randomized controlled trials (RCTs) for the effect of non-drug interventions on anxiety and depression in HF patients, followed by a collection of the related data. This meta-analysis was conducted based on Bayesian network, and the statistical analysis was conducted using R4.2 software. RESULTS: A total of 23 papers were enrolled into this study. The results of Bayesian network meta-analysis showed that compared with the control group and the structured video conferencing support (SVCS) group, telephone case management (TCM) could effectively reduce the anxiety and depression of HF patients. The ranking results revealed that TCM may be the most effective intervention to lower the risk of depression in HF patients, followed by Tai Chi Chuan and Chi Kung training (TCC) and structured telephone support (STS). CONCLUSION: TCM is the most effective intervention to prevent HF patients from anxiety and depression.

An autocatalytically-activatable hydrogen peroxide photoacoustic sensor for in situ visualization precise diagnosis and drug intervention tracing in diabetes syndrome.

In situ visualization for the diagnosis of diabetic syndrome and visual monitoring the response to drug treatment is a challenge. Herein, we designed and prepared an autocatalytically-activatable hydrogen peroxide photoacoustic (PA) sensor. We first prepared the FeMoOx nanoparticle with catalase activity, then combined it to 2,2'-azino-bis(3-ethylbenzothi-azoline-6-sulfonic acid) (ABTS) and distearoylphos-phoethanola-mine-polyethylene-glycol (DSPE-PEG) to construct a autocatalytically-activatable PA sensor (FeMoOx@ABTS@DSPE-PEG). In its presence, ABTS can be converted into oxidized ABTS·+ by H2O2. ABTS·+ exhibits strong light absorption in the near-infrared region, and can serve as an ideal contrast agent for PA imaging. H2O2 as a biomarker of oxidative stress response is closely related to the occurrence and development of diabetes mellitus and its complications. Therefore, FeMoOx@ABTS@DSPE-PEG was used as a PA sensor of H2O2 for visual monitoring of the progression of diabetes-induced liver injury and metformin-mediated treatment of diabetes. The autocatalytically-activatable PA sensor developed in this study provides a promising platform for in situ visual diagnosis of diabetes and its syndrome and monitoring the response to therapy.

[Thinking about the appropriation of gerontechnologies in non-drug interventions]. / Penser l'appropriation des gérontechnologies dans les interventions non médicamenteuses.

Today, many digital technical objects are introduced in geriatric care as part of non-medicinal interventions. This arrival generates both rejection and enthusiasm among caregivers. Moreover, many of these objects remain in the closet. It is therefore necessary to take into account a few elements in order to consider their appropriation.

Elevated circulating GPHB5 levels in women with insulin resistance and polycystic ovary syndrome: A cross-sectional study and multiple intervention studies.

Objective: GPHB5 has been found to be associated with glucose and lipid metabolism in animal studies. However, the association of GPHB5 with IR and metabolic disorders remains unknown, and there is a lack of research in humans. Our aim in this study was to investigate the relationship between circulating GPHB5 and metabolic disorders in humans. Methods: Bioinformatics analysis was performed to understand the relationship between GPHB5 and metabolic disorders. GPHB5 mRNA expression in mice and rats was determined using RT-qPCR. Circulating GPHB5 concentrations were measured with an ELISA kit. EHC and OGTT were performed in humans. Results: Bioinformatics analysis shows that GPHB5 is associated with metabolic disorders and PCOS. GPHB5 mRNA expression levels in the metabolic-related tissues of HFD-fed mice, db/db and ob/ob mice, and PCOS rats were significantly higher than those of WT mice or rats. In human studies, we find that circulating GPHB5 levels were significantly higher in women with IR and PCOS. GPHB5 levels were positively correlated with age, BMI, WHR, BP, FBG, 2 h-BG, FIns, 2 h-Ins, TC, LDL-C, HbA1c, and FFA, but negatively correlated with adiponectin. Furthermore, GPHB5 was positively correlated with DHEAS and FAI, while negatively correlated with SHBG, FSH, SHBG and FSH. The increased GPHB5 concentration was related to IR and PCOS. After the treatment of metformin, GLP-1RA (Lira), and TZDs, circulating GPHB5 levels were decreased. Conclusions: Our results reveal that circulating GPHB5 could be a biomarker and potential therapeutic target for IR and PCOS in women.

[Integrative oncology: Report and place for a dedicated consultation in a comprehensive cancer center]. / L'oncologie intégrative : état des lieux et place d'une consultation dédiée dans un centre de lutte contre le cancer.

Progress in the care of cancer patients has brought out new needs that go beyond the scope of conventional medicine regularly. Integrative oncology allows patients, besides specific care, to access complementary therapies (CT); with the aim of improving in this case the quality of life and the future of the patients and to help them become actors, before, during and after the treatment of their cancer. As for breast cancer management, international recommendations have been given for several years in favor of the use of CT, especially mind-body therapies, and regarded as effective care. Being able to refer patients suffering from any tumors to CT, through a structured procedure, integrated into the care pathway, would improve overall cancer management and the quality of life of the patients during chemotherapy. Improved communication from the oncologist about CT could better the relationships between the oncologist and the patient, and would be a better way to reduce the choice of practices that might be at risk, while improving compliance with conventional treatment. In this context, we report the opening of an integrative oncology consultation within a comprehensive cancer center, detailing the procedure of the consultation, describing the patients and their expectations, as well as the proposals made to them. This type of consultation is still underdeveloped in France and will be the subject of studies in the field of Humanities and social sciences.

A Realist Review of How Community-Based Drug Checking Services Could Be Designed and Implemented to Promote Engagement of People Who Use Drugs.

With rising numbers of drug-related deaths in the UK and globally, exploration of interventions that seek to reduce drug-related harm is essential. Drug checking services (DCS) allow people to submit drug samples for chemical analysis and receive feedback about the sample, as well as harm reduction advice. The use of DCS is often linked to festival and/or nightlife settings and to so-called 'recreational' drug use, but research has also shown the potential of community-based DCS as an intervention serving more varied demographics of people who use drugs, including more marginalised individuals and those experiencing drug dependence. Whilst there is a growing evidence base on the effectiveness of drug checking as a harm reduction intervention, there is still limited evidence of the underlying mechanisms and processes within DCS which may aid implementation and subsequent engagement of people who use drugs. This presents a challenge to understanding why engagement differs across types of DCS, and how best to develop and deliver services across different contexts and for different populations. To explore the contexts and mechanisms which impact engagement in community-based DCS, a realist review was undertaken to synthesise the international evidence for the delivery and implementation of DCS. There were 133 sources included in the review. From these sources the underlying contexts, mechanisms, and outcomes relating to DCS implementation and engagement were developed and refined into seven programme theories. The findings of this review are theoretically novel and hold practical relevance for the design of DCS, with implications for optimisation, tailoring, and implementing services to reach individuals in different settings.

The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment.

Recently, in the field of cancer treatment, the paradigm has changed to immunotherapy that activates the immune system to induce cancer attacks. Among them, immune checkpoint inhibitors (ICI) are attracting attention as excellent and continuous clinical results. However, it shows not only limitations such as efficacy only in some patients or some indications, but also side-effects and resistance occur. Therefore, it is necessary to understand the factors of the tumor microenvironment (TME) that affect the efficacy of immunotherapy, that is, the mechanism by which cancer grows while evading or suppressing attacks from the immune system within the TME. Tumors can evade attacks from the immune system through various mechanisms such as restricting antigen recognition, inhibiting the immune system, and inducing T cell exhaustion. In addition, tumors inhibit or evade the immune system by accumulating specific metabolites and signal factors within the TME or limiting the nutrients available to immune cells. In order to overcome the limitations of immunotherapy and develop effective cancer treatments and therapeutic strategies, an approach is needed to understand the functions of cancer and immune cells in an integrated manner based on the TME. In this review, we will examine the effects of the TME on cancer cells and immune cells, especially how cancer cells evade the immune system, and examine anti-cancer strategies based on TME.

Epigallocatechin-3-Gallate Ameliorated Iron Accumulation and Apoptosis and Promoted Neuronal Regeneration and Memory/Cognitive Functions in the Hippocampus Induced by Exposure to a Chronic High-Altitude Hypoxia Environment.

We aimed to explore the protective effects and potential treatment mechanism of Epigallocatechin-3-gallate (EGCG) in an animal model of chronic exposure in a natural high-altitude hypoxia (HAH) environment. Behavioral alterations were assessed with the Morris water maze test. Iron accumulation in the hippocampus was detected by using DAB enhanced Perls' staining, MRI, qPCR and colorimetry, respectively. Oxidative stress (malondialdehyde, MDA), apoptosis (Caspase-3), and neural regeneration (brain-derived neurotrophic factor, BDNF) were detected by using ELISA and western blotting. Neural ultrastructural changes were evaluated by transmission electron microscopy (TEM). The results showed that learning and memory performance of rats decreased when exposure to HAH environment. It was followed by iron accumulation, dysfunctional iron metabolism, reduced BDNF and the upregulation of MDA and Caspase-3. TEM confirmed the ultrastructural changes in neurons and mitochondria. EGCG reduced HAH-induced cognitive impairment, iron deposition, oxidative stress, and apoptosis and promoted neuronal regeneration against chronic HAH-mediated neural injury.

Role of abnormal energy metabolism in the progression of chronic kidney disease and drug intervention.

Chronic kidney disease (CKD) is a severe clinical syndrome with significant socioeconomic impact worldwide. Orderly energy metabolism is essential for normal kidney function and energy metabolism disorders are increasingly recognized as an important player in CKD. Energy metabolism disorders are characterized by ATP deficits and reactive oxygen species increase. Oxygen and mitochondria are essential for ATP production, hypoxia and mitochondrial dysfunction both affect the energy production process. Renin-angiotensin and adenine signaling pathway also play important regulatory roles in energy metabolism. In addition, disturbance of energy metabolism is a key factor in the development of hereditary nephropathy such as autosomal dominant polycystic kidney disease. Currently, drugs with clinically clear renal function protection, such as Angiotensin II Type 1 receptor blockers and fenofibrate, have been proven to improve energy metabolism disorders. The sodium-glucose co-transporter inhibitors 2 that can mediate glucose metabolism disorders not only delay the progress of diabetic nephropathy, but also have significant protective effects in non-diabetic nephropathy. Hypoxia-inducible factor enhances ATP production to the kidney by improving renal oxygen supply and increasing glycolysis, and the mitochondria targeted peptides (SS-31) plays a protective role by stabilizing the mitochondrial inner membrane. Moreover, several drugs are being studied and are predicted to have potential renal protective properties. We propose that the regulation of energy metabolism represents a promising strategy to delay the progression of CKD.

Pharmacological interventions to prevent Covid-19 disease: A rapid review.

The aim of this rapid review was to determine the effectiveness of pharmacological interventions (excluding vaccines) to prevent coronavirus disease 2019 (Covid-19) or reduce the severity of disease. A systematic search of published peer-reviewed articles and non-peer-reviewed pre-prints was undertaken from 1 January 2020 to 17 August 2021. Four randomised controlled trials (RCTs) and one non-RCT were included; three trials (two RCTs and one non-RCT) tested ivermectin with or without carrageenan. While all reported some potential protective effect of ivermectin, these trials had a high risk of bias and the certainty of evidence was deemed to be 'very low'. One RCT tested bamlanivimab compared to placebo and reported a significantly reduced incidence of Covid-19 in the intervention group; this trial had a low risk of bias however the certainty of evidence was deemed 'very low'. The fifth RCT tested casirivimab plus imdevimab versus placebo and reported that the combination of monoclonal antibodies significantly reduced the incidence of symptomatic and asymptomatic SARS-CoV-2 infection, viral load, duration of symptomatic disease and the duration of a high viral load; this trial was deemed to have a low risk of bias, and the certainty of evidence was 'low'. The designations 'low' and 'very low' regarding the certainty of evidence indicate that the estimate of effect is uncertain and therefore is unsuitable for informing decision-making. At the time of writing, there is insufficient high quality evidence to support the use of pharmacological interventions to prevent Covid-19.

Research progress on non-drug intervention for patients with perimenopausal depression / 四川精神卫生

This article gives a review on domestic and foreign researches on the non-drug intervention for patients with perimenopausal depression published from 2012 to 2022， so as to provide a reference for clinical treatment and nursing. Currently， pharmacotherapy is the mainstay of treatment for perimenopausal depression， while many existing problems remain to be solved such as the variation in treatment effect and the difficulty in maintaining emotional stability. however，high safety and relatively low cost are the characteristics of non-drug intervention， so this article expounds on the non-drug intervention measures for perimenopausal depression， such as music therapy， dietary therapy， exercise therapy， acupuncture therapy and repetitive transcranial magnetic stimulation （rTMS）.