Reperfusion through thrombolytic therapy or primary percutaneous coronary intervention is commonly used to deal with acute myocardial infarction. However, the reperfusion procedure is accompanied by myocardial ischemia-reperfusion injury (MIRI). Currently, there is no therapeutics that can effectively deal with MIRI in clinical practice. Herein, the potential of ceria nanoparticles (CNPs) coated by different ligands in the treatment of rat MIRI is evaluated. The results demonstrate that CNPs can effectively modulate the oxidative stress in the heart tissue through the elimination of reactive oxygen species (ROS) and stimulation of endogenous antioxidant system. The inhibition of oxidative stress results in the reduction of p-Drp1 (Ser 616) which is critical in driving the fission and fragmentation of mitochondria. The improved mitochondrial dynamics saves the cardiomyocytes from apoptosis and reduces the acute injury of left ventricular wall during the MIRI. The ejection function of the left ventricle for both the short-term and long-term MIRI rats is well preserved. We therefore believe based on these results that the administration of CNPs is beneficial in the attenuation of MIRI during the acute stage. These findings provide useful information for the future fabrication of inorganic antioxidant nanomedicine for the treatment of MIRI.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The pathophysiology of PD is complex and multifactorial involving genetic factors, oxidative stress, mitochondrial dysfunction, impaired protein clearance, and neuroinflammation but recent evidence emphasizes the role of impaired brain insulin signaling. Insulin is a metabolic hormone with extensive effects on metabolic substrates but recent studies have demonstrated that it is also involved in central signaling pathways and induces different brain areas related to food craving, motor activities, cognitive abilities, and emotional feelings. Hence it has been suggested that induction of brain insulin sensitivity may be a promising treatment for PD. Glucagon-like peptide-1 (GLP-1) mimetics are a new-generation class of antidiabetics that normalize glucose homeostasis via several pathways. Recent studies suggest extra-glycemic benefits for GLP-1 mimetics against PD. GLP-1 mimetics can prevent or slow PD progression. Additionally, these agents can improve cognitive functions by improving brain insulin signaling pathways. In this review, we aim to highlight the role of brain insulin signaling in PD pathophysiology and discuss the possible benefits of GLP-1 mimetics in PD management.

Atrial fibrillation (AF) is increasingly recognized not merely as an arrhythmia, but as a clinical manifestation of atrial cardiomyopathy (AtCM)-a progressive, multifaceted disease of the atrial myocardium involving structural, electrical, mechanical, and molecular remodeling. AtCM often precedes AF onset, sustains its perpetuation, and contributes to thromboembolic risk independently of rhythm status. Emerging evidence implicates diverse pathophysiological drivers of AtCM, including inflammation, epicardial adipose tissue, metabolic dysfunction, oxidative stress, ageing, and sex-specific remodeling. The NLRP3 inflammasome has emerged as a central effector in atrial inflammation and remodeling. Gut microbial dysbiosis, lipid dicarbonyl stress, and fibro-fatty infiltration are also increasingly recognized as contributors to arrhythmogenesis. AtCM is further linked to atrial functional valve regurgitation and adverse outcomes in AF. Therapeutically, substrate-directed strategies-ranging from metabolic modulation and immunomodulation to early rhythm control-offer promise for altering the disease trajectory. This review synthesizes mechanistic insights into AtCM and discusses emerging therapeutic paradigms that aim not merely to suppress arrhythmia but to modify the underlying substrate. Recognizing AF as a syndrome of atrial disease reframes management strategies and highlights the urgent need for precision medicine approaches targeting the atrial substrate.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the small intestine upon food intake. GLP-1 enhances insulin secretion, suppresses glucagon release, and promotes satiety, resulting in reduced food consumption and subsequent weight loss. Endogenous GLP-1 has a very short half-life and is rapidly degraded by the enzyme dipeptidyl-peptidase-IV (DPP-4). To address this limitation, GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors (DPP-4is) were developed and have demonstrated potency in clinical practice. In recent years, GLP-1RA and DPP4-i therapies are known to have pleiotropic effects, such as a reduction in oxidative stress, autophagy regulation, metabolic reprogramming, enhancement of anti-inflammatory signaling, regulation of gene expression, and being neuroprotective. These effects imply a therapeutic perspective for GLP-1RA and DPP-4i therapies in neuropathic pain treatment. Preclinical and clinical studies increasingly support the hypothesis that these therapies may alleviate neuropathic pain by targeting multiple mechanisms that induce neuropathic pain, such as inflammation, oxidative stress, and mitochondrial dysfunction. This review explores the mechanisms by which GLP-1RAs and DPP-4is alleviate neuropathic pain. It also highlights current advancements in incretin research, focusing on the therapeutic effects of GLP-1RAs and DPP-4-is for neuropathic pain.

In addition to the classically accepted pathophysiological features of Alzheimer's disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The present review aims to offer a comprehensive overview of the neuroprotective properties of GLP-1R agonists (GLP-1RAs), with a particular focus on experimental animal models of AD. Ameliorated amyloid-β plaque and neurofibrillary tangle formation and deposition following exenatide, liraglutide, and lixisenatide treatment was confirmed in several models. The GLP-1RAs studied alleviated central insulin resistance, as evidenced by the decreased serine phosphorylation of insulin receptor substrate 1 (IRS-1) and restored downstream phosphoinositide 3-kinase/RAC serine/threonine-protein kinase (PI3K/Akt) signaling. Furthermore, the GLP-1RAs influenced multiple mitogen-activated protein kinases (extracellular signal-regulated kinase: ERK; c-Jun N-terminal kinase: JNK, p38) positively and suppressed glycogen synthase kinase 3 (GSK-3β) hyperactivation. A lower proportion of reactive microglia and astrocytes was associated with better neuronal preservation following their administration. Finally, restoration of cognitive functions, particularly spatial memory, was also observed for semaglutide and dulaglutide. GLP-1RAs, therefore, hold promising disease-modifying potential in the management of AD.

Myocardial oxidative stress increases under conditions of hyperglycemia and ischemia/reperfusion (I/R) injury, leading to cellular damage. Inhibition of oxidative stress is involved in the cardioprotective effects of hydrogen sulfide (H2S) during I/R and diabetes, and H2S has the potential to protect the heart. However, the mechanism by which H2S regulates the level of cardiac reactive oxygen species (ROS) during I/R and hyperglycemic conditions remains unclear. Therefore, the objective of this study was to evaluate the cytoprotective effect of H2S in primary cardiomyocyte cultures subjected to hyperglycemia, hypoxia-reoxygenation (HR), or both conditions, by assessing the PPAR-α/Keap1/Nrf2/p47phox/NOX4/p-eNOS/CAT/SOD and the PPAR-γ/PGC-1α/AMPK/GLUT4 signaling pathways. Treatment with NaHS (100 μM) as an H2S donor in cardiomyocytes subjected to hyperglycemia, HR, or a combination of both increased cell viability, total antioxidant capacity, and tetrahydrobiopterin (BH4) concentrations, while reducing ROS production, malondialdehyde concentrations, 8-hydroxy-2'-deoxyguanosine, and dihydrobiopterin (BH2) concentrations. Additionally, the H2S donor treatment increased the expression and activity of PPAR-α, reversed the reduction in the expression of PPAR-γ, PGC-1α, AMPK, GLUT4, Nrf2, p-eNOS, SOD, and CAT, and decreased the expression of Keap1, p47phox and NOX4. Therefore, the treatment with the H2S donor protects cardiomyocytes from damage caused by hyperglycemia, HR, or both conditions by reducing oxidative stress markers and improving antioxidant mechanisms, thereby increasing cell viability and "cardiomyocyte ultrastructure".

To investigate whether the antidiabetic agent glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can exert anti-inflammatory effects while lowering blood glucose, we performed a meta-analysis and systematic review.

We searched 4 online databases (Medline, Embase, Cochrane Library and the Web of Science) for randomised controlled trials (RCTs) that examined changes after GLP-1RAs intervention in commonly accepted biomarkers of inflammation: C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1(MCP-1) and advanced glycation end products (AGEs).

This meta-analysis included 52 eligible RCTs (n = 4734) with a median follow-up of 24 weeks, a mean age of 54.13 years, 44.46% females, body mass index (BMI) 29.80 kg/m2, glycated haemoglobin (HbA1c) 8.28% and diabetes duration 7.27 years. GLP-1 RAs treatment, compared to placebo or conventional diabetes therapies (including oral medicine and insulin), resulted in significant reductions in CRP, TNF-α, IL-6, IL-1β and leptin (standard mean difference [SMD] -0.63 [-1.03, -0.23]; SMD -0.92 [-1.57, -0.27]; SMD -0.76 [-1.32, -0.20], SMD -3.89 [-6.56, -1.22], SMD -0.67 [-1.09, -0.26], respectively), as well as significant increases in adiponectin (SMD 0.69 [0.19, 1.19]).

Our meta-analysis demonstrates that GLP-1 RAs exert significant anti-inflammatory effects in patients with T2DM. Our findings provide important insights that may guide the therapeutic application of GLP-1 RAs and inform the development of related therapies.

Atherosclerosis is a closely related complication of diabetes mellitus (DM), driven by endothelial dysfunction, inflammation, and oxidative stress. The progression of atherosclerosis is accelerated by hyperglycemia, insulin resistance, and hyperlipidemia. Novel antidiabetic agents, SGLT2 inhibitors, and GLP-1 agonists improve glycemic control and offer cardiovascular protection, reducing the risk of major adverse cardiovascular events (MACEs) and heart failure hospitalization. These agents, along with nonsteroidal mineralocorticoid receptor antagonists (nsMRAs), promise to mitigate metabolic disorders and their impact on endothelial function, oxidative stress, and inflammation. This review explores the potential molecular mechanisms through which these drugs may prevent the development of atherosclerosis and cardiovascular disease (CVD), supported by a summary of preclinical and clinical evidence.

The gut-brain axis, i.e. the bidirectional communication system between the gut and the brain, has become of central importance in Parkinson disease (PD) research over the past 20 years.

We aimed to describe the milestones of the gut-brain axis research in PD and the development of theories proposing the involvement of the gastrointestinal tract in PD pathogenesis.

We searched PubMed using the terms 'gut-brain axis' AND 'Parkinson disease', and selected relevant articles to provide the foundation for reconstructing an historical overview of the gut-brain axis research in PD.

Mounting evidence from preclinical, clinical and post-mortem studies suggests that a subgroup of PD patients present with a range of prodromal symptoms (e.g., autonomic dysfunction, rapid eye movement sleep behaviour disorder) which reflect initial accumulation and later spread of pathological α-synuclein rostrally from the gastrointestinal tract ("body-first" PD). Through neural connections along the gut-brain axis, pathological α-synuclein may spread to the brain, producing clinically manifest disease. Recently, two mechanisms involving the gut-brain axis have attracted increasing attention for their role in PD pathogenesis and progression, namely the perturbation of the composition of the microorganisms living in the gut (the gut microbiome), and the dysfunction of enteroendocrine cells.

Treatments targeting the gut-brain axis, especially the gut microbiome and the enteroendocrine cells pathway, could potentially slow disease progression or even prevent disease onset. Among these, pre/probiotics, faecal microbiota transplantation, and glucagon-like peptide-1 receptor agonists, have entered advanced stages of clinical trials in humans and shown potential symptomatic and disease-modifying effects.

Alport syndrome (AS) is a progressive monogenic glomerular kidney disease characterised by kidney function decline, hearing loss, and ocular abnormalities, often leading to early-onset kidney failure (KF). While current therapies, such as renin-angiotensin system inhibitors (RASi), offer some benefits, many patients still experience KF at a young age, highlighting the need for additional treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as promising agents with demonstrated cardiovascular and nephroprotective effects in type 2 diabetes (T2D) and chronic kidney disease (CKD) patients. Evidence from several major clinical trials has shown that GLP-1 RAs can reduce cardiovascular events and slow CKD progression by reducing albuminuria. Their potential mechanisms of action include anti-inflammatory, anti-fibrotic, and antioxidative effects, making them particularly relevant for the treatment of AS, where inflammation and fibrosis play crucial roles in disease progression. This review explores the therapeutic potential of GLP-1 RAs in AS, summarising pre-clinical and clinical data and elucidating the pathways through which GLP-1 RAs might offer renoprotective benefits. We advocate for further research into their application in AS and recommend the inclusion of AS patients in future clinical trials to better understand their impact on disease progression and patient outcomes.

The gut microbiome is critical for the pathophysiology of depression, and inflammation is one of the factors contributing to depression. Fzd6 has been implicated in depression. This study aimed to elucidate the effects of the Fzd6 mutation on gut microbiota structure and the possible regulatory mechanisms involved in depression-associated neuroinflammation.

Wild-type (Fzd6WT) and Fzd6 mutant (Fzd6Q152E) male mice were treated with lipopolysaccharide (LPS) for 7 days. Behavioral experiments were used to detect the behavioral changes of mice in each group, and the composition of intestinal flora and systemic inflammation levels of mice were further detected.

In LPS mice, the Fzd6 mutation enhanced depression-like behavior symptoms, increased the release of pro-inflammatory cytokines, decreased the release of anti-inflammatory cytokines, and caused intestinal flora disturbance. Subsequently, 16SrRNA sequencing revealed significant changes in the relative abundance of the inflammation-associated bacterial groups Ruminococcaceae and Lachnospiraceae in Fzd6Q152E mice. In mice with depression, the levels of G protein-coupled receptors, GPR41 and GPR43, and glucagon-like peptide-1 (GLP-1) in the small intestine were down-regulated, and the expression of GLP-1 receptor (GLP-1R), peroxisome proliferators activated receptors gamma (PPAR-γ), and nuclear factor kappa-B inhibitor alpha (IκBα) in the hippocampus was also down-regulated, while the expression of nuclear factor kappa-B p65 (NF-κB p65) was up-regulated.

The size of the spleen was not studied in this model, and the Fzd6 mutation itself does not cause systemic inflammation such as IL-6.

These results demonstrate that mutations in Fzd6 regulate the composition of the gut flora, which contributes to depression-associated inflammation.

Cardiovascular disease (CVD) claims millions of lives every year, with atherosclerotic cardiovascular disease (ASCVD) being the main cause. ASCVD treatment includes drug therapy, lifestyle intervention, and Percutaneous Coronary Intervention (PCI) all of which significantly enhance cardiovascular function and reduce mortality. However, hyperplasia can lead to vascular obstruction, worsen angina symptoms, or even cause heart disease, affecting patients' long-term prognosis. Therefore, finding effective ways to combat hyperplasia is crucial for cardiovascular therapy. In recent years, ferroptosis has gained attention as a new form of cell death closely associated with several diseases, including cardiovascular diseases. It involves complex metabolic processes critical for cellular homeostasis and normal function. Abnormal proliferation and phenotypic transformation of vascular smooth muscle cells (VSMC) are crucial mechanisms underlying cardiovascular disease development. Inhibiting ferroptosis in VSMC has the potential to significantly reduce neointima proliferation. Glucagon-like peptide-1 receptor agonist (GLP-1RA) constitutes a widely employed class of hypoglycemic agents with direct implications for the cardiovascular system, mitigating adverse cardiovascular events. Research indicates that the stimulation of GLP-1 holds promise as a therapeutic strategy in mitigating cardiovascular events such as restenosis. Hence, investigating the potential of GLP-1RA as a treatment option for cardiovascular ailments carries immense clinical significance.

Monosodium glutamate (MSG) is one of the most commonly used food additives, known for its adverse health effects. Alogliptin (ALO) is a highly selective dipeptidyl peptidase-4 inhibitor, but its role in male reproductive function remains debated. The study was designed to evaluate and compare the potential of ALO in mitigating MSG-induced testicular toxicity in juvenile and adult male rats. Juvenile and adult male rats were treated with either MSG or pretreated with ALO before MSG administration. The rats then received ALO and MSG concurrently for 28 days. Testicular tissues were isolated and subjected to histo-biochemical and molecular assessments. Our results demonstrated that ALO reversed MSG-induced testicular injury, as evidenced by the restoration of reproductive hormone balance (increased serum luteinizing hormone and testosterone concentrations), suppression of oxidative stress injury (decreased testicular malondialdehyde, increased superoxide dismutase activity, and minimal 8-hydroxy-2'-deoxyguanosine immunoreactivity), inflammation (reduced testicular tumor necrosis factor-alpha levels), and fibrosis (decreased testicular collagen fiber deposition). Additionally, ALO impeded apoptosis and activated autophagy by decreasing caspase-3 activity, stimulating the AMPK/mTOR pathway, downregulating Bax and SQSTM-1/p62 expression, upregulating Bcl2 and Beclin 1, promoting testicular proliferation (increased number of proliferating cell nuclear antigen-positive cells in the testis), restoring glycogen content in the testis (mild to moderate periodic acid-Schiff reaction), and preserving testicular architecture. MSG induced more severe adverse testicular effects in juvenile rats, while ALO pretreatment was more protective in adult rats. ALO's anti-inflammatory, antioxidant, antiapoptotic, pro-autophagic, antifibrotic, and proliferative actions in the testis suggest its promising potential for combating male reproductive dysfunction.

Chronic and acute wounds represent significant challenges in healthcare, often leading to prolonged recovery times and increased complications. While chronic wounds, such as diabetic foot ulcers and venous leg ulcers, persist due to underlying conditions and biofilm formation, acute wounds, including surgical incisions and burns, can also benefit from innovative therapeutic approaches. Cold atmospheric plasma (CAP) has emerged as a promising non-invasive therapy capable of enhancing wound healing outcomes across both wound types. This review examines the cellular and molecular mechanisms by which CAP promotes wound repair, focusing on its modulation of inflammation, stimulation of angiogenesis, facilitation of tissue remodeling, and antimicrobial effects, which can potentially be used in regenerative medicine. CAP generates reactive oxygen and nitrogen species that influence key cellular processes, accelerating tissue regeneration while reducing bacterial load and preventing biofilm formation. Clinical applications of CAP have demonstrated its efficacy in improving wound healing metrics for both chronic and acute wounds. Despite promising results, translating CAP into routine clinical practice requires addressing challenges such as standardizing treatment protocols, assessing long-term safety, and developing portable devices. Future research should prioritize optimizing CAP parameters and exploring combination therapies to maximize its therapeutic potential. Overall, CAP represents a safe, effective, and versatile modality in wound management, with the potential to significantly improve patient outcomes in both chronic and acute wound care.

Sesquiterpenes are a class of organic compounds found in plants, fungi, and some insects. They are characterized by the presence of three isoprene units, resulting in a molecular formula that typically contains 15 carbon atoms (C₁₅H₂₄). Nerolidol and farnesol are both sesquiterpene alcohols present in the essential oils of numerous plants. They have drawn attention due to their potential neuroprotective properties. Nerolidol and farnesol are structural isomers, specifically geometric isomers, haring the same molecular formula (C₁₅H₂₄O) but differing in the spatial arrangement of their atoms. This variation in structure may contribute to their distinct biological activities. Scientific evidence suggests that nerolidol and farnesol exhibit antioxidant and anti-inflammatory characteristics which are crucial for neuroprotection. Nerolidol has been specifically noted for its ability to alleviate conditions such as Alzheimer's disease, Parkinson's disease, encephalomyelitis, depression, and anxiety by modulating inflammatory and oxidative stress pathways. Moreover, research indicates that both nerolidol and farnesol may modulate the Nrf-2/HO-1 antioxidant signaling pathway to mitigate oxidative stress-induced neurological damage. Activation of Nrf-2/HO-1 signaling cascade promotes cell survival and enhances the brain's ability to resist various insults. Nerolidol has also been reported to alleviate neuroinflammation by inhibiting the TLR-4/NF-κB and COX-2/NF-κB inflammatory signaling pathway. Besides, this nerolidol also modulates BDNF/TrkB/CREB signaling pathway to improve neuronal health. To date, limited research has delved into the anti-inflammatory properties of farnesol concerning neurodegenerative diseases. Further investigation is warranted to comprehensively elucidate the mechanisms underlying its action and potential therapeutic uses in neuroprotection. Initial observations indicate that farnesol exhibits promising prospects as a natural agent for safeguarding brain functions. Henceforth, drawing upon existing literature elucidating the neuroprotective attributes of nerolidol and farnesol, the current review endeavors to provide a detailed analysis of their mechanistic underpinnings in neuroprotection.

Maternally inherited diabetes and deafness (MIDD) is a mitochondrial disorder characterized primarily by hearing impairment and diabetes. m.3243A>G, the most common phenotypic variant, causes a complex rewiring of the cell with discontinuous remodeling of both mitochondrial and nuclear genome expressions. We propose that MIDD depends on a combination of insulin resistance and impaired β-cell function that occurs in the presence of high skeletal muscle heteroplasmy (approximately ≥60%) and more moderate cell heteroplasmy (∼25%-72%) for m.3243A>G. Understanding the complex mechanisms of MIDD is necessary to develop disease-specific management guidelines that are presently lacking.

Type 2 diabetes is a chronic disease requiring comprehensive pharmacological and non-pharmacological interventions to slow its progression and prevent or delay its micro- and macrovascular complications. Oxidative stress contributes to the development and progression of type 2 diabetes as well as to the development of its complications through several mechanisms. Therefore, therapeutic targeting of oxidative stress could aid in managing this disease and its complications. In our study, we have collected information on the most frequently used antidiabetic drugs (metformin, glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors) in the EU and the USA based on their antioxidant effects. Based on our results, we can conclude that the antioxidant effects of the investigated antidiabetics may contribute significantly to the management of the disease and its complications and may open new therapeutic perspectives in their prevention.

Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.

Astrocytes produce and export glutathione (GSH), an important thiol antioxidant essential for protecting neural cells from oxidative stress and maintaining optimal brain health. While it has been established that oxidative stress increases GSH production in astrocytes, with Nrf2 acting as a critical transcription factor regulating key components of the GSH synthetic pathway, the role of Nrf2 in controlling constitutive GSH synthetic and release mechanisms remains incompletely investigated. Our data show that naïve primary mouse astrocytes cultured from the cerebral cortices of Nrf2 knockout (Nrf2-/-) pups have significantly less intracellular and extracellular GSH levels when compared to astrocytes cultured from Nrf2 wild-type (Nrf2+/+) pups. Key components of the GSH synthetic pathway, including xCT (the substrate-specific light chain of the substrate-importing transporter, system xc-), glutamate-cysteine ligase [catalytic (GCLc) and modifying (GCLm) subunits], were affected. To wit: qRT-PCR analysis demonstrates that naïve Nrf2-/- astrocytes have significantly lower basal mRNA levels of xCT and both GCL subunits compared to naïve Nrf2+/+ astrocytes. No change in mRNA levels of glutathione synthetase (GS) or the GSH exporting transporter, Mrp1, was found. Western blot analysis reveals reduced protein levels of both subunits of GCL, while (seleno)cystine uptake into Nrf2-/- astrocytes was reduced compared to Nrf2+/+ astrocytes, confirming decreased system xc- activity. These findings suggest that Nrf2 regulates the basal production of GSH in astrocytes through constitutive transcriptional regulation of GCL and xCT.

High blood sugar caused by diabetic encephalopathy(DE) can lead to excessive accumulation of reactive oxygen species in the brain, induce oxidative stress, and subsequently cause neuronal degeneration and apoptosis. The Nrf2/HO-1 signaling pathway is one of the most important pathways in oxidative stress response, but the precise mechanism of EA treatment for DE and its specific mechanism of action on the Nfr2/HO-1 pathway remain unclear.

Male Wistar rats were randomly assigned to four groups: normal, solvent, model, and EA, with 10 rats per group. A DE rat model was induced by intraperitoneal injection of streptozotocin. EA was applied to stimulate the "Zusanli" (ST36) and "Weiwanxiashu" (EXB3) points bilaterally, alternately for 30 min each, once a day for 4 weeks in the EA group. The rats' fasting blood glucose(FBG) levels were measured with a glucometer. The Morris water maze was used to evaluate their learning and memory abilities. The morphology of neurons in the CA1 area of the hippocampus was observed by Nissl staining. Detection of protein expression of Nrf2 and HO-1 in the CA1 area of the hippocampus was performed by immunohistochemistry and immunoblotting.

EA treatment reduced blood glucose levels, improved learning and memory abilities, increased the number of neurons in the hippocampal CA1 area, and upregulated the expression of Nrf2 and HO-1 in rats with DE. EA treatment may inhibit oxidative stress by modulating the Nrf2/HO-1 pathway in the hippocampal CA1 area, exerting a protective effect on neuronal cells in the hippocampal area in DE.

EA enhances the learning and memory abilities of rats with DE by regulating the Nrf2/HO-1 pathway in the CA1 area of the hippocampus. This indicates that EA has the potential to protect neurons by reducing oxidative stress.

Sonneratia caseolaris, has been widely utilized by the Indonesian. S. caseolaris leaves contain various active compounds, contributing to their popularity in the treatment of various diseases. Mangrove leaves are also known to exhibit very high antioxidant activity. This study aims to assess the antioxidant activity of S . caseolaris leaves extracted using different solvents. The resulting extract was evaluated for antioxidant activity by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity (DPPH) techniques.

Analysis of total flavonoids, total phenols, identification of active compounds with Liquid Chromatography High Resolution Mass Spectrometry (LC-HRMS), and bioinformatics were also carried out to obtain temporary conclusions about the antioxidant activity of S. caseolaris leaf extract.

The results indicated that S. caseolaris leaves extracted with methanol and distilled water exhibited the highest antioxidant activity compared to other extracts. The analysis of total flavonoids and total phenols yielded results consistent with the antioxidant activity tests. LC-HRMS results identified three compounds in all S. caseolaris leaf extracts with antioxidant activity, namely TEMPO, Choline, and Betaine. TEMPO demonstrated a higher antioxidant activity than Choline and Betaine, as indicated by the binding affinity values in the bioinformatics analysis.

It is evident that S. caseolaris leaf extracts has the potential to serve as an effective antioxidant agent. Further research is needed to confirm how the potential compounds in S. caseolaris leaf water extracts interact with the target protein Keap1. This research aims to utilize S. caseolaris as active components in food products, thereby enhancing antioxidant consumption among consumers.

Atrial fibrosis is a hallmark of atrial cardiomyopathy and plays a pivotal role in the pathogenesis of atrial fibrillation (AF), contributing to its onset and progression. The mechanisms underlying atrial fibrosis are multifaceted, involving stretch-induced fibroblast activation, oxidative stress, inflammation, and coagulation pathways. Variations in fibrosis types-reactive and replacement fibrosis-are influenced by patient-specific factors such as age, sex, and comorbidities, complicating therapeutic approaches. The heterogeneity of fibrosis leads to distinct electrophysiological abnormalities that promote AF via reentrant activity and enhanced automaticity mechanisms. Despite advancements in imaging, such as late gadolinium enhancement CMR and electroanatomical mapping, challenges in accurately quantifying fibrosis persist. Emerging therapeutic strategies include antifibrotic agents targeting the renin-angiotensin-aldosterone system, novel pathways like TGF-β signaling, and cardio-metabolic drugs like SGLT2 inhibitors and GLP-1 receptor agonists. Innovative interventions, including microRNA modulation and lipid nanoparticle-based therapies, show promise but require validation. Knowledge gaps remain in correlating clinical outcomes with fibrosis patterns and optimizing diagnostic tools. Future research should focus on precise phenotyping, integrating advanced imaging with molecular biomarkers, and conducting robust trials to evaluate antifibrotic therapies' efficacy in reducing AF burden and related complications.

Parkinson's disease (PD) is a chronic, progressive neurological disorder primarily affecting motor control, clinically characterized by resting tremor, bradykinesia, rigidity, and other symptoms that significantly diminish the quality of life. Currently, available treatments only alleviate symptoms without halting or delaying disease progression. There is a significant association between PD and type 2 diabetes mellitus (T2DM), possibly due to shared pathological mechanisms such as insulin resistance, chronic inflammation, and mitochondrial dysfunction. PD is caused by a deficiency of dopamine, a neurotransmitter in the brain that plays a critical role in the control of movement. Glucose metabolism and energy metabolism disorders also play an important role in the pathogenesis of PD. This review investigates the neuroprotective mechanisms of glucagon-like peptide-1 (GLP-1) and its receptor agonists, offering novel insights into potential therapeutic strategies for PD. GLP-1 class drugs, primarily used in diabetes management, show promise in addressing PD's underlying pathophysiological mechanisms, including energy metabolism and neuroprotection. These drugs can cross the blood-brain barrier, improve insulin resistance, stabilize mitochondrial function, and enhance neuronal survival and function. Additionally, they exhibit significant anti-inflammatory and antioxidative stress effects, which are crucial in neurodegenerative diseases like PD. Research indicates that GLP-1 receptor agonists could improve both motor and cognitive symptoms in PD patients, marking a potential breakthrough in PD treatment and prevention. Further exploration of GLP-1's molecular mechanisms in PD could provide new preventive and therapeutic approaches, especially for PD patients with concurrent T2DM. By targeting both metabolic and neurodegenerative pathways, GLP-1 receptor agonists represent a multifaceted approach to PD treatment, offering hope for better disease management and improved patient outcomes.

Empty zein nanoparticles (NP) have been shown to lower glycemia in rats by stimulating the secretion of endogenous GLP-1. This study evaluated the effect of these nanoparticles on the lifespan of two animal models: C. elegans fed with a glucose-rich diet and the senescence accelerated mouse-prone 8 (SAMP8 mice). In C. elegans, NP increased the mean lifespan of worms by 7 days (from 17.1 for control to 24.5 days). This observation was in line with the observed significant reductions of glucose and fat contents, lipofuscin accumulation, and ROS expression. Furthermore, NP supplementation led to an upregulation of the expression of daf-16 and skn-1 genes. DAF-16 (orthologue of the FOXO family) and SKN-1 (orthologue of mammalian Nrf/CNC proteins) are implicated in activating detoxification mechanisms against oxidative damage. In SAMP8, oral administration of NP also extended the mean lifespan of mice (by 28 % compared to controls), corroborating the protective effect of these nanoparticles.

Lung cancer, a malignant neoplasm originating from the epithelial cells of the lung, is characterized by its aggressive growth and poor prognosis, making it a leading cause of cancer-related mortality globally [...].

Glucagon-like peptide-1 receptor agonists (GLP1RAs), originally developed for the treatment of type 2 diabetes mellitus, have attracted attention for their potential therapeutic benefits in asthma due to their anti-inflammatory properties and effects on airway smooth muscle function. However, concerns have been raised about the possibility of GLP1RAs inducing or exacerbating asthma symptoms.

We reviewed data from the US Food and Drug Administration's (FDA) adverse event (AE) reporting system (FAERS) to examine reports of cases of asthma observed in the real-world during treatment with GLP1RAs.

Analysis of the FAERS reporting system database has shown that certain GLP1RAs, particularly exenatide, semaglutide and liraglutide, were associated with a higher proportion of respiratory AEs, particularly asthma or asthma-like events. This association was statistically significant at least for semaglutide and liraglutide. Serious asthma-related events and deaths were also reported, with exenatide having the highest proportion of deaths.

The reasons for the observed differences in the AE profiles of the GLP1RAs remain unclear and may involve various factors such as pharmacological properties, patient characteristics and reporting biases. The complex interplay between the therapeutic benefits of GLP1RAs and the potential respiratory risks requires careful monitoring by clinicians, underpinned by ongoing research efforts to improve patient care and safety.

Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer's disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM).

T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings.

SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues.

These findings highlight SITG's neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations.

Glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes and obesity. Despite the development of several drugs for neuropathic pain management, their poor efficacy, tolerance, addiction potential, and side effects limit their usage. Teneligliptin, a DPP-4 inhibitor, has been shown to reduce spinal astrocyte activation and neuropathic pain caused by partial sciatic nerve transection. Additionally, we showed its capacity to improve the analgesic effects of morphine and reduce analgesic tolerance. Recent studies indicate that GLP-1 synthesized in the brain activates GLP-1 receptor signaling pathways, essential for neuroprotection and anti-inflammatory effects. Multiple in vitro and in vivo studies using preclinical models of neurodegenerative disorders have shown the anti-inflammatory properties associated with glucagon-like peptide-1 receptor (GLP-1R) activation. This study aimed to investigate the mechanism of antinociception and the effects of the GLP-1 agonist semaglutide (SEMA) on diabetic neuropathic pain in diabetic rats.

Male Wistar rats, each weighing between 300 and 350 g, were categorized into four groups: one non-diabetic sham group and three diabetic groups. The diabetic group received a single intraperitoneal injection of streptozotocin (STZ) at a dosage of 60 mg/kg to induce diabetic neuropathy. After 4 weeks of STZ injection, one diabetic group was given saline (vehicle), and the other two were treated with either 1× SEMA (1.44 mg/kg, orally) or 2× SEMA (2.88 mg/kg, orally). Following a 4-week course of oral drug treatment, behavioral, biochemical, and immunohistochemical analyses were carried out. The mechanical allodynia, thermal hyperalgesia, blood glucose, advanced glycation end products (AGEs), plasma HbA1C, and spinal inflammatory markers were evaluated.

SEMA treatment significantly reduced both allodynia and hyperalgesia in the diabetic group. SEMA therapy had a limited impact on body weight restoration and blood glucose reduction. In diabetic rats, SEMA lowered the amounts of pro-inflammatory cytokines in the spinal cord and dorsal horn. It also lowered the activation of microglia and astrocytes in the dorsal horn. SEMA significantly reduced HbA1c and AGE levels in diabetic rats compared to the sham control group.

These results indicate SEMA's neuroprotective benefits against diabetic neuropathic pain, most likely by reducing inflammation and oxidative stress by inhibiting astrocyte and microglial activity. Our findings suggest that we can repurpose GLP-1 agonists as potent anti-hyperalgesic and anti-inflammatory drugs to treat neuropathic pain without serious side effects.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasing cause of cirrhosis. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are effective in improving liver inflammation in patients with MASLD.

To determine whether use of GLP-1 RAs is associated with lower risk of developing cirrhosis and its complications, including decompensation and hepatocellular cancer (HCC), among patients with MASLD.

This retrospective cohort study with an active comparator, new-user design used data from the national Veterans Health Administration Corporate Data Warehouse and Central Cancer Registry. Patients with MASLD and diabetes who were seen at 130 Veterans Health Administration hospitals and associated ambulatory clinics and who initiated either a GLP-1 RA or dipeptidyl peptidase 4 inhibitor (DPP-4i) between January 1, 2006, and June 30, 2022, were included. Patients were followed up from baseline until one of the study outcomes or the end of the study period (December 31, 2022), whichever came first.

Each GLP-1 RA new user was propensity score matched in 1:1 ratio to a patient who initiated a DPP-4i during the same month. Separate analyses were conducted among patients without and with cirrhosis at baseline.

For patients without cirrhosis, the primary outcome was progression to cirrhosis defined by validated diagnoses codes or a noninvasive marker of liver fibrosis, and secondary outcomes were cirrhosis complications defined both as a composite and individual complications, including decompensation, HCC, or liver transplant, and all-cause mortality. For patients with cirrhosis, the primary outcome was a composite outcome of cirrhosis complications, and secondary outcomes were decompensation, HCC, and all-cause mortality.

Of 16 058 patients who initiated GLP-1 RAs, 14 606 did not have cirrhosis (mean [SD] age, 60.56 [10.31] years; 13 015 [89.1%] male), and 1452 had cirrhosis (mean [SD] age, 66.99 [7.09] years; 1360 [93.7%] male) at baseline. These patients were matched to an equal number of patients who initiated a DPP-4i. In patients without cirrhosis, GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of cirrhosis (9.98 vs 11.10 events per 1000 person-years; hazard ratio [HR], 0.86; 95% CI, 0.75-0.98). Similar results were seen for the secondary outcomes. GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of the composite outcome of cirrhosis complications (1.89 vs 2.55 events per 1000 person-years; HR, 0.78; 95% CI, 0.59-1.04) and mortality (21.77 vs 24.43 events per 1000 person-years; HR, 0.89; 95% CI, 0.81-0.98). There were no associations between GLP-1 RA use and outcomes in patients with cirrhosis.

In this cohort study, GLP-1 RA use was associated with a lower risk of progression to cirrhosis and mortality among patients with MASLD and diabetes. The protective association was not seen in patients with existing cirrhosis, underscoring the importance of treatment earlier in the disease course.

Recent studies have linked sarcopenia development to the hallmarks of diabetes, oxidative stress, and insulin resistance. The anti-oxidant and insulin sensitivityenhancing effects of incretin-based therapies may provide a promising option for the treatment of sarcopenia. This review aimed to unveil the role of oxidative stress and insulin resistance in the pathogenesis of sarcopenia and explore the potential benefits of incretin-based therapies in individuals with sarcopenia.

PubMed, the Cochrane Library, and Google Scholar databases were searched by applying keywords relevant to the main topic, to identify articles that met our selection criteria.

Incretin-based therapies manifested anti-oxidant effects by increasing the anti-oxidant defense system and decreasing free radical generation or by indirectly minimizing glucotoxicity, which was mainly achieved by improving insulin signaling and glucose homeostasis. Likewise, these drugs exhibit insulin-sensitizing activities by increasing insulin secretion, transduction, and β-cell function or by reducing inflammation and lipotoxicity.

Incretin-based therapies, as modulators of oxidation and insulin resistance, may target the main pathophysiological factors of sarcopenia, thus providing a promising strategy for the treatment of this disease.

Oxidative stress plays a major role in the formation of the cataract that is the result of advancing age, diabetes or which follows vitrectomy surgery. Glutathione (GSH) is the principal antioxidant in the lens, and so supplementation with GSH would seem like an intuitive strategy to counteract oxidative stress there. However, the delivery of glutathione to the lens is fraught with difficulties, including the limited bioavailability of GSH caused by its rapid degradation, anatomical barriers of the anterior eye that result in insufficient delivery of GSH to the lens, and intracellular barriers within the lens that limit delivery of GSH to its different regions. Hence, more attention should be focused on alternative methods by which to enhance GSH levels in the lens. In this review, we focus on the following three strategies, which utilize the natural molecular machinery of the lens to enhance GSH and/or antioxidant potential in its different regions: the NRF2 pathway, which regulates the transcription of genes involved in GSH homeostasis; the use of lipid permeable cysteine-based analogues to increase the availability of cysteine for GSH synthesis; and the upregulation of the lens's internal microcirculation system, which is a circulating current of Na+ ions that drives water transport in the lens and with it the potential delivery of cysteine or GSH. The first two strategies have the potential to restore GSH levels in the epithelium and cortex, while the ability to harness the lens's internal microcirculation system offers the exciting potential to deliver and elevate antioxidant levels in its nucleus. This is an important distinction, as the damage phenotypes for age-related (nuclear) and diabetic (cortical) cataract indicate that antioxidant delivery must be targeted to different regions of the lens in order to alleviate oxidative stress. Given our increasing aging and diabetic populations it has become increasingly important to consider how the natural machinery of the lens can be utilized to restore GSH levels in its different regions and to afford protection from cataract.

Parkinson's disease (PD) is an age-related chronic neurological condition characterized by progressive degeneration of dopaminergic neurons and the presence of Lewy bodies, primarily composed of alpha-synuclein and ubiquitin. The pathophysiology of PD encompasses alpha-synuclein aggregation, oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired autophagy and ubiquitin-proteasome systems. Among these, the Keap1-Nrf2 pathway is a key regulator of antioxidant defense mechanisms. Nrf2 has emerged as a crucial factor in managing oxidative stress and inflammation, and it also influences ubiquitination through p62 expression. Keap1 negatively regulates Nrf2 by targeting it for degradation via the ubiquitin-proteasome system. Disruption of the Nrf2-Keap1 pathway in PD affects cellular responses to oxidative stress and inflammation, thereby playing a critical role in disease progression. In addition, the role of neuroinflammation in PD has gained significant attention, highlighting the interplay between immune responses and neurodegeneration. This review discusses the various mechanisms responsible for neuronal degeneration in PD, with a special emphasis on the neuroprotective role of the Nrf2-Keap1 pathway. Furthermore, it explores the implications of inflammopharmacology in modulating these pathways to provide therapeutic insights for PD.

The increasing incidence of chronic kidney disease (CKD) poses a significant public health concern, prompting heightened attention to its treatment. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, are intestinal peptides released after nutrient intake, known for their hypoglycemic effects in diabetes management. Recent advancements highlight the promising outcomes of GLP-1 receptor agonists in reducing CKD risk factors and improving renal outcomes. The multifaceted functions of GLP-1, such as its anti-obesity, anti-hypertensive, anti-hyperglycemic, anti-lipid, anti-inflammatory, and endothelial function protective properties, contribute to its potential as a therapeutic agent for CKD. Although experiments suggest the potential benefits of incretin in CKD, a comprehensive understanding of its specific mechanisms is still lacking. This review aims to provide a detailed examination of current evidence and potential future directions, emphasizing the promising yet evolving landscape of incretin agonists in the context of CKD.

Doxorubicin (DOX) is a highly effective and widely used cytotoxic agent with application for various malignancies, but it's clinically limited due to its cardiotoxicity Oxidative stress and inflammation were reported to take part in DOX-induced cardiotoxicity. Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist has been approved to treat type 2 diabetes. However, its role in DOX-induced cardiotoxicity and the underlying mechanisms has not been explored.

The cardioprotective properties of Tirzepatide against DOX-induced cardiotoxicity are examined in this work both in vivo and in vitro. For four weeks, an intraperitoneal injection of 4 mg/kg DOX was used to cause cardiotoxicity in C57BL/6 mice. To ascertain the cardioprotective function and underlying mechanisms of Tirzepatide against DOX-induced cardiotoxicity, mice and H9c2 cells were treated with and without Tirzepatide.

Tirzepatide treatment significantly inhibited DOX-induced oxidative stress, inflammation and cardiac injury. Mechanistically, PI3K/Akt signaling pathway contributes to the protective effect of Tirzepatide against DOX-induced cardiotoxicity and inhibited PI3K/Akt signaling pathway with LY294002 almost blocked its therapeutic effect.

Collectively, Tirzepatide could alleviate DOX-induced oxidative stress, inflammation and cardiac injury via activating PI3K/Akt signaling pathway and Tirzepatide may be a novel therapeutic target for DOX-induced cardiotoxicity.

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors ("multi-agonists"), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment.

Currently, there is no known cure for diabetes. Different pharmaceutical therapies have been approved for the management of type 2 diabetes mellitus (T2DM), some are in clinical trials and they have been classified according to their route or mechanism of action. Insulin types, sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, sodium-glucose cotransporter type 2 inhibitors, and incretin-dependent therapies (glucagon-like peptide-1 receptor agonists: GLP-1R, and dipeptidyl peptidase 4 inhibitors: DPP-4). Although some of the currently available drugs are effective in the management of T2DM, the side effects resulting from prolonged use of these drugs remain a serious challenge. GLP-1R agonists are currently the preferred medications to include when oral metformin alone is insufficient to manage T2DM. Medicinal plants now play prominent roles in the management of various diseases globally because they are readily available and affordable as well as having limited and transient side effects. Recently, studies have reported the ability of phytochemicals to activate glucagon-like peptide-1 receptor (GLP-1R), acting as an agonist just like the GLP-1R agonist with beneficial effects in the management of T2DM. Consequently, we propose that careful exploration of phytochemicals for the development of novel therapeutic candidates as GLP-1R agonists will be a welcome breakthrough in the management of T2DM and the co-morbidities associated with T2DM.

Chronic kidney disease is a debilitating condition associated with significant morbidity and mortality. In recent years, the kidney effects of incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), have garnered substantial interest in the management of type 2 diabetes and obesity. This review delves into the intricate interactions between the kidney, GLP-1RAs, and glucagon, shedding light on their mechanisms of action and potential kidney benefits. Both GLP-1 and glucagon, known for their opposing roles in regulating glucose homeostasis, improve systemic risk factors affecting the kidney, including adiposity, inflammation, oxidative stress, and endothelial function. Additionally, these hormones and their pharmaceutical mimetics may have a direct impact on the kidney. Clinical studies have provided evidence that incretins, including those incorporating glucagon receptor agonism, are likely to exhibit improved kidney outcomes. Although further research is necessary, receptor polypharmacology holds promise for preserving kidney function through eliciting vasodilatory effects, influencing volume and electrolyte handling, and improving systemic risk factors.

In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups.

We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug.

Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group.

In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated.

Novo Nordisk.