Targeting PI3K/AKT signaling pathway in obesity

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 159, С. 114244 - 114244

Опубликована: Янв. 11, 2023

Obesity is a disorder with an increasing prevalence, which impairs the life quality of patients and intensifies societal health care costs. The development safe innovative prevention strategies therapeutic approaches thus great importance. complex pathophysiology obesity involves multiple signaling pathways that influence energy metabolism in different tissues. phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT) pathway critical for metabolic homeostasis its function insulin-sensitive tissues described context health, obesity-related complications. PI3K family participates regulation diverse physiological processes including but not limited to cell growth, survival, differentiation, autophagy, chemotaxis, depending on cellular context. AKT downstream insulin pathway, promotes by targeting plethora regulatory proteins control glucose lipid metabolism. Natural products are essential treatment many human diseases, obesity. Anti-obesity natural compounds effect pathophysiological mechanisms involved development. Numerous recent preclinical studies reveal advances using plant secondary metabolites target PI3K/AKT management. In this paper druggability as anti-obesity potential evaluated. Perspectives limitations clinical implementation management modulating suggested.

Язык: Английский

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Cognitive impairment and type 2 diabetes mellitus: Focus of SGLT2 inhibitors treatment

Pharmacological Research, Год журнала: 2022, Номер 176, С. 106062 - 106062

Опубликована: Янв. 10, 2022

Gliflozins are a novel class of oral anti-diabetic drugs, acting as inhibitors sodium-glucose co-transporters (SGLTs) through the proximal convoluted tubules (PCT) and intestinal epithelium. The 2 (SGLT2) mainly expressed in S1 S2 segments tubule kidneys. Clinical guidelines recommend their use especially Type Diabetes mellitus (T2DM) patients with vascular complications and/or heart failure highlighting importance co-transporter (SGLT2i) pleiotropic effects. Interestingly, cognitive decline is widely recognized complication T2DM and, addition, to clarify its pathophysiology, there an urgent need understand how if diabetes therapies can control diabetes-related dysfunction. At time, although SGLT2 proteins present Central Nervous System (CNS), SGLT2i effects on impairments remain partly unknown. In pre-clinical studies, ameliorates dysfunction obese mice, reducing oxidative stress, neuroinflammation improving neuronal plasticity mitochondrial brain pathway. could bring back mTOR physiological state activation, stopping neurodegenerative diseases' onset or progression. Instead, clinical studies T2DM-related treated by much more limited. For these reasons, further needed better elucidate therapy affect decline. this scenario, review aims summarize knowledge role stimulate new trials.

Язык: Английский

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Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(23), С. 15287 - 15287

Опубликована: Дек. 4, 2022

The global prevalence of diabetes mellitus and Alzheimer's disease is increasing alarmingly with the aging population. Numerous epidemiological data suggest that there a strong association between type 2 an increased risk dementia. These diseases are both degenerative progressive share common factors. amyloid cascade plays key role in pathophysiology disease. accumulation beta peptides gradually leads to hyperphosphorylation tau proteins, which then form neurofibrillary tangles, resulting neurodegeneration cerebral atrophy. In disease, apart from these processes, alteration glucose metabolism insulin signaling brain seems induce early neuronal loss impairment synaptic plasticity, years before clinical manifestation large amount evidence on existence resistance during has led description this as "type 3 diabetes". Available animal models have been valuable understanding relationships but date, mechanistical links poorly understood. non-exhaustive review, we describe main molecular mechanisms may link two diseases, emphasis impaired IGF-1 signaling. We also focus GSK3β DYRK1A, markers closely associated pancreatic β-cell dysfunction diabetes, thus represent therapeutic targets for diseases.

Язык: Английский

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Metabolic Syndrome as a Risk Factor for Alzheimer’s Disease: A Focus on Insulin Resistance

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(5), С. 4354 - 4354

Опубликована: Фев. 22, 2023

Alzheimer's disease (AD) is the main type of dementia and a with profound socioeconomic burden due to lack effective treatment. In addition genetics environmental factors, AD highly associated metabolic syndrome, defined as combination hypertension, hyperlipidemia, obesity 2 diabetes mellitus (T2DM). Among these risk connection between T2DM has been deeply studied. It suggested that mechanism linking both conditions insulin resistance. Insulin an important hormone regulates not only peripheral energy homeostasis but also brain functions, such cognition. desensitization, therefore, could impact normal function increasing developing neurodegenerative disorders in later life. Paradoxically, it demonstrated decreased neuronal signalling can have protective role aging protein-aggregation-associated diseases, case AD. This controversy fed by studies focused on signalling. However, action other cell types, astrocytes, still unexplored. Therefore, worthwhile exploring involvement astrocytic receptor cognition, well onset and/or development

Язык: Английский

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The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium

Journal of Affective Disorders, Год журнала: 2023, Номер 331, С. 300 - 312

Опубликована: Март 28, 2023

Язык: Английский

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The physiological control of eating: signals, neurons, and networks

Physiological Reviews, Год журнала: 2021, Номер 102(2), С. 689 - 813

Опубликована: Сен. 6, 2021

During the past 30 yr, investigating physiology of eating behaviors has generated a truly vast literature. This is fueled in part by dramatic increase obesity and its comorbidities that coincided with an ever increasing sophistication genetically based manipulations. These techniques have produced results remarkable degree cell specificity, particularly at signaling level, played lead role advancing field. However, putting these findings into brain-wide context connects physiological signals neurons to behavior somatic requires thorough consideration neuronal connections: field also seen extraordinary technological revolution. Our goal present comprehensive balanced assessment how associated energy homeostasis interact many brain levels control behaviors. A major theme engage sets interacting neural networks throughout are defined specific connections. We begin discussing some fundamental concepts, including ones still engender vigorous debate, provide necessary frameworks for understanding controls meal initiation termination. include key word definitions, ATP availability as pivotal regulated variable homeostasis, neuropeptide signaling, homeostatic hedonic eating, structure. Within this context, we discuss network models regions endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, spinal cord work together gastrointestinal tract enable complex motor events permit animals eat diverse situations.

Язык: Английский

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Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease

Molecular Psychiatry, Год журнала: 2022, Номер 28(1), С. 217 - 229

Опубликована: Окт. 18, 2022

Abstract Despite an ever-growing prevalence and increasing economic burden of Alzheimer’s disease (AD) Parkinson’s (PD), recent advances in drug development have only resulted minimally effective treatment. In AD, along with amyloid tau phosphorylation, there is associated increase inflammation/glial activation, a decrease synaptic function, astrocyte state insulin resistance. PD, α-synuclein accumulation, inflammation, dysfunction, dopaminergic neuronal loss, some data to suggest Therapeutic strategies for neurodegenerative disorders commonly targeted individual pathological processes. An treatment might require either utilization multiple drugs which target the processes underlie or use single agent could influence Insulin incretins are compounds effects on Preclinical studies demonstrated that GLP-1 receptor agonists reduce neuroinflammation, deposition, improve memory formation. Incretin mimetics may act through restoration signaling pathways, inducing further neuroprotective effects. Currently, phase 2 3 trials underway AD PD populations. Here, we provide comprehensive review therapeutic potential incretin PD.

Язык: Английский

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Type 2 diabetes mellitus and cognitive function: understanding the connections

Current Opinion in Endocrinology Diabetes and Obesity, Год журнала: 2022, Номер 30(1), С. 7 - 13

Опубликована: Ноя. 17, 2022

Purpose of review To the connection between type 2 diabetes and cognitive dysfunction, including its epidemiology, potential mechanisms pathophysiology, risk factors, possible prevention, treatment considerations. Recent findings Diabetes is a factor for mild decline, in addition to Alzheimer's disease vascular dementia. Duration diabetes, concomitant or associated co-morbidities, hyper- hypoglycemia may lead worsening dysfunction. Unfortunately, there lack evidence-based guidance on prevention dysfunction population. Studies medications, metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 inhibitors (SGLT2) have shown some benefit with cardiovascular morbidity affect cognition. In absence clearly defined preventive tools, practice guidelines recommend annual screening as standard care adults aged 65 years older. Summary People living are at significant decline function. Epidemiology factors well defined. Prevention strategies limited require further study.

Язык: Английский

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Pathogenesis of Dementia

International Journal of Molecular Sciences, Год журнала: 2022, Номер 24(1), С. 543 - 543

Опубликована: Дек. 29, 2022

According to Alzheimer’s Disease International, 55 million people worldwide are living with dementia. Dementia is a disorder that manifests as set of related symptoms, which usually result from the brain being damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, accompanied emotional problems, difficulties language, decreased motivation. most common variant dementia disease dominated cognitive disorders, particularly memory loss, impaired personality, judgmental disorders. So far, all attempts treat dementias removing their rather than causes have failed. Therefore, presented narrative review, I will attempt explain etiology perspective energy metabolism dysfunction an aging brain. hope this perspective, though perhaps too simplified, bring us closer essence aging-related neurodegenerative disorders soon allow develop new preventive/therapeutic strategies our struggle dementia, disease, Parkinson’s

Язык: Английский

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Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Май 4, 2022

Alzheimer’s disease (AD) is a chronic, complex neurodegenerative disorder mainly characterized by the irreversible loss of memory and cognitive functions. Different hypotheses have been proposed thus far to explain etiology this devastating disorder, including those centered on Amyloid-β (Aβ) peptide aggregation, Tau hyperphosphorylation, neuroinflammation oxidative stress. Nonetheless, therapeutic strategies conceived treat AD neurodegeneration proven unsuccessful, probably due use single-target drugs unable arrest progressive deterioration brain For reason, theoretical description has recently switched from over-emphasizing single deleterious process considering as result different pathogenic mechanisms their interplay. Moreover, much relevance conferred several comorbidities inducing insulin resistance energy hypometabolism, diabetes obesity. As consequence, interest currently accorded in treatment multi-target approach interfering with pathways at same time, life-style interventions aimed preventing modifiable risk-factors strictly associated aging. In context, phytochemical compounds are emerging an enormous source draw search for agents completing or assisting traditional pharmacological medicine. Intriguingly, many plant-derived efficacy counteracting processes such Aβ neuroinflammation, stress resistance. Many also overcome limitations some promising phytochemicals related poor pharmacokinetic profiles, nanotechnology synthetic routes. Considering potential natural medicine, aim present review therefore highlight most belonging two major classes, polyphenols monoterpenes, report main findings about action relating pathogenesis.

Язык: Английский

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