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The metabolic syndrome (MetS) is a clustering of abdominal obesity, hypertension, hyperglycaemia, hypertriglyceridemia and low high-density lipoprotein (HDL) level. MetS development is affected by endocrine hormones such as prolactin (PRL) hormone which induce insulin resistance and central obesity because PRL is implicated in the pathogenesis of MetS. Pituitary PRL controls mammary gland, however extra-pituitary PRL is highly intricate in the regulation of adipose tissue function. In addition, cAMP activators enhance expression and release of PRL which involved in the control of lipogenesis and energy homeostasis. Consequently, hyperprolactinaemia may be associated with the development of MetS. However, normal physiological level of PRL is essential for insulin sensitivity and regulation of adipose tissue function and energy metabolism. Therefore, PRL has dual effects on the components of MetS. Hence, the present review aims to discuss the modulatory mechanistic role of PRL on MetS regarding its beneficial and detrimental effects., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Type 2 diabetes mellitus (T2DM) is developed due to the development of insulin resistance (IR) and pancreatic β cell dysfunction with subsequent hyperglycaemia. Hyperglycaemia-induced oxidative stress and endoplasmic reticulum (ER) stress enhances inflammatory disorders, leading to further pancreatic β cell dysfunction. These changes trigger autophagy activation, which recycles cytoplasmic components and injured organelles. Autophagy regulates pancreatic β cell functions by different mechanisms. Though the exact role of autophagy in T2DM is not completely elucidated, that could be beneficial or detrimental. Therefore, this review aims to discuss the exact role of autophagy in the pathogenesis of T2DM., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Leukaemia, a group of haematological malignancies, presents ongoing diagnosis, prognosis, and treatment challenges. A major obstacle in treating this disease is the development of drug resistance. Overcoming drug resistance poses a significant barrier to effective leukaemia treatment. The emergence of exosome research has unveiled new insights into the probable theragnostic implementations in leukaemia. Various research has exhibited the diagnostic possibilities of exosomes in identifying leukaemia-specific biomarkers, including genetic mutations and fusion transcripts. Additionally, exosomes have been implicated in disease progression and treatment response, rendering them appealing targets for therapeutics. Exosomes, originating from diverse cell types, are instrumental in intercellular communication as they participate in the functional transportation of molecules like proteins, nucleic acids and lipids across space. Exosomes have a dual role in immune regulation, mediating immune suppression and modulating anti-leukaemia immune responses. Interestingly, exosomes can even act as drug transport vehicles. This review delves into the intricate process of exosome biogenesis, shedding light on their formation and release from donor cells. The key mechanisms engaged in exosome biogenesis, for instance, the endosomal sorting complexes required for transport (ESCRT) machinery and ESCRT-independent pathways, are thoroughly discussed. Looking ahead, future approaches that leverage innovative technologies hold the promise of revolutionizing disease management and improving patient outcomes., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The metabolic syndrome or syndrome X is a clustering of different components counting insulin resistance (IR), glucose intolerance, visceral obesity, hypertension and dyslipidemia. It has been shown that IR and dysregulation of insulin signalling play a critical role in the development of metabolic syndrome by initiating the pathophysiology of metabolic syndrome through induction of glucolipotoxicity, impairment of glucose disposal and triggering of pro-inflammatory response. Furthermore, metabolic syndrome unfavourably affects the cognitive function and the development of different neurodegenerative diseases such as Alzheimer disease (AD) by inducing oxidative stress, neuroinflammation and brain IR. These changes together with brain IR impair cerebrovascular reactivity leading to cognitive impairment. In addition, metabolic syndrome increases the risk for the development of AD. However, the central mechanisms by which metabolic syndrome amplify AD risk are not completely elucidated. Consequently, this narrative review aims to revise from published articles the association between metabolic syndrome and AD regarding cellular and subcellular pathways. In conclusion, metabolic syndrome is regarded as a potential risk factor for the induction of AD neuropathology by different signalling pathways such as initiation of brain IR, activation of inflammatory signalling pathways and neuroinflammation., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD neuropathology through modulation of oxidative stress, mitochondrial dysfunction and neuroinflammation. Therefore, modulation of brain RAS by angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may be effective in reducing the risk and PD neuropathology. It has been shown that all components including the peptides and enzymes of the RAS are present in the different brain areas. Brain RAS plays a critical role in the regulation of memory and cognitive function, and in the controlling of central blood pressure. However, exaggerated brain RAS is implicated in the pathogenesis of different neurodegenerative diseases including PD. Two well-known pathways of brain RAS are recognized including; the classical pathway which is mainly mediated by AngII/AT1R has detrimental effects. Conversely, the non-classical pathway which is mostly mediated by ACE2/Ang1-7/MASR and AngII/AT2R has beneficial effects against PD neuropathology. Exaggerated brain RAS affects the viability of dopaminergic neurons. However, the fundamental mechanism of brain RAS in PD neuropathology was not fully elucidated. Consequently, the purpose of this review is to disclose the mechanistic role of RAS in in the pathogenesis of PD. In addition, we try to revise how the ACEIs and ARBs can be developed for therapeutics in PD., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Parkinson's disease (PD) is a neurodegenerative disorder of the brain and is manifested by motor and non-motor symptoms because of degenerative changes in dopaminergic neurons of the substantia nigra. PD neuropathology is associated with mitochondrial dysfunction, oxidative damage and apoptosis. Thus, the modulation of mitochondrial dysfunction, oxidative damage and apoptosis by growth factors could be a novel boulevard in the management of PD. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase type B (TrkB) are chiefly involved in PD neuropathology. BDNF promotes the survival of dopaminergic neurons in the substantia nigra and enhances the functional activity of striatal neurons. Deficiency of the TrkB receptor triggers degeneration of dopaminergic neurons and accumulation of α-Syn in the substantia nigra. As well, BDNF/TrkB signalling is reduced in the early phase of PD neuropathology. Targeting of BDNF/TrkB signalling by specific activators may attenuate PD neuropathology. Thus, this review aimed to discuss the potential role of BDNF/TrkB activators against PD. In conclusion, BDNF/TrkB signalling is decreased in PD and linked with disease severity and long-term complications. Activation of BDNF/TrkB by specific activators may attenuate PD neuropathology., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon-like peptide 1 (GLP-1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP-1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%-40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)