Mubarak Alruwaili

Neuroinflammation is increasingly implicated in Alzheimer’s disease (AD), but how distinct CSF inflammatory biomarkers relate to AD pathology remains unclear. This study examined whether CSF biomarkers reflecting astrocytic activation (GFAP), microglial activation (TREM2), systemic inflammation (CRP), TNF-related signaling (TNFR2), and inflammatory proteolysis (ADAM17) were associated with CSF Aβ42/40, CSF p-tau181, and cognitive performance across the AD clinical spectrum. Data were obtained from 933 ADNI participants, including 312 cognitively normal (CN) individuals, 471 participants with mild cognitive impairment (MCI), and 150 participants with AD dementia. Analyses were corrected for multiple comparisons using the FDR method. The results showed that CSF neuroinflammatory biomarkers differed across diagnostic groups, with GFAP showing the strongest progressive increase from CN to MCI and AD dementia. Higher GFAP, TREM2, TNFR2, and ADAM17 levels were associated with lower CSF Aβ42/40, higher CSF p-tau181, and poorer cognitive performance, particularly in MCI, whereas CRP showed weaker and less consistent associations. In joint models including all inflammatory and core AD biomarkers, both higher GFAP and higher TNFR2 remained independently associated with worse cognitive function. Mediation analyses showed that lower CSF Aβ42/40 partly mediated the associations of higher GFAP and TREM2 with worse cognitive performance. Higher CSF p-tau181 mediated broader associations linking higher GFAP, TREM2, TNFR2, and ADAM17 levels to worse cognitive performance, with the strongest effects observed in MCI. Overall, higher CSF neuroinflammatory biomarkers may be linked to AD pathology and cognitive impairment; however, given the observational design, causality cannot be established, and longitudinal mechanistic studies are needed to validate these findings. Graphical abstract Graphical summary of CSF neuroinflammatory biomarkers and AD-related cognitive impairment. Higher neuroinflammatory biomarkers, including GFAP, TREM2, TNFR2, and ADAM17, were associated with higher CSF p-tau181, lower CSF Aβ42/40, and worse cognition, with the strongest findings observed in the mild cognitive impairment (MCI) stage

Purpose of Review Obesity is a complex metabolic disorder driven by factors such as chronic inflammation, insulin resistance, and significant alterations in the gut microbiota. Dipeptidyl peptidase-4 (DPP-4), an enzyme primarily known for inactivating incretin hormones like glucagon-like peptide-1 (GLP-1), is now recognized as a critical link between metabolic dysfunction and gut microbiome dysbiosis. This review aims to examine the mechanistic role of DPP-4 and its inhibitors in obesity, specifically focusing on how they modulate the gut microbiome to influence host energy balance and metabolic health. Recent Findings Recent experimental and clinical evidence indicates that DPP-4 activity contributes to obesity by influencing microbial composition, diversity, and function. Studies demonstrate that DPP-4 inhibitors can reshape the gut microbiota by reducing dysbiosis, decreasing the Firmicutes-to-Bacteroidetes ratio, and enhancing the production of short-chain fatty acids (SCFAs). Furthermore, these inhibitors improve gut barrier integrity and regulate bile acid metabolism, which helps attenuate systemic inflammation and restore insulin sensitivity. While DPP-4 inhibitors are often weight-neutral in clinical settings, they appear to assist in maintaining metabolic stability by enhancing central satiety signaling and reducing neuroinflammation. Summary The gut microbiome acts as a key intermediary in the metabolic regulation managed by DPP-4. By restoring microbial balance and promoting beneficial metabolites, DPP-4 inhibitors offer therapeutic advantages that extend beyond traditional glycemic control to include improved energy equilibrium and reduced adiposity. Targeting the interactions between DPP-4 and the microbiota represents a promising future therapeutic strategy for managing obesity and its associated metabolic complications.

Broken heart syndrome (Takotsubo or stress cardiomyopathy) is a transient form of acute left ventricular dysfunction commonly triggered by emotional or physical stress. Despite its reversible nature, it may lead to severe complications such as pulmonary edema, arrhythmias, or cardiac arrest. Current management remains largely supportive, with no established pharmacological therapy. Metformin, a well-known anti-diabetic drug, has emerged as a potential cardioprotective agent due to its multifaceted actions on cellular metabolism, vascular function, and neuro-hormonal balance. By activating the AMP-activated protein kinase (AMPK) pathway, Metformin improves microvascular perfusion, enhances endothelial nitric oxide bioavailability, and inhibits oxidative stress and NLRP3 inflammasome activation, thereby reducing myocardial inflammation and injury. It also restores the adiponectin/leptin ratio, attenuates macrophage polarization, and modulates the PI3K/AKT/mTOR signaling cascade, thereby preserving mitochondrial function and cardiomyocyte viability. Furthermore, metformin contributes to stabilization of the autonomic and brain–heart axes by mitigating catecholamine-driven sympathetic surges and monoamine oxidase-mediated oxidative damage. Collectively, these mechanisms suggest that Metformin may have significant cardioprotective potential in broken heart syndrome by targeting endothelial dysfunction, neurogenic stress, and inflammatory responses, warranting further preclinical and clinical investigation to validate its therapeutic role. Graphical abstract The alternative text for this image may have been generated using AI. Proposed mechanisms of Metformin in mitigating broken heart syndrome under hyperglycemic conditions. Hyperglycemia contributes to sympathetic overactivity, promoting excessive catecholamine release, coronary vasospasm, and endothelial dysfunction, all of which culminate in broken heart syndrome. Metformin exerts protective effects through multiple mechanisms: it improves coronary microcirculation by enhancing microvascular perfusion, reducing oxidative stress, and alleviating peri-coronary inflammation; restores autonomic regulation by normalizing catecholamine levels and improving brain-heart axis function; and modulates key signaling pathways, including suppression of the PI3K/AKT/mTOR and NLRP3 inflammasome cascades via AMPK-dependent mechanisms. (Created with BioRender.com).

Asthma is a clinically and biologically heterogeneous disease for which current anti-inflammatory therapies, including inhaled corticosteroids, remain insufficient for many patients. Therefore, repurposing other FDA-approved drugs, such as phosphodiesterase (PDE) inhibitors, may be beneficial in the management of asthma. PDEs are central regulators of cyclic nucleotide signaling, modulating airway smooth-muscle tone, mucociliary function, and immune-cell activity by compartmentalizing the control of cAMP and cGMP. Although PDE4 inhibitors have shown strong pre-clinical efficacy, their translation into clinical practice has been hindered by dose-limiting systemic toxicities, revealing a persistent gap between mechanistic promise and therapeutic utility. This review synthesizes emerging insights into PDE isoenzyme selectivity, spatial localization, and cross-regulatory interactions across structural and immunocompetent airway cells. We outline how isoform- and splice-variant–specific functions contribute to key asthmatic phenotypes and evaluate innovative therapeutic strategies, including dual PDE3/4 inhibition, inhaled delivery approaches, and next-generation selective modulators designed to overcome historical limitations. By integrating these advances within an endotype-driven precision-medicine framework, this review provides a path toward unlocking the full therapeutic potential of PDE-targeted interventions in asthma.

Neurosteroids (NSs) are endogenous progesterone derivatives that act as natural allosteric modulators of GABA_A ​receptors, exerting distinct effects from conventional receptor agonists. They play critical roles in modulating neuronal excitability, cognitive function, and stress responses, and have shown potential in mitigating seizure severity and frequency, particularly in temporal lobe epilepsy (TLE). TLE is a common drug-resistant focal epilepsy characterized by complex pathophysiology involving hippocampal sclerosis, neuroinflammation, synaptic dysfunction, and alterations in GABA_A ​receptor subunits. Accumulating evidence indicates that NSs, including Allopregnanolone, brexanolone, and ganaxolone, may exert neuroprotective and anti-epileptogenic effects through both direct GABAergic modulation and indirect regulation of mTORC1, AMPK, and BDNF signaling pathways, as well as autophagy activation. Experimental studies demonstrate that NSs can prolong the latent period before epilepsy onset, reduce seizure recurrence, and potentially improve cognitive outcomes. However, clinical findings remain inconsistent, and prolonged NS exposure may lead to reduced receptor sensitivity. This review synthesizes current knowledge on the mechanistic roles of NSs in TLE, highlighting their potential as adjuvant therapies alongside antiepileptic drugs. Further translational studies are warranted to clarify optimal dosing strategies, identify patient subgroups most likely to benefit, and develop targeted NS analogues for refractory TLE management.