Cardiovascular diseases (CVD) are the main cause of death worldwide and in Saudi Arabia, accounting for about 31% of all deaths globally and 45% of deaths in the Kingdom. The aim of this review was to review the epidemiology, pathophysiology, and management of lipid disorders (mainly dyslipidemia) which are major contributors to CVD in Saudi Arabia. The unique risk profile of the Saudi population with a high prevalence of dyslipidemia (especially low high-density lipoprotein cholesterol [HDL-C] and high triglycerides), in addition to the genetic factors, urbanization, sedentary lifestyle, and change in diet to a western style has been described. National surveys showed prevalence rates of dyslipidemia > 50% in adults and high prevalence in adolescents with high regional and gender differences. Low HDL-C was the most common and important lipid abnormality, which was significantly related to all-cause and CVD mortality and independently predicts adverse outcomes. This review summarizes the limits of the current treatment strategy that mainly focuses on LDL-C lowering and shows the need for the development of new therapies targeting HDL-C and triglycerides. The public health implications include an increasing economic burden, the need for early screening, culture-adapted prevention programs, and integration of genetic risk prediction. Large-scale epidemiological studies, national registries, and personalized medicine approaches are needed to fill the gaps in knowledge and optimize management. Implementing population-based programs is a must to decrease the burden of CVD and improve the outcome in Saudi Arabia which may be an example for other countries experiencing the same epidemiological transition.

Background/Objectives: Obesity-related insulin resistance is accompanied by chronic low-grade inflammation, but the extent to which weight loss modifies circulating cytokines in a sex-specific manner remains insufficiently understood. The aim of this study was to assess sex-specific cytokine responses and metabolic adaptation in adults with obesity and insulin resistance following a six-month weight-reduction program (WRP). Methods: Thirty-six participants (24 women and 12 men) with a value of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) ≥ 2 underwent an individualized low-calorie diet combined with moderate physical activity and health education. Anthropometric, body composition, biochemical, oxidative stress, and cytokine parameters were evaluated before and after the intervention. Results: Both women and men showed significant reductions in body mass, Body Mass Index (BMI), waist circumference, visceral fat area (VFA), body fat mass (BFM), fasting glucose, HOMA-IR, modified Atherogenic Index of Plasma (new-AIP), malondialdehyde (MDA), and Oxidative Stress Index (OSI). Women additionally showed significant decreases in fat-free mass (FFM), skeletal-muscle mass (SMM), total body water (TBW), glycated hemoglobin A1c (HbA1c), and triacylglycerols, whereas cholesterol in high-density lipoproteins (HDL-C) increased significantly in men. Cytokine changes were selective rather than uniform. Interleukin-1 receptor antagonist (IL-1ra), Interleukin 6 (IL-6), and Tumor Necrosis Factor alpha (TNF-α) decreased in both women and men. In sex-stratified analyses, IL-1β decreased significantly only in women, whereas IL-7 decreased significantly only in men. ClinicalTrials.gov Registration: [NCT07645105] (retrospectively registered on [11 June 2026]). Conclusions: A 6-month lifestyle-based weight-reduction program in adults with overweight or obesity and insulin resistance was associated with metabolic improvement, reduced oxidative stress, and partial attenuation of obesity-related low-grade inflammation. The observed cytokine and metabolic changes suggest sex-related patterns of immunometabolic adaptation to weight reduction. However, these findings should be interpreted cautiously because of the relatively small sex-stratified subgroups and the number of cytokine endpoints analyzed, and they require confirmation in larger, sex-balanced studies.

Background/Objectives: The aim of the study was to assess the metabolic response of women to a six-week consumption of full-fat sheep milk yogurt, with a focus on cardiovascular risk markers, lipid profile, and subfractions of low-density (LDL) and high-density (HDL) lipoproteins of both atherogenic and non-atherogenic nature. Methods: A total of 55 women were enrolled in the nutritional intervention after the application of inclusion criteria. Blood samples were collected at baseline and after the six-week intervention period. Lipoprotein subfractions were determined in serum using the Lipoprint System LDL/HDL Subfractions Kit in combination with the Lipoprint[®] analyzer. Results: In the group of women over 40 years of age with overweight or obesity, without adjustment for total cholesterol, a significant increase was observed in selected HDL subfractions (intermediate HDL-6, HDL-7 and small HDL-8, HDL-9; p < 0.05), while the small/large HDL ratio, LDL subfractions, and mean LDL particle size remained unchanged (p > 0.05). A decrease in triglycerides, LDL/HDL ratio, TG/HDL ratio, and cardiovascular risk index was recorded, alongside a slight increase in LDL-C and HDL-C levels. After adjustment for total cholesterol (T-C), no significant deterioration in the lipid profile was observed in either the group with normal or elevated T-C levels; in the group with elevated T-C, only the intermediate HDL-7 subfraction increased significantly (p < 0.05). Despite the presence of risk-level values in some parameters already at baseline (VLDL, IDL-A, IDL-B, small HDL), no worsening was observed. Conclusions: Six-week consumption of full-fat sheep milk yogurt did not lead to deterioration of the lipid profile or lipoprotein subfractions. The results suggest a neutral to mildly beneficial effect on selected cardiovascular risk markers.

Background and Objectives: Many patients suffer from chronic pain of the shoulder, neck, upper back, and/or arm. They may be diagnosed with fibromyalgia, complex regional pain syndrome, myofascial pain, thoracic outlet, subacromial pain, cervical radiculopathy, cervicogenic headaches, post-mastectomy pain, and/or occupational shoulder disorder. The pectoralis minor (PM) is the only muscle of the scapula controlled by the lower trunk of the brachial plexus. In the Human Disharmony Loop (HDL), this neurologic asymmetry produces persistent protraction of the scapula. Protraction deforms the scapula's connections, generating headaches and neck stiffness, upper back tightness, shoulder weakness, and hand numbness. We hypothesize patients with the above who meet HDL diagnostic criteria will benefit from PM tenotomy with brachial plexus neurolysis (PM+ICN). Materials and Methods: Patients diagnosed with the above disorders who also met HDL criteria of medial coracoid tenderness and scapula protraction on exam underwent PM+ICN, with secondary neurolysis after 3 months if needed. Clinical neuropathy was diagnosed via the scratch-collapse test. Outcomes included self-reported Visual Analogue Score pain scores, active shoulder abduction range of motion (ROM), prevalence of occipital headaches. Results: N = 318 patients were included. Average age was 51; 68.0% were female. Following treatment, average pain decreased from 7.3/10 to 2.1/10 (p < 0.001), average shoulder ROM increased from 96 to 170 degrees (p < 0.001), and occipital headaches decreased from 76.7% to 1.6% (p < 0.001). Scapular protraction normalized from 98.8% static to 92.5% none (p < 0.001). Overall, 17% required subsequent neurolysis, chiefly of the axillary, radial, and ulnar nerves. The pain reductions were statistically indistinguishable across all diagnoses (p = 0.709, I2 = 0.02%). Average follow-up was 22 months. Conclusions: PM+ICN significantly reduced self-reported pain and headaches in select intractable patients. The PM pathologizing the scapula may constitute a shared anatomic mechanism that contributes to chronic pain across heterogenous disorders of the upper limb.

Background: Atherosclerosis is the major pathological basis of cardiovascular diseases, while current lipid-lowering therapies remain limited by suboptimal efficacy and safety. Natural flavonoids, with their multi-target pharmacological activities, are promising candidates for anti-atherosclerotic intervention. This study investigated the protective effects and mechanisms of total flavonoids from Berberis kaschgarica Rupr. (BTF) against high-fat diet (HFD)-induced atherosclerosis in ApoE[-/-] mice. Methods: Bioavailable constituents of BTF were identified by UPLC-Q-TOF-MS. Network pharmacology and bioinformatics analyses were performed to predict therapeutic targets and pathways. Male ApoE[-/-] mice were fed an HFD and treated with low, medium, or high doses of BTF or atorvastatin. Serum lipid profiles, oxidative stress markers, and aortic histopathology were evaluated. Hepatic proteins related to lipid metabolism were measured by Western blotting, and fecal gut microbiota were analyzed by 16S rRNA sequencing. Results: Seven flavonoid monomers, including kaempferol, apigenin, calycosin, and dihydromyricetin, were identified as absorbed constituents in serum. Bioinformatics suggested that BTF regulates targets involved in lipid metabolism, oxidative stress, and inflammation. BTF dose-dependently decreased serum TC, TG, LDL-C, MDA, and LDH, while increasing HDL-C and the activities of SOD, GSH, and CAT. BTF also reduced atherosclerotic plaque formation and preserved aortic wall structure. Mechanistically, BTF downregulated hepatic SREBP1, ACC1, FAS, APOB, and MTP expression and improved HFD-induced gut microbiota dysbiosis by enriching Akkermansia and Lactobacillus. Conclusions: BTF attenuated HFD-induced atherosclerosis by improving lipid metabolism, enhancing antioxidant capacity, and modulating gut microbiota composition, supporting its potential as a natural anti-atherosclerotic agent.

Endothelial function is impaired in patients with diabetes. Normal high-density lipoprotein (nHDL) protects endothelial function; however, HDL from patients with diabetes becomes dysfunctional (dHDL) and impairs endothelial function. Ferroptosis is a novel iron-dependent form of cell death driven by the accumulation of lipid peroxidation. Nevertheless, it remains unclear whether dHDL impairs endothelial function by inducing ferroptosis. Human umbilical vein endothelial cells (HUVECs) were treated with nHDL or dHDL; consequently, intracellular levels of ferrous ion, lipid peroxidation, superoxide anions (O2•-), and nitric oxide (NO) were detected. The expressions of ferritin heavy polypeptide 1 (FTH1), glutathione peroxidase 4 (GPX4), nuclear receptor coactivator 4 (NCOA4), and sphingosine 1-phosphate receptor 1 (S1P1) were measured, while endothelial cell (EC) tube formation was studied. In addition, the mitochondrial membrane potential (MMP), mitophagy, and ferritinophagy were determined. Moreover, vasodilation in C57BL/6 and diabetic db/db mice was examined. dHDL increased ferrous ion levels, lipid peroxidation, O2•- production, mitophagy, ferritinophagy, and NCOA4 expression; however, it inhibited FTH1, GPX4, and S1P1 expression, NO generation, and EC tube formation. dHDL decreased MMP and impaired endothelium-dependent vasodilation. These effects of dHDL were reversed by ferrostatin-1 or S1P1 overexpression. The expressions of FTH1, GPX4, and S1P1 decreased, whereas NCOA4 expression increased in diabetic db/db mice compared to wild-type mice. Taken together, dHDL impairs endothelial function by inducing mitochondrial damage and EC ferroptosis through the S1P1-NCOA4 axis. Our findings provide a novel mechanism by which dHDL impairs endothelial function and offer a therapeutic target for diabetic vascular dysfunction.

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated efficacy for weight loss in obesity; however, up to 40% of weight lost may derive from lean body mass. The ketogenic diet independently improves insulin sensitivity and promotes fat oxidation while preserving lean tissue. This study aimed to describe changes in body composition, insulin sensitivity, and cardiometabolic markers in patients who followed a personalized ketogenic dietary protocol while receiving low-dose semaglutide over a 6-month insulin resistance reversal program. Methods: Seven analyzed adults (six female, one male) with overweight or obesity (baseline BMI 25.6-47.2 kg/m2) participated in a clinician-supervised 6-month program combining a whole-food ketogenic diet with semaglutide (≤1.0 mg/week). Body composition and fasting metabolic markers were assessed at 1, 3, and 6 months. Results: Mean total weight loss was 21.9 kg, of which a mean of 92% was attributable to BIA-estimated fat mass. Skeletal muscle mass was largely preserved as measured by BIA (mean loss 1.2 kg), and one patient gained lean tissue. Fasting insulin declined by a mean of 15.6 µIU/mL. Visceral fat decreased by a mean of 37.0%. Six of seven patients showed reductions in high-sensitivity C-reactive protein. Triglycerides decreased in six of seven patients, and HDL cholesterol increased in all seven. LDL cholesterol responses were heterogeneous. Conclusions: In this small, uncontrolled case series, combining a ketogenic diet with low-dose semaglutide was associated with substantial fat loss, apparent preservation of lean mass as measured by BIA, and improvements in insulin sensitivity and cardiometabolic markers. Because the semaglutide dose and dietary protocol were individualized to each patient's response, the program illustrates a personalized approach to insulin resistance. These preliminary findings are hypothesis-generating and warrant confirmation in controlled prospective studies.

Background: Obesity is an independent and major risk factor for cardiovascular diseases. However, the presence of common comorbidities such as diabetes and hypertension makes it difficult to understand the direct impact of obesity on the myocardium. The aim of this study is to evaluate the isolated effects of weight loss achieved after bariatric surgery on left ventricular (LV) geometry and diastolic functions in individuals with the "Metabolically Healthy Obese" (MHO) phenotype. Materials and Methods: The study included 28 patients (Surgical Group) who underwent Laparoscopic Sleeve Gastrectomy (LSG) between January 2022 and December 2025, had a preoperative Body Mass Index (BMI) > 40 kg/m2, and had no known cardiovascular or metabolic diseases. The control group consisted of 25 age- and gender-matched metabolically healthy morbidly obese patients who had not undergone surgery. Demographic and echocardiographic data of all participants were analyzed at baseline and at 6 months. Results: Weight Loss: In the surgical group, BMI decreased from 46.21 kg/m2 to 37.11 kg/m2 at the 6th month, while no significant change was observed in the control group. Cardiac Structure: In the surgical group, Left Ventricular Mass Index was significantly decreased from 51.11 g/m2 to 44.57 g/m2. Cardiac Function: The E/A ratio, an indicator of diastolic function, increased significantly from 1.19 to 1.34 in the surgical group, indicating notable improvement. No clinically meaningful change in systolic function was detected. Metabolic Parameters: The surgical group exhibited marked improvements in glucose and lipid profiles (decrease in Total Cholesterol, increase in HDL). Conclusions: The study demonstrates that bariatric surgery, independent of metabolic comorbidities, directly provides "reverse remodeling" of cardiac structure and improves function through reduction of adipose tissue and alleviation of hemodynamic load. These results support the effectiveness of surgery in reducing cardiovascular risk and preserving cardiac structure even in morbidly obese patients without comorbidities.

Zinc (Zn) is an essential trace element that plays important roles in growth, digestion, antioxidant defense, immunity, and inflammation regulation in fish. This study investigated the effects of graded dietary Zn levels on growth performance, serum biochemistry, digestive enzyme activity, zinc transporter expression, antioxidant capacity, immune responses, and inflammatory regulation in juvenile black carp (Mylopharyngodon piceus). Six isonitrogenous and isoenergetic diets were formulated to contain 27.95, 34.38, 44.90, 66.52, 116.14, and 199.56 mg/kg Zn by supplementing ZnSO4·7H2O. Juvenile fish with an initial weight of 2.88 ± 0.12 g were fed the experimental diets for 60 days in triplicate tanks. Growth performance increased with dietary Zn and then plateaued at 44.90-199.56 mg/kg; broken-line regression estimated the optimal dietary Zn requirement at 44.6 mg/kg. Adequate Zn supplementation also reduced whole-body lipid content, increased digestive enzyme activities, improved serum HDL-C and ALP levels, and decreased AST and ALT activities. In addition, adequate dietary Zn (44.90 mg/kg) significantly modulated the expression of zinc transporter genes in the liver and intestine. Adequate dietary Zn supplementation enhanced antioxidant capacity by activating the Nrf2/Keap1 signaling pathway, improved intestinal immunity, and strengthened barrier function by increasing the expression of tight junction proteins and mucins. Moreover, adequate dietary Zn could alleviate inflammatory responses by upregulating anti-inflammatory factors and downregulating pro-inflammatory cytokines via the MAPK14 signaling pathway. These findings suggest that dietary zinc at 44.60 mg/kg is sufficient to promote growth, antioxidant status, immune function, and intestinal health in juvenile black carp.

Apolipoprotein A-I (apoA-I), the major structural and functional protein of plasma high-density lipoprotein (HDL), mediates cholesterol removal from the body and has other beneficial properties. APOA1 gene mutations can cause diseases including human hereditary AApoAI amyloidosis, a life-threatening multiorgan disorder caused by apoA-I misfolding and amyloid deposition. We report esophageal AApoAI amyloidosis in a 66-year-old patient. Amyloid fibrils are comprised of a novel p.Trp96Arg (W72R) apoA-I variant identified by protein mass spectrometry and gene sequencing. Both variant and wild-type apoA-I circulate in plasma at low HDL levels typical of this dominant negative disorder. To understand why W72R substitution promotes amyloid formation, we generated recombinant full-length W72R and wild-type proteins and compared their structural, stability and ligand-binding properties using spectroscopic (circular dichroism, fluorescence, absorption) and biochemical approaches. High-resolution structures of apoA-I in native and in amyloid states were harnessed to propose structural underpinning for the pro-amyloidogenic effects of W72R substitution. W72R substitution slightly destabilized native lipid-free protein; decreased structural protection of amyloid-promoting regions; accelerated lipid solubilization by apoA-I and destabilized model lipoproteins; facilitated apoA-I binding to heparin (a proxy for heparan sulfate) and to type-I collagen; accelerated amyloid formation and potentially stabilized the amyloid structure. All these effects are pro-amyloidogenic. The results help explain the pro-amyloidogenic nature of this mutation, suggest apoA-I binding to extracellular matrix components such as heparan sulfate and collagen as therapeutic targets, and expand our knowledge of the clinical presentation and molecular basis of this complex disease.