Search Results (693)

Chronic kidney disease (CKD) confers a high burden of atherosclerotic cardiovascular disease (ASCVD) and a characteristic, evolving dyslipidaemia that is incompletely addressed by conventional care. Statin-based therapy remains first-line in most non-dialysis CKD populations, yet many patients fail to reach lipid goals or remain at substantial residual risk. This structured narrative review evaluates injectable lipid-lowering agents across the CKD spectrum, focusing on the pharmacology and clinical utility of therapies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). The monoclonal antibodies evolocumab and alirocumab are subcutaneous biologics that bind circulating PCSK9, prevent PCSK9-mediated degradation of the low-density lipoprotein (LDL) receptor, and enhance hepatic LDL-cholesterol (LDL-C) clearance. Their catabolic elimination and negligible cytochrome-P450 interaction burden are advantageous in polypharmacy-heavy CKD care. Inclisiran is a hepatocyte-directed, GalNAc-conjugated small interfering RNA that silences PCSK9 messenger RNA, enabling durable LDL-C lowering with twice-yearly maintenance dosing after initiation. Across major programmes, injectable PCSK9 inhibition produces a ~50–60% LDL-C reduction, with consistent efficacy and safety across renal function strata, although outcome data in advanced CKD and dialysis remain limited. Importantly, cardiovascular outcome benefit is established for the monoclonal antibodies evolocumab and alirocumab, whereas inclisiran currently has robust LDL-C-lowering evidence but no completed cardiovascular outcome trial; these agents should not be regarded as having equivalent outcome evidence. Historical dialysis statin trials showed attenuated or neutral cardiovascular benefit, underscoring the biological and trial-design complexity of late-stage kidney disease and the need for dedicated injectable-era trials. We propose a stage-specific framework for integrating injectable therapies into CKD pathways—covering patient selection, sequencing, monitoring and implementation—and outline priorities for CKD-enriched outcome trials, kidney-relevant endpoints, and the integration of emerging lipoprotein(a)-targeted injectables into cardio-renal risk reduction. Full article

This study examined the effects of dietary carbohydrate levels on growth performance, immune response, and antioxidant capacity of male giant freshwater prawn Macrobrachium rosenbergii. Prawns with an initial body weight of 15.04 ± 0.08 g were fed for 9 weeks on five isonitrogenous, isolipidic diets formulated to contain 10%, 15%, 20%, 25%, and 30% carbohydrate (designated CHO10–CHO30). Weight gain rate and specific growth rate rose from CHO10 to CHO20 and then declined (peak in CHO20); broken-line regression of weight gain rate estimated the optimal dietary carbohydrate level at approximately 19.36% under the present experimental conditions. Moderate carbohydrate inclusion (15–20%) enhanced hepatopancreatic total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and catalase (CAT) activities together with the transcription of cu/znsod, cat and glutathione peroxidase (gsh-px), whereas levels ≥ 25% lowered these defenses and raised hepatopancreatic malondialdehyde (MDA). High-carbohydrate diets also increased hemolymph glucose, triglyceride, total cholesterol and low-density lipoprotein cholesterol, progressively altered the mRNA expression of genes involved in the Toll-like receptor (TLR)/myeloid differentiation primary response 88 (MyD88) signaling pathway (upregulated tlr, myd88, relish and tumor necrosis factor; downregulated inhibitor of NF-κB alpha (IκB-α)), and altered the expression of apoptosis-related genes (downregulated B-cell lymphoma 2 (bcl-2), upregulated caspase-3). These results suggest that M. rosenbergii has an estimated optimal dietary carbohydrate level of approximately 19.36% under the present experimental conditions; intakes at or above 25% are associated with compromised hepatopancreatic health and growth, likely through the induction of oxidative stress, altered transcription of TLR/MyD88 pathway-related genes, and changes in apoptosis-related gene expression. Full article

Organophosphorus pesticides (OPPs) are widely used and have recently been linked to metabolic syndrome (MS). This study aimed to investigate the probable association between chronic OPP exposure and MS among farm workers in Sharkia Governorate, Egypt, and to assess the potential role of peroxisome proliferator-activated receptor gamma (PPARγ). This comparative cross-sectional study included 140 participants, equally divided into OPP-exposed farm workers and non-exposed subjects. OPP exposure was confirmed by detecting plasma residues and cholinesterase activity. MS was diagnosed by assessing body mass index (BMI), waist circumference (WC), blood pressure, plasma glucose, serum insulin, and lipid parameters. Oxidative and inflammatory markers, including malondialdehyde (MDA), gamma-glutamyl transferase (GGT), ferritin, superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), and high-sensitivity C-reactive protein (hs-CRP), were measured. The mRNA expression of the PPARγ and paraoxonase 1 (PON1) genes was also investigated. In total, 60% of farm workers demonstrated MS, compared with 10% of non-exposed participants. Workers exhibited elevated oxidative and inflammatory indices and reduced PPARγ and PON1 expression. PPARγ positively correlated with high-density lipoprotein (HDL), SOD, and PON1, while negatively correlating with glucose, insulin resistance (IR), low-density lipoprotein (LDL), triglycerides (TGs), MDA, GGT, ferritin, TNF-α, and hs-CRP. The study concluded that chronic OPP exposure was associated with increased oxidative stress and inflammation, reduced PPARγ and PON1 expression, disturbed glucose and lipid metabolism, and increased IR. The observed associations between PPARγ downregulation, metabolic disturbances, and oxidative and inflammatory markers suggest that PPARγ dysregulation may represent a potential mechanistic link between chronic OPP exposure and MS. However, this proposed mechanism requires further validation. Full article

Pancreatic β cells require tightly controlled cholesterol distribution to maintain glucose sensing, insulin-granule trafficking, and regulated exocytosis. ATP-binding cassette transporter A1 (ABCA1) exports cellular cholesterol and phospholipids to lipid-poor apolipoprotein A-I and is a central component of β-cell cholesterol homeostasis. β-cell-specific Abca1 deletion causes cholesterol accumulation and impaired glucose-stimulated insulin secretion, whereas human studies of rare ABCA1 loss-of-function mutations have reported heterogeneous secretory phenotypes. Endocrine, metabolic, inflammatory, lipoprotein, and post-transcriptional signals regulate pancreatic ABCA1. Exendin-4 activates CaMKK/CaMKIV/PREB-dependent transcription, insulin-like growth factor-1 acts through PI3K/Akt/FoxO1 signaling, and pemafibrate increases ABCA1 through PPAR-α-dependent regulation in experimental models. Conversely, angiotensin II, tumor necrosis factor-α, oxidized low-density lipoprotein, and N-methyl-D-aspartate suppress ABCA1 through distinct or partially convergent pathways, while miR-33a directly suppresses ABCA1 in human and mouse islets. β-cell function depends on the balance among LDLR-dependent cholesterol uptake, PCSK9-mediated receptor regulation, intracellular sterol trafficking and esterification, ABCG1-dependent handling, and ABCA1-dependent export rather than on total cellular cholesterol alone. Although several regulator-specific mechanisms remain preclinical and await independent replication, this review integrates these pathways and discusses their nutritional and translational relevance in type 2 diabetes. Full article

Background/Objectives: We investigated whether preoperative serum low-density lipoprotein cholesterol (LDL-C) is associated with prognosis and midkine (MK; encoded by MDK)-related molecular features in colorectal cancer (CRC). Methods: This exploratory translational study integrated a retrospective cohort of 437 surgically treated patients, CRC-focused public transcriptomic analyses of MDK, independent functional enrichment of STRING-derived MK interactors, and immunohistochemistry in tumors from the lowest and highest LDL-C quartiles (n = 10 per group). Overall survival was analyzed using Cox proportional hazards regression. Results: MDK mRNA expression was elevated in CRC and was associated with adverse clinicopathological features. STRING-derived MK interactors showed significant Gene Ontology enrichment for lipoprotein- and low-density lipoprotein-particle receptor-related functions. KEGG cholesterol metabolism showed nominal enrichment but did not remain significant after multiple-testing correction. In the clinical cohort, each 1 mmol/L increase in LDL-C was independently associated with a lower mortality risk (adjusted HR = 0.612, 95% CI, 0.361–0.998; p = 0.048). Tumors from the lowest LDL-C quartile showed higher MK and c-Fos expression and lower ABCA1 expression than tumors from the highest quartile. Conclusions: Lower preoperative LDL-C was associated with poorer overall survival and with exploratory tissue-level molecular differences in CRC. These independent data layers support an associative, hypothesis-generating framework that requires prospective and mechanistic validation. Full article

Background and Objectives: Oxidized LDL (oxLDL) and Toll-like receptor (TLR) signaling are implicated in inflammatory bone loss and periodontitis, but their cooperative effects on osteoclastogenesis remain unclear. We investigated whether TLR2/4 stimulation regulates the transcription of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a receptor for oxLDL, and whether oxLDL enhances TLR-mediated osteoclastogenic responses in the absence of exogenous RANKL. Materials and Methods: Mouse bone marrow cells (BMCs) were differentiated into bone marrow macrophages (BMMs) with M-CSF and stimulated with TLR ligands (Pam3CSK4 for TLR2 and Lipid A for TLR4) and/or oxLDL, with or without exogenous RANKL. Raw264.7 cells were stimulated with TLR ligands or Porphyromonas gingivalis lipopolysaccharide (LPS). LOX-1 transcriptional activity and osteoclastogenic responses were evaluated using luciferase assays, quantitative RT-PCR, and tartrate-resistant acid phosphatase (TRAP) staining. Results: In Raw264.7 cells, stimulation with Pam3CSK4, Lipid A, or LPS significantly increased LOX-1 promoter activity. In BMCs, Pam3CSK4 significantly increased LOX-1 and MyD88 mRNA expression on day 1, whereas expression decreased by day 3; these changes were suppressed by a TLR2 inhibitor. Lipid A significantly increased LOX-1 and MyD88 mRNA expression on day 3, and the increase in LOX-1 expression was inhibited by a TLR4 inhibitor. Functionally, Pam3CSK4 or Lipid A alone increased mononuclear TRAP-positive cells but did not induce multinucleated TRAP-positive cells. In contrast, co-stimulation of oxLDL with either Pam3CSK4 or Lipid A promoted multinucleated TRAP-positive cell formation even in the absence of exogenous RANKL. Conclusions: TLR2/4 stimulation transiently enhanced LOX-1 transcription and expression in association with increased MyD88 expression. TLR ligands cooperated with oxLDL to promote multinucleated TRAP-positive cell formation in the absence of exogenous RANKL, suggesting that inflammatory and metabolic signals may act synergistically during osteoclastogenesis. These findings improve our understanding of how dyslipidemia-associated factors may contribute to inflammatory bone-resorptive diseases, including periodontitis. Full article

Ovarian cancer (OC) remains the most lethal gynecological malignancy, mostly due to its frequent diagnosis at advanced stages, early peritoneal dissemination, ascites formation, and limited sensitivity of currently available approaches for early detection. Extracellular vesicles (EVs), particularly exosomes, mediate intercellular communication through the transfer of proteins, lipids, metabolites, and nucleic acids. In OC, EV-associated protein profiles reflect both tumor-cell-intrinsic programs and the complex interactions between malignant cells and the peritoneal microenvironment. This review summarizes current evidence regarding the involvement of exosomal proteins in OC progression, with particular emphasis on epithelial–mesenchymal transition, mesothelial reprogramming, extracellular matrix remodeling, angiogenesis, immune suppression, peritoneal dissemination, and platinum resistance. Mechanistic studies indicate that exosomal proteins, including CD44, the integrin α5β1/asparaginyl endopeptidase complex, annexin A2, low-density lipoprotein receptor-related protein 1, and programmed death-ligand 1, can directly contribute to metastatic niche formation and tumor progression. In parallel, proteomic studies of plasma-, serum-, ascites-, peritoneal-fluid-, and uterine-lavage-derived EVs have identified candidate liquid-biopsy biomarkers, including MUC1, EpCAM, FOLR1, integrins, complement- and coagulation-related proteins, and proteins associated with treatment resistance. To integrate the biological significance of proteins reported in OC-associated exosomes, we additionally performed protein–protein interaction and functional enrichment analyses. These analyses revealed interconnected protein groups associated with cell adhesion, oxidative stress adaptation, secretory remodeling, lipid metabolism, extracellular matrix organization, and inflammatory signaling. Taken together, the available evidence supports exosomal proteome profiling as a promising approach for investigating OC dissemination and developing minimally invasive diagnostic and prognostic tools. However, standardized EV isolation, quantitative proteomics, functional validation, and independent clinical cohorts remain essential for translation into clinical practice. Full article

The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and its role in promoting the degradation of the low-density lipoprotein receptor (LDLR) has revolutionized lipid-lowering therapy, offering new therapy for patients with hypercholesterolemia. Notably, PCSK9 is now being explored for functions beyond lipid regulation. Emerging evidence implicates PCSK9 in vascular pathology by influencing endothelial dysfunction, inflammatory signaling, oxidative stress, and vascular homeostasis—potentially through LDLR-independent mechanisms. This review critically evaluates PCSK9’s potential as a regulator of endothelial dysfunction, synthesizing findings from in vitro, in vivo, and clinical studies. While current PCSK9-targeted therapies, including monoclonal antibodies and siRNA-based agents, have demonstrated robust efficacy in lowering lipid levels and reducing cardiovascular risk, their direct effects on endothelial PCSK9 signaling remain unclear. On the other hand, novel approaches—such as peptide-based inhibitors, intracellular modulation, and natural compounds—resulted in new insights into endothelial-specific PCSK9 pathways. Overall, this review highlights the need to bridge experimental and clinical evidence by applying endothelial-focused models, multi-omics analyses, and functional vascular assessments to clarify the role of PCSK9 in endothelial dysfunction and to propose future strategies for cardiovascular interventions targeting PCSK9-mediated endothelial dysfunction. Full article

Background and Objectives: Cornerstone therapies for metastatic prostate cancer include androgen deprivation and androgen receptor pathway inhibition, but cognitive impairment is a recognized, life-altering potential adverse effect of this treatment. Abiraterone acetate (AA), an androgen receptor pathway and CYP17A1 inhibitor, suppresses androgen synthesis and may contribute to cognitive changes. This cell culture-based study uses the BE(2)M17 human male neuroblastoma model to investigate AA-induced alterations in gene and protein expression that may underlie cognitive decline, laying the foundation for a mechanistic investigation aimed at identifying molecular targets to mitigate cognitive impairment in men with prostate cancer receiving androgen-directed therapies. Materials and Methods: BE(2)M17 cells were pretreated for 12 h with dihydrotestosterone (DHT; 5 nM) or vehicle control, then exposed to AA (0, 5, 10 µM, 24 h). RNA and protein were analyzed by qRT-PCR and Western blot for markers of amyloid processing, neuronal health, and mitochondrial function. Results: AA significantly altered multiple neurobiological markers. BACE1 mRNA increased in DHT + 10 µM AA compared to control and DHT alone (p = 0.0416 and p = 0.0118). However, BACE1 protein decreased in 10 µM AA + DHT versus DHT alone (p = 0.0132). Immunoblot revealed reduced amyloid precursor protein (APP) in 10 µM AA versus control (p = 0.0057) and 10 µM versus 5 µM (p = 0.0263). APP was reduced in 10 µM AA + DHT versus control (p = 0.0015) and versus DHT alone (p = 0.0467). LRP1 and BDNF were significantly reduced with 10 µM AA versus 5 µM AA (p = 0.0092 and p = 0.0081), while synaptophysin decreased in 10 µM AA + DHT versus DHT alone (p = 0.0049). BDNF also declined in 10 µM AA + DHT compared to 5 µM AA + DHT (p = 0.0301). PGC1α mRNA increased in AA + DHT versus DHT alone (p = 0.0332). MitoTracker analysis showed reduced fluorescence with 5 µM AA alone but increased fluorescence with 5 µM AA + DHT relative to control and DHT (p = 0.0019; p < 0.0001), while 10 µM AA + DHT reduced fluorescence compared to 5 µM AA + DHT (p = 0.0003). Conclusions: AA, alone or combined with DHT, disrupts key pathways involved in neuronal health, amyloid processing, and mitochondrial function. These findings suggest a potential mechanistic link between AA treatment and cognitive impairment. Full article

Cell surface markers are essential for lineage tracing and for understanding cellular mechanisms of regeneration, yet they remain largely unavailable for echinoderms. Using the starfish Asterias rubens as a model for physiological coelomocyte renewal, we combined Percoll density-gradient fractionation with label-free LC-MALDI proteomics to identify candidate surface proteins that distinguish subpopulations of coelomocytes and coelomic epithelium (CE) cells. However, LC-MALDI is prone to signal variability, sample depletion and nonlinear response. To address the quantitative limitations of LC-MALDI, we implemented a chi-square test with an empirically derived probability density function, which we validated on control mixtures, achieving high precision. Four fractions enriched in distinct cell types were analyzed: coelomocyte fractions 1 (roundish cells) and 4 (large agranulocytes that form cell nets) and CE fractions 1 (type 2 small CE cells) and 4 (ciliated cells), together with a weakly attached CE subpopulation enriched in small putative progenitor cells. LC-MALDI identified 714 protein groups, of which 160 showed significant differential abundance across fractions. Functional enrichment revealed actin cytoskeleton and integrin signaling in coelomocytes, and catenin-related terms in CE-W. Among the 101 predicted membrane proteins, 31 candidate cell surface markers were selected. These include integrins α8β1 and α9β1, three-finger proteins, scavenger receptors, and low-density lipoprotein receptor-related proteins, as well as metallopeptidases. This work provides the first proteome-scale set of candidate surface markers for starfish cell subpopulations, enabling future lineage-tracing studies to resolve the origin of coelomocytes from the coelomic epithelium. Full article

Background/Objectives: Neonatal hypoxic–ischemic encephalopathy (HIE) is a major cause of neurodevelopmental diseases. In a previous retrospective study, we revealed that the levels of the soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) are linked to HIE severity. We conducted a prospective investigation to evaluate the association between sLOX-1 levels and HIE severity using the Sarnat staging system, as well as a multicenter study to assess neurodevelopmental sequelae in the short term. Methods: A total of 193 infants were enrolled in the study between April 2018 and March 2021. We divided the infants into groups as follows: infants without HIE were assigned to a normal control group, and those with HIE to mild, moderate, and severe HIE groups. We measured 191 samples, excluding three participants. The distribution of 191 participants was as follows: 88 normal samples of 50 umbilical cord (UC) arteries and 38 venous blood samples (control; CTL), as well as 103 HIE samples of 34 mild, 55 moderate, and 14 severe HIE samples. All the plasma samples were collected until 6 h after birth. Results: The mean sLOX-1 value in the CTL group was 613 pg/mL (IQR: 474–925 pg/mL) and that in the UC group was 497 pg/mL (IQR: 337–693 pg/mL), with no significant difference (p = 0.136). The mean sLOX-1 value in the mild HIE group was 1030 pg/mL (IQR: 658–1547 pg/mL), 1026 pg/mL (IQR: 710–2051 pg/mL) in the moderate HIE group, and 1444 pg/mL (IQR: 766–3927 pg/mL) in the severe HIE group. There were significant differences between the CTL and HIE groups (p = 0.006) and between the CTL and mild HIE groups (p < 0.05), but not between the mild HIE and the moderate and severe HIE groups (p = 0.088). The other blood markers exhibited no correlation with Sarnat severity. Interestingly, blood sLOX-1 levels increased with Sarnat severity. Conclusions: The results of this study indicated that sLOX-1 level was correlated with Sarnat severity. Moreover, early assessment of sLOX-1 level may be useful for deciding whether to induce therapeutic hypothermia and/or other treatments, and sLOX-1 may serve as a short-term outcome biomarker of HIE. Full article

Background/Objectives: Cholesterol homeostasis is often framed as a dietary problem, but circulating low-density lipoprotein (LDL) biology is governed largely by endogenous sterol handling, with the liver acting as the principal integrative organ for cholesterol synthesis, LDL receptor-mediated clearance, very-low-density lipoprotein (VLDL) export, bile acid production, and biliary sterol disposal. This narrative review evaluates the hepatic basis of cholesterol regulation, statin pharmacology, gut microbial sterol metabolism, chronic hepatic inflammation, and a proposed oral–gut–liver–artery axis in atherogenesis. The aim of this narrative review is to clarify which elements of the proposed axis are established, which are supported but incomplete, and which remain hypothesis-generating. Methods: Mechanistic, translational, clinical, and review literature were synthesized to separate established mechanisms from emerging and speculative links. PubMed/MEDLINE, Scopus, and Google Scholar were searched from January 2000 through May 2026. Primary search terms included: cholesterol homeostasis, LDL receptor, SREBP2, statin pleiotropic effects, statin-associated muscle symptoms, gut microbiota cholesterol, bile salt hydrolase, MASLD, Porphyromonas gingivalis liver, phosphorylated dihydroceramides, serine dipeptide lipids Bacteroidetes, ceramide atherosclerosis, and oral–gut–liver–artery axis. Results: LDL/apoB causality and hepatic statin mechanism are well-established. Gut microbiota can alter cholesterol absorption, coprostanol formation, bile acid pools, and portal signaling, but these effects are context-dependent. Hepatic free cholesterol loading and lysosomal sterol stress are strongly implicated in the biology of metabolic dysfunction-associated steatotic liver disease (MASLD). Periodontal pathogens, especially Porphyromonas gingivalis, may contribute to liver and vascular inflammation through bacteremia, oral–gut translocation, innate immune activation, and bioactive bacterial sphingolipids. Phosphorylated dihydroceramides (PDHCs) and Bacteroidetes-derived serine dipeptide lipids have been detected in human arterial specimens and shown to enter host ceramide pools, providing a direct lipid metabolic pathway linking microbial community composition to vascular disease. Viridans streptococci and the Streptococcus anginosus group are inflammatory cofactors rather than proven causes of hepatic cholesterol overproduction. Conclusions: The strongest model involves microbial amplification of hepatic cholesterol dysmetabolism, endothelial activation, foam-cell formation, and plaque vulnerability acting on a host-derived LDL/apoB scaffold. This model is testable and should complement guideline-based LDL-lowering therapy. Full article

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome (NS). The remission rate of MN remains limited, and effective strategies for refractory MN are not established. We present the case of a 49-year-old Japanese woman with severe NS caused by MN. Kidney biopsy revealed glomerular basement membrane thickening with granular deposition of immunoglobulin G (IgG) and complement component 3. IgG subclass analysis showed predominant IgG1 deposition, with weak IgG2 and IgG3 deposition. Phospholipase A2 receptor (PLA2R) deposition was equivocal in the first kidney biopsy and negative in the second. Serum anti-PLA2R antibody was not detected. Electron microscopy revealed subepithelial, subendothelial, and mesangial electron-dense deposits. Detailed screening revealed no significant abnormalities other than appendiceal findings, suggesting secondary MN associated with appendiceal infection. Although combined therapy with prednisolone, cyclosporine, rituximab, and low-density lipoprotein apheresis was administered during the first 6 months, remission of MN was not achieved. During dialysis, initiated because of kidney failure, long-term multidisciplinary management, including control of appendiceal infection and inflammation and initiation of angiotensin II receptor blocker therapy, ultimately led to remission of MN and discontinuation of dialysis. Overall, even refractory MN requiring dialysis may have a reversible clinical course with careful conservative management and long-term follow-up. Full article

Familial hypercholesterolemia (FH) and familial hypertriglyceridemia (FHTG) represent a spectrum of inherited conditions with profoundly different etiologies, risk profiles, and therapeutic implications. Despite decades of clinical experience, their formal diagnostic definitions remain rooted in frameworks developed before the genomic era (the Dutch Lipid Clinic Network (DLCN) score), leading to substantial gaps in diagnostic accuracy. This review traces the historical evolution of diagnostic criteria for FH and FHTG from early phenotypic observation to contemporary genomic and biomarker-driven models. It systematically evaluates the major limitations of current criteria, including the (DLCN) score, and integrates evidence from landmark Mendelian randomization (MR) studies to identify persistent gaps. A narrative synthesis of landmark clinical, epidemiological, and genetic studies was performed, encompassing the original discovery of the low-density lipoprotein cholesterol (LDL-C) receptor pathway, the development of international diagnostic criteria, and contemporary mendelian randomization (MR) evidence on the causal roles of LDL-C, lipoprotein (a) [Lp(a)], triglyceride-rich lipoprotein remnants, and apolipoprotein B (ApoB). Current diagnostic frameworks suffer from age-dependent confounding of LDL-C measurements, failure to account for Lp(a)-mediated phenocopies, inadequate discrimination between monogenic and polygenic etiologies, sex differences, ethnicity, and inapplicability to pediatric populations. MR data reveal that the causal architecture of cardiovascular risk in these disorders is particle-centric (ApoB) rather than LDL-C-centric, and that remnant cholesterol, not triglyceride per se, drives atherosclerotic cardiovascular disease risk in FHTG. We evidenced the evolution of treatment options and the morbidity and mortality rates for FH and FHTG from the 1970s until the 2020s. Future diagnostic paradigms should integrate lifetime Lp(a) measurement, polygenic risk scoring, ApoB quantification, and cascade genomic testing to replace phenotype-only approaches. This review concludes by proposing a four-step integrated diagnostic algorithm for FH and FHTG. Full article

Exploration of the gene-level changes that occur during post-ischemic neurodegeneration in the frontal cortex is crucial for understanding the development of dementia. An ischemic model of Alzheimer’s disease was used to evaluate changes in the expression of the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1), which are associated with amyloid and tau protein, in the frontal cortex after 10 min of cerebral ischemia, with survival at 2, 7, and 30 days and 0.5, 1, 1.5, and 2 years. LRP1 and RAGE expression was assessed by reverse transcription-quantitative polymerase chain reaction. After two days and 1.5 and 2 years post-ischemia, LRP1 expression was increased, after 7 days and 0.5 years it was decreased, and after 30 days and 1 year it oscillated around control values. The decrease in RAGE expression was statistically significant compared to the control group after 2 and 7 days and after 0.5 years, and after 30 days it oscillated around the control value, while after 1–2 years it increased significantly. RAGE and LRP1 expression showed the same pattern of changes from day 7 to year 2, peaking at 1 and 1.5 years, respectively. Another peak of RAGE overexpression was noted 2 years after ischemia. After 1, 1.5 and 2 years, overexpression of RAGE and LRP1 was observed after ischemia, with the dynamics of LRP1 changes being lower. Overall, the data showed a predominance of RAGE expression over LRP1 expression at 1-, 1.5-, and 2-years post-ischemia. The modification of LRP1 and RAGE after ischemia is useful in studying the molecular ischemic pathways involved in the development of Alzheimer’s disease. Full article