Beyond Statins and PCSK9 Inhibitors: Updates in Management of Familial and Refractory Hypercholesterolemias

Rached, Fabiana; Santos, Raul D.

doi:10.1007/s11886-021-01514-2

Cited by 7 publications

(5 citation statements)

References 57 publications

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“…While the HFSS diet elevated total cholesterol and HDL levels, supplementation with a low dose of hesperidin (70 mg/kg/day) effectively mitigated these increases. This observation aligns with the mechanism of action of statins, the primary treatment for high cholesterol and dyslipidemia, [ 57 ], which function by inhibiting the hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme essential for cholesterol production. Recent studies and our findings suggest that hesperidin may also inhibit HMG-CoA reductase, indicating a threshold effect where low doses are sufficient to significantly impact cholesterol biosynthesis [ 58 ].…”

Section: Discussionsupporting

confidence: 71%

Reduced Insulin Resistance and Oxidative Stress in a Mouse Model of Metabolic Syndrome following Twelve Weeks of Citrus Bioflavonoid Hesperidin Supplementation: A Dose–Response Study

Jamal,

Brettle,

Jamil

et al. 2024

Biomolecules

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Metabolic syndrome (MetS) is a cluster of metabolic abnormalities affecting ~25% of adults and is linked to chronic diseases such as cardiovascular disease, cancer, and neurodegenerative diseases. Oxidative stress and inflammation are key drivers of MetS. Hesperidin, a citrus bioflavonoid, has demonstrated antioxidant and anti-inflammatory properties; however, its effects on MetS are not fully established. We aimed to determine the optimal dose of hesperidin required to improve oxidative stress, systemic inflammation, and glycemic control in a novel mouse model of MetS. Male 5-week-old C57BL/6 mice were fed a high-fat, high-salt, high-sugar diet (HFSS; 42% kcal fat content in food and drinking water with 0.9% saline and 10% high fructose corn syrup) for 16 weeks. After 6 weeks of HFSS, mice were randomly allocated to either the placebo group or low- (70 mg/kg/day), mid- (140 mg/kg/day), or high-dose (280 mg/kg/day) hesperidin supplementation for 12 weeks. The HFSS diet induced significant metabolic disturbances. HFSS + placebo mice gained almost twice the weight of control mice (p < 0.0001). Fasting blood glucose (FBG) increased by 40% (p < 0.0001), plasma insulin by 100% (p < 0.05), and HOMA-IR by 150% (p < 0.0004), indicating insulin resistance. Hesperidin supplementation reduced plasma insulin by 40% at 140 mg/kg/day (p < 0.0001) and 50% at 280 mg/kg/day (p < 0.005). HOMA-IR decreased by 45% at both doses (p < 0.0001). Plasma hesperidin levels significantly increased in all hesperidin groups (p < 0.0001). Oxidative stress, measured by 8-OHdG, was increased by 40% in HFSS diet mice (p < 0.001) and reduced by 20% with all hesperidin doses (p < 0.005). In conclusion, hesperidin supplementation reduced insulin resistance and oxidative stress in HFSS-fed mice, demonstrating its dose-dependent therapeutic potential in MetS.

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Section: Discussionsupporting

confidence: 71%

Reduced Insulin Resistance and Oxidative Stress in a Mouse Model of Metabolic Syndrome following Twelve Weeks of Citrus Bioflavonoid Hesperidin Supplementation: A Dose–Response Study

Jamal,

Brettle,

Jamil

et al. 2024

Biomolecules

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“…Several new combination strategies, i.e., the combinations of ezetimibe-lomitapide or -PCSK9 inhibitors, demonstrated promising potential against AS in patients not statin tolerant. 187 , 188 …”

Section: Atherosclerosis (As)mentioning

confidence: 99%

Multifunctional nanoparticle-mediated combining therapy for human diseases

Li,

Peng,

Zoulikha

et al. 2024

Sig Transduct Target Ther

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Combining existing drug therapy is essential in developing new therapeutic agents in disease prevention and treatment. In preclinical investigations, combined effect of certain known drugs has been well established in treating extensive human diseases. Attributed to synergistic effects by targeting various disease pathways and advantages, such as reduced administration dose, decreased toxicity, and alleviated drug resistance, combinatorial treatment is now being pursued by delivering therapeutic agents to combat major clinical illnesses, such as cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders and neurodegenerative diseases. Combinatorial therapy involves combining or co-delivering two or more drugs for treating a specific disease. Nanoparticle (NP)-mediated drug delivery systems, i.e., liposomal NPs, polymeric NPs and nanocrystals, are of great interest in combinatorial therapy for a wide range of disorders due to targeted drug delivery, extended drug release, and higher drug stability to avoid rapid clearance at infected areas. This review summarizes various targets of diseases, preclinical or clinically approved drug combinations and the development of multifunctional NPs for combining therapy and emphasizes combinatorial therapeutic strategies based on drug delivery for treating severe clinical diseases. Ultimately, we discuss the challenging of developing NP-codelivery and translation and provide potential approaches to address the limitations. This review offers a comprehensive overview for recent cutting-edge and challenging in developing NP-mediated combination therapy for human diseases.

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“…The mechanism of action of newer lipid-regulating agents that targets the kinetic defects of apoB and/or apo(a) metabolism in patients with FH, elevated Lp(a) and/or T2DM also merits detailed investigation. These include nucleic acid-based therapeutics targeting RNA with antisense oligonucleotides and small interfering RNA against PCSK9, ANGPTL3, apo(a) and apoC-III [51 ▪▪ ,57,58,64–66]. This approach may address the outstanding treatment gaps in the care of high-risk patients with dyslipidemia.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Recent dynamic studies of the metabolism of atherogenic lipoproteins: elucidating the mode of action of new therapies

Chan

Ying

Watts

2021

Current Opinion in Lipidology

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Purpose of review LDL, triglyceride-rich lipoprotein (TRL) and lipoprotein(a) [Lp(a)] particles are the key atherogenic lipoproteins. Deranged metabolism of these lipoproteins accounts for a spectrum of clinically important dyslipidemias, such as FH, elevated Lp(a) and diabetic dyslipidemia. We review the findings from recent dynamic and tracer studies that have contributed to expanding knowledge in this field. Recent findings Deficiency in LDL receptor activity does not only impair the catabolism of LDL-apoB-100 in FH, but also induces hepatic overproduction and decreases catabolism of TRLs. Patients with elevated Lp(a) are characterized by increased hepatic secretion of Lp(a) particles. Elevation of TRLs in diabetes is partly mediated by increased production of apoB-48 and apoC-III, and impaired clearance of apoB-48 in the postprandial state. Tracer kinetic studies show that proprotein convertase subtilisin/kexin type 9 mAbs alone or in combination with statin can increase the catabolism and decrease production of LDL and Lp(a) particles. By contrast, angiopoietin-like protein 3 inhibitors (e.g. evinacumab) reduce VLDL production and increase LDL clearance in FH. Glucagon-like peptide-1 receptor agonists can improve diabetic dyslipidemia by increasing the catabolism of apoB-48 and decreasing the production of apoB-48 and apoC-III. Summary Dynamic studies of the metabolism of atherogenic lipoproteins provide new insight into the nature of dyslipidemias and point to how new therapies with complementary modes of action may have maximal clinical impact.

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Beyond Statins and PCSK9 Inhibitors: Updates in Management of Familial and Refractory Hypercholesterolemias

Cited by 7 publications

References 57 publications

Reduced Insulin Resistance and Oxidative Stress in a Mouse Model of Metabolic Syndrome following Twelve Weeks of Citrus Bioflavonoid Hesperidin Supplementation: A Dose–Response Study

Reduced Insulin Resistance and Oxidative Stress in a Mouse Model of Metabolic Syndrome following Twelve Weeks of Citrus Bioflavonoid Hesperidin Supplementation: A Dose–Response Study

Multifunctional nanoparticle-mediated combining therapy for human diseases

Recent dynamic studies of the metabolism of atherogenic lipoproteins: elucidating the mode of action of new therapies

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