RESUMO
As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking.
Assuntos
Cinesinas/química , Cinesinas/metabolismo , Microtúbulos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Animais , Proteínas de Transporte/metabolismo , Membrana Celular/metabolismo , Suscetibilidade a Doenças , Humanos , Espaço Intracelular/metabolismo , Ligação Proteica , Transporte Proteico , Relação Estrutura-AtividadeRESUMO
A phytochemical study on the whole plant of Spermacoce latifolia led to the isolation of a new anthraquinone, 1,2,6-trihydroxy-5-methoxy-9,10-anthraquinone (1), and a new naphthoquinone, (2R)-6-hydroxy-7-methoxy-dehydroiso-α-lapachone (2), together with three known anthraquinones (3-5). Their structures were established on the basis of detailed spectroscopic analysis, including one- and two-dimensional NMR, ESI-MS, and HR-ESI-MS techniques. All the compounds were isolated from S. latifolia for the first time. Compounds 1, 2, 4, and 5 showed significant antibacterial activity toward Bacillus subtilis with MIC values ranging from 0.9 to 31.2 µg/ml, and compound 4 aslo exhibited antibacterial activity against Bacillus cereus with a MIC value 62.5 µg/ml. Compound 1 was further revealed to show significant in vitro α-glucosidase inhibitory activity with IC50 value of 0.653 mM.
Assuntos
Antraquinonas/isolamento & purificação , Antibacterianos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Naftoquinonas/isolamento & purificação , Rubiaceae/química , Antraquinonas/química , Antraquinonas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus cereus/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Escherichia coli/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Concentração Inibidora 50 , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/farmacologia , Salmonella typhimurium/efeitos dos fármacos , Shigella dysenteriae/efeitos dos fármacos , alfa-Glucosidases/efeitos dos fármacosRESUMO
BACKGROUND: Curcumin nicotinate (Curtn), derived from curcumin and niacin, reduces serum LDL-C levels, partly due to its influence on PCSK9. This study investigates IDOL's role in Curtn's lipid-lowering effects. OBJECTIVE: To elucidate Curtn's regulation of the IDOL/LDLR pathway and potential molecular mechanisms in hepatocytes. METHODS: Differential metabolites in Curtn-treated HepG2 cells were identified via LC-MS. Molecular docking assessed Curtn's affinity with IDOL. Cholesterol content and LDLR expression effects were studied in high-fat diet Wistar rats. In vitro evaluations determined Curtn's influence on IDOL overexpression's LDL-C uptake and LDLR expression in hepatocytes. RESULTS: Lipids were the main differential metabolites in Curtn-treated HepG2 cells. Docking showed Curtn's higher affinity to IDOL's FERM domain compared to curcumin, suggesting potential competitive inhibition of IDOL's binding to LDLR. Curtn decreased liver cholesterol in Wistar rats and elevated LDLR expression. During in vitro experiments, Curtn significantly enhanced the effects of IDOL overexpression in HepG2 cells, leading to increased LDL-C uptake and elevated expression of LDL receptors. CONCLUSION: Curtn modulates the IDOL/LDLR pathway, enhancing LDL cholesterol uptake in hepatocytes. Combined with its PCSK9 influence, Curtn emerges as a potential hyperlipidemia therapy.
Assuntos
Curcumina , Curcumina/análogos & derivados , Niacina/análogos & derivados , Pró-Proteína Convertase 9 , Ratos , Animais , LDL-Colesterol , Curcumina/farmacologia , Ratos Wistar , Simulação de Acoplamento Molecular , Ubiquitina-Proteína Ligases/metabolismo , Hepatócitos/metabolismo , Receptores de LDL/metabolismo , Colesterol , Lipoproteínas LDL/metabolismoRESUMO
Human health is threatened by obesity which causes the increasing incidence of various diseases, especially stroke. Ischemic stroke (IS) is mostly caused by the rupture of arterial plaque, whose instability is positively associated with matrix metalloproteinases (MMPs) that degrades extracellular matrix components. Studies have shown that matrix metalloproteinase-12 (MMP-12) may be involved in the pathogenesis of IS. Because of the higher incidence of stroke in obese patients than that in normal weight people, it is urgent for obesity to forecast stroke early. Considering high levels MMP-12 in obesity, we put forward that MMP-12 may be a potential biomarker for IS in obese patients.
Assuntos
Isquemia Encefálica/diagnóstico , AVC Isquêmico/diagnóstico , Metaloproteinase 12 da Matriz/metabolismo , Obesidade/fisiopatologia , Animais , Apoptose , Biomarcadores/metabolismo , Isquemia Encefálica/complicações , Humanos , Incidência , Inflamação , AVC Isquêmico/complicações , Longevidade , Obesidade/complicações , Trombina/metabolismoRESUMO
The SREBP2/LDLR pathway is sensitive to cholesterol content in the endoplasmic reticulum (ER), while membrane low-density lipoprotein receptor (LDLR) is influenced by sterol response element binding protein 2 (SREBP2), pro-protein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL). LDL-C, one of the risk factors in cardiovascular disease, is cleared through endocytosis recycling of LDLR. Therefore, we propose that a balance between LDLR endocytosis recycling and PCSK9-mediated and IDOL-mediated lysosomal LDLR degradation is responsible for cholesterol homeostasis in the ER. For statins that decrease serum LDL-C levels via cholesterol synthesis inhibition, the mechanism by which the statins increase the membrane LDLR may be regulated by cholesterol homeostasis in the ER.
Assuntos
Colesterol/metabolismo , Receptores de LDL/metabolismo , Animais , Endocitose , Humanos , Receptores de LDL/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Transcrição GênicaRESUMO
Oxidative stress induces the formation of oxidized lowdensity lipoprotein (oxLDL), which accelerates the development of atherosclerosis and the rupture of atherosclerotic plaques by promoting lipid accumulation and inhibiting autophagy in vascular cells. Lipophagy is known to be involved in maintaining the balance of neutral lipid metabolism; however, the phenomenon of lipophagy deficiency in oxLDLtreated endothelial cells (ECs) remains to be elucidated. It has been demonstrated that lipid accumulation caused by oxLDL inhibits autophagy, which promotes apoptosis in ECs. The aim of the present study was to investigate the association between decreased autophagy and lipid accumulation in ECs treated with oxLDL. Electron microscopy demonstrated that the formation of autolipophagosomes was decreased in oxLDLtreated human umbilical vein ECs compared with that in the LDLtreated group and was accompanied by a decrease in the autophagyassociated proteins via western blotting analysis. Using laser focal colocalization detection, decreased lipid processing was observed in the lysosomes of oxLDLtreated ECs, which indicated that lipophagy may be attenuated and subsequently result in lipid accumulation in oxLDLtreated ECs.
Assuntos
Autofagia/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Lipoproteínas LDL/efeitos adversos , Linhagem Celular , Sobrevivência Celular , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Metabolismo dos Lipídeos , Microscopia Eletrônica , Estresse Oxidativo/efeitos dos fármacosRESUMO
OBJECTIVE: The aim of the study was to investigate apolipoprotein(apo) E polymorphism and its relationship with serum lipids and apolipoprotein, serum high density lipoprotein(HDL) subclasses in patients with type IV hyperlipidemia. METHODS: apoE genotype was assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The subclasses of serum HDL in 103 patients with type IV hyperlipidemia and 146 normolipidemic subjects were determined by two-dimensional gel electrophoresis in conjunction with immunodetection method. RESULTS: The apoE3/3 genotype frequency and allele epsilon 3 frequency were both the highest in the frequency distribution profiles of the type IV hyperlipidemia group and the control group. In type IV hyperlipidemia group, the genotype of apoE2 had higher serum HDL-C,apoE, HDL(2a) apoE/apoCIII ratio but lower TG/HDL-C,apoCIII, HDL(3c) levels when compared with the genotype of apoE(3) (P<0.05). In control group, the genotype of apoE(2) had higher serum TG, apoE levels and apoE/aopCIII ratio but lower HDL (3a) level when compared with the genotype of apoE(3) (P<0.05). CONCLUSION: An association of allele epsilon 2 of apoE gene with the maturation of HDL in type IV hyperlipidemia was noted in the study.
Assuntos
Apolipoproteínas E/genética , Hiperlipoproteinemia Tipo IV/genética , Lipoproteínas HDL/sangue , Polimorfismo Genético , Adulto , Idoso , Apolipoproteína C-III/sangue , Apolipoproteína E2/sangue , Apolipoproteína E2/genética , Apolipoproteína E3/sangue , Apolipoproteína E3/genética , Apolipoproteínas E/sangue , HDL-Colesterol/sangue , Feminino , Humanos , Hiperlipoproteinemia Tipo IV/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Triglicerídeos/sangueRESUMO
OBJECTIVE: To investigate apolipoprotein E(apoE) polymorphism and its relationship with serum lipids and apolipoprotein, serum high density lipoprotein (HDL) subclasses in patients with hyperlipidemia(HL). METHODS: APOE genotype was assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The subclasses of serum HDL in 112 patients with hyperlipidemia and 73 healthy subjects were determined by two-dimensional gel electrophoresis in conjunction with immunodetection method. RESULTS: APOE3/3 genotypes and allele epsilon3 frequency in HL group and control group were both the highest. In HL group, the genotype of APOE2 had higher serum APOE/CIII ratio and lower HDL3b levels, compared with the genotype of APOE3 (P<0.05). In control group, the genotype of apoE2 had higher serum triglycerides, APOE levels and APOE/CIII ratio, compared with the genotype of APOE3 and APOE4 (P<0.05). CONCLUSION: Polymorphism of APOE gene may relate to the distribution of HDL particles.
Assuntos
Apolipoproteínas E/genética , Hiperlipidemias/genética , Lipoproteínas HDL/sangue , Adulto , Idoso , Apolipoproteína E2 , Apolipoproteína E3 , Apolipoproteínas E/sangue , Colesterol/sangue , Feminino , Frequência do Gene , Genótipo , Humanos , Hiperlipidemias/sangue , Lipoproteínas HDL/classificação , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Triglicerídeos/sangueRESUMO
OBJECTIVE: To investigate the role of protein kinase C (PKC) in the down-regulation of fibroblast proliferation in normal skin (NFb) and hyperplastic scar (SFb) by adrenaline. METHODS: Human NFb and SFb cells were cultured in vitro. Phentolamine (in final concentrations of 0 and 3 x 10(-6) micromol/L) was added to the culture medium. One hour later, adrenaline in different final concentrations (0.00, 0.05, 0.10, 0.20 micromol/L) was added to the culture medium and incubated for 24 hours. The cellular proliferation activity and cell viability rate were determined with MTT. The cell culture supernatant was harvested for the determination of LDH activity to assess the toxicity of phentolamine and adrenaline. The phosph-PKC activity was determined with Western-blotting and was semiquantitatively analyzed. RESULTS: (1) After stimulation with adrenaline alone, or combined 0.20 micromol/L adrenaline with 3 x 10(-6) micromol/L phentolamine, the cell viability of both NFb and SFb decreased significantly (P < 0.05 or 0.01). (2) There was no difference in the LDH activity between the cells either stimulated by adrenaline in all concentrations or by combination of adrenaline and phentolamine (P > 0.05). (3) The phosphorylation of PKC in NFb and SFb cells stimulated by 0.05, 0.10, 0.20 micromol/L adrenaline was obviously higher than that before stimulation (P < 0.01). When phentolamine in the concentration of 3 x 10(-6) micromol/L was used alone for stimulation, the phosphorylation of PKC in NFb cells (123 +/- 5) was also evidently higher than that before stimulation (80 +/- 5, P < 0.01). But there was no such effect on SFb cells (P > 0.05). When adrenaline in the concentration of 0.05, 0.10 or 0.20 micromol/L was separately added together with phentolamine in the dose of 3 x 10(6) micromol/L for the stimulation, the phosphorylation of PKC in NFb and SFb cells was evidently lower than that when 3 different concentrations of adrenaline was used alone for stimulation (P < 0.01). CONCLUSION: Adrenaline can inhibit the proliferation of NFb and SFb by activating PKC through binding alpha adrenaline receptor.