-
Frontiers in Molecular Neuroscience 2024Rho guanine nucleotide exchange factors (Rho GEFs) activate Rho GTPases, which act as molecular switches regulating various essential cellular functions. This study...
Rho guanine nucleotide exchange factors (Rho GEFs) activate Rho GTPases, which act as molecular switches regulating various essential cellular functions. This study investigated the role of ARHGEF5, a Rho GEF known for its involvement in cell migration and invasion processes, in the context of brain development. We found that ARHGEF5 is essential for dendrite development during the early stages of neuronal growth. We also discovered that ARHGEF5 binds to Drebrin E, which is vital for coordinating actin and microtubule dynamics, and facilitates the interaction between Drebrin E and Cyclin-dependent kinase 5, which phosphorylates Drebrin E. Notably, ARHGEF5 deficiency resulted in a decrease in acetylated α-tubulin levels, and the expression of an α-tubulin acetylation mimetic mutant (K40Q) rescued the defects in dendrite development and neuronal migration, suggesting ARHGEF5's role in modulating microtubule stability. Additionally, ARHGEF5 was shown to influence Golgi positioning in the leading processes of migrating cortical neurons during brain development. Our study suggests that ARHGEF5 plays a crucial role in integrating cytoskeletal dynamics with neuronal morphogenesis and migration processes during brain development.
PubMed: 38932934
DOI: 10.3389/fnmol.2024.1421932 -
Nutrients Jun 2024High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and...
BACKGROUND
High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and fish oil are considered to be a part of healthy diets. However, their differential effects on gut microbiome perturbations in mice fed high concentrations of these fats, in the absence of sucrose, remains to be elucidated. The aim of the study was to test whether the sucrose-free cocoa butter-based high-fat diet (C-HFD) feeding in mice leads to gut dysbiosis that associates with a pathologic phenotype marked by hepatic steatosis, low-grade inflammation, perturbed glucose homeostasis, and insulin resistance, compared with control mice fed the fish oil based high-fat diet (F-HFD).
RESULTS
C57BL/6 mice (5-6 mice/group) were fed two types of high fat diets (C-HFD and F-HFD) for 24 weeks. No significant difference was found in the liver weight or total body weight between the two groups. The 16S rRNA sequencing of gut bacterial samples displayed gut dysbiosis in C-HFD group, with differentially-altered microbial diversity or relative abundances. , and were highly abundant in C-HFD group, while the , (TM7), , and were more abundant in F-HFD group. Other taxa in C-HFD group included the (AF12), and An increased Firmicutes/Bacteroidetes (F/B) ratio in C-HFD group, compared with F-HFD group, indicated the gut dysbiosis. These gut bacterial changes in C-HFD group had predicted associations with fatty liver disease and with lipogenic, inflammatory, glucose metabolic, and insulin signaling pathways. Consistent with its microbiome shift, the C-HFD group showed hepatic inflammation and steatosis, high fasting blood glucose, insulin resistance, increased hepatic de novo lipogenesis (Acetyl CoA carboxylases 1 (), Fatty acid synthase (), Stearoyl-CoA desaturase-1 (), Elongation of long-chain fatty acids family member 6 (), Peroxisome proliferator-activated receptor-gamma () and cholesterol synthesis (β-(hydroxy β-methylglutaryl-CoA reductase (). Non-significant differences were observed regarding fatty acid uptake (Cluster of differentiation 36 (), Fatty acid binding protein-1 () and efflux (ATP-binding cassette G1 (), Microsomal TG transfer protein () in C-HFD group, compared with F-HFD group. The C-HFD group also displayed increased gene expression of inflammatory markers including Tumor necrosis factor alpha (), C-C motif chemokine ligand 2 (), and Interleukin-12 (), as well as a tendency for liver fibrosis.
CONCLUSION
These findings suggest that the sucrose-free C-HFD feeding in mice induces gut dysbiosis which associates with liver inflammation, steatosis, glucose intolerance and insulin resistance.
Topics: Animals; Dysbiosis; Gastrointestinal Microbiome; Insulin Resistance; Diet, High-Fat; Mice, Inbred C57BL; Male; Mice; Fatty Liver; Liver; Dietary Fats; Sucrose
PubMed: 38931284
DOI: 10.3390/nu16121929 -
Plants (Basel, Switzerland) Jun 2024, popularly used in México, possesses bioactive lignans. These compounds are low in the bark, and its extraction endangers the life of the trees. The aim of the present...
, popularly used in México, possesses bioactive lignans. These compounds are low in the bark, and its extraction endangers the life of the trees. The aim of the present investigation was to search for alternative sources of cytotoxic compounds in . prepared as leaves and in vitro callus cultures. The friable callus of was established using a combination of plant growth regulators: 4 mgL of 2,4-dichlorophenoxyacetic acid (2,4-D), 1 mgL Naphthaleneacetic Acid (NAA) and 1 mgL Zeatin. The maximum cell growth was at day 28 with a specific growth rate of μ = 0.059 days and duplication time td = 11.8 days. HPLC quantification of the dichloromethane callus biomass extract showed that Scopoletin, with a concentration of 10.7 µg g dry weight, was the main compound inducible as a phytoalexin by the addition of high concentrations of 2,4-D, as well as by the absence of nutrients in the culture medium. In this same extract, the compounds γ-sitosterol and stigmasterol were also identified by GC-MS analysis. Open column chromatography was used to separate and identify yatein, acetyl podophyllotoxin and 7',8'-dehydropodophyllotoxin in the leaves of the wild plant. Cytotoxic activity on four cancer cell lines was tested, with PC-3 prostate carcinoma (IC of 12.6 ± 4.6 µgmL) being the most sensitive to the wild-type plant extract and HeLa cervical carcinoma (IC of 72 ± 5 µgmL) being the most sensitive to the callus culture extract.
PubMed: 38931054
DOI: 10.3390/plants13121622 -
Molecules (Basel, Switzerland) Jun 20241,2-Dihydroisoquinolines are important compounds due to their biological and medicinal activities, and numerous approaches to their synthesis have been reported....
1,2-Dihydroisoquinolines are important compounds due to their biological and medicinal activities, and numerous approaches to their synthesis have been reported. Recently, we reported a facile synthesis of trisubstituted allenamides via -acetylation followed by DBU-promoted isomerization, where various substituted allenamides were conveniently synthesized from readily available propargylamines with high efficiency. In light of this research background, we focused on the utility of this methodology for the synthesis of substituted 1,2-dihydroisoquinolines. In this study, a palladium-catalyzed cascade cyclization-coupling of trisubstituted allenamides containing a bromoaryl moiety with arylboronic acids is described. When -acetyl diphenyl-substituted trisubstituted allenamide and phenylboronic acid were treated with 10 mol% of Pd(OAc), 20 mol% of P(-tolyl), and 5 equivalents of NaOH in dioxane/HO (4/1) at 80 °C, the reaction proceeded to afford a substituted 1,2-dihydroisoquinoline. The reaction proceeded via intramolecular cyclization, followed by transmetallation with the arylboronic acid of the resulting allylpalladium intermediate. A variety of highly substituted 1,2-dihydroisoquinolines were concisely obtained using this methodology because the allenamides, as reaction substrates, were prepared from readily available propargylamines in one step.
PubMed: 38930982
DOI: 10.3390/molecules29122917 -
Molecules (Basel, Switzerland) Jun 2024Organic arsenic compounds such as -aminophenylarsine oxide (-APAO) are easier for structural optimization to improve drug-like properties such as pharmacokinetic...
Organic arsenic compounds such as -aminophenylarsine oxide (-APAO) are easier for structural optimization to improve drug-like properties such as pharmacokinetic properties, therapeutic efficacy, and target selectivity. In order to strengthen the selectivity of 4-(1,3,2-dithiarsinan-2-yl) aniline 7 to tumor cell, a thiourea moiety was used to strengthen the anticancer activity. To avoid forming a mixture of α/β anomers, the strategy of 2-acetyl's neighboring group participation was used to lock the configuration of 2,3,4,6-tetra--acetyl-β-d-glucopyranosyl isothiocyanate from 2,3,4,6-tetra--acetyl-α-d-glucopyranosyl bromide. 1-(4-(1,3,2-dithiarsinan-2-yl) aniline)-2-N-(2,3,4,6-tetra--acetyl-β-d-glucopyranos-1-yl)-thiourea 2 can increase the selectivity of human colon cancer cells HCT-116 (0.82 ± 0.06 μM vs. 1.82 ± 0.07 μM) to human embryonic kidney 293T cells (1.38 ± 0.01 μM vs. 1.22 ± 0.06 μM) from 0.67 to 1.68, suggesting a feasible approach to improve the therapeutic index of arsenic-containing compounds as chemotherapeutic agents.
Topics: Humans; Thiourea; Antineoplastic Agents; Drug Design; Glucose; Cell Line, Tumor; Cell Proliferation; HCT116 Cells; Molecular Structure; Arsenicals; Structure-Activity Relationship
PubMed: 38930915
DOI: 10.3390/molecules29122850 -
Molecules (Basel, Switzerland) Jun 2024A new series of chiral 4,5-dihydro-1-[1,2,4]-triazoline molecules, featuring a β-ᴅ-glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition...
Stereoselective Asymmetric Syntheses of Molecules with a 4,5-Dihydro-1-[1,2,4]-Triazoline Core Possessing an Acetylated Carbohydrate Appendage: Crystal Structure, Spectroscopy, and Pharmacology.
A new series of chiral 4,5-dihydro-1-[1,2,4]-triazoline molecules, featuring a β-ᴅ-glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition reaction between various hydrazonyl chlorides and carbohydrate Schiff bases. The isolated enantiopure triazolines (-) were identified through high-resolution mass spectrometry (HRMS) and vibrational spectroscopy. Subsequently, their solution structures were elucidated through NMR spectroscopic techniques. Single-crystal X-ray analysis of derivative provided definitive evidence for the 3-D structure of this compound and revealed important intermolecular forces in the crystal lattice. Moreover, it confirmed the ()-configuration at the newly generated stereo-center. Selected target compounds were investigated for anti-tumor activity in 60 cancer cell lines, with derivative showing the highest potency, particularly against leukemia. Additionally, substituent-dependent anti-fungal and anti-bacterial behavior was observed.
Topics: Humans; Crystallography, X-Ray; Triazoles; Cell Line, Tumor; Antineoplastic Agents; Carbohydrates; Molecular Structure; Stereoisomerism; Acetylation; Structure-Activity Relationship; Magnetic Resonance Spectroscopy
PubMed: 38930904
DOI: 10.3390/molecules29122839 -
Molecules (Basel, Switzerland) Jun 2024In this study, we report a novel per-6-substituted β-cyclodextrin () featuring seven phosphoramidate moieties as an innovative host for inclusion. This structurally...
In this study, we report a novel per-6-substituted β-cyclodextrin () featuring seven phosphoramidate moieties as an innovative host for inclusion. This structurally well-defined host has remarkable water solubility and was isolated in pure form. Analytical techniques such as NMR and ITC were used to probe the molecular interactions with different drug molecules. Our investigations revealed that host can form 2:1 inclusion complexes with various drugs. Further studies showed that the inclusions of drugs by β-CD host () are mostly enthalpy driven, highlighting the potential roles played by the phosphoramidate functionalities of the host. Comparatively, a per-O2, O3-acetylated analog () of compound was also obtained, which also shows unusual water solubility but diminished inclusion capability.
PubMed: 38930780
DOI: 10.3390/molecules29122714 -
Life (Basel, Switzerland) Jun 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as the most prevalent chronic liver disease, closely linked to the escalating rates...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as the most prevalent chronic liver disease, closely linked to the escalating rates of diabesity. The Western diet's abundance of fat and fructose significantly contributes to MASLD, disrupting hepatic glucose metabolism. We previously demonstrated that a high-fat and high-fructose diet (HFHFD) led to increased body and liver weight compared to the low-fat diet (LFD) group, accompanied by glucose intolerance and liver abnormalities, indicating an intermediate state between fatty liver and liver fibrosis in the HFHFD group. Sirtuins are crucial epigenetic regulators associated with energy homeostasis and play a pivotal role in these hepatic dysregulations. Our investigation revealed that HFHFD significantly decreased Sirt1 and Sirt7 gene and protein expression levels, while other sirtuins remained unchanged. Additionally, glucose 6-phosphatase (G6Pase) gene expression was reduced in the HFHFD group, suggesting a potential pathway contributing to fibrosis progression. Chromatin immunoprecipitation analysis demonstrated a significant increase in histone H3 lysine 18 acetylation within the G6Pase promoter in HFHFD livers, potentially inhibiting G6Pase transcription. In summary, HFHFD may inhibit liver gluconeogenesis, potentially promoting liver fibrosis by regulating Sirt7 expression. This study offers an epigenetic perspective on the detrimental impact of fructose on MASLD progression.
PubMed: 38929712
DOI: 10.3390/life14060729 -
Medicina (Kaunas, Lithuania) May 2024Chronic kidney disease (CKD) is characterized by persistent kidney dysfunction, ultimately resulting in end-stage renal disease (ESRD). Renal fibrosis is a crucial... (Review)
Review
Chronic kidney disease (CKD) is characterized by persistent kidney dysfunction, ultimately resulting in end-stage renal disease (ESRD). Renal fibrosis is a crucial pathological feature of CKD and ESRD. However, there is no effective treatment for this condition. Despite the complex molecular mechanisms involved in renal fibrosis, increasing evidence highlights the crucial role of histone modification in its regulation. The reversibility of histone modifications offers promising avenues for therapeutic strategies to block or reverse renal fibrosis. Therefore, a comprehensive understanding of the regulatory implications of histone modifications in fibrosis may provide novel insights into more effective and safer therapeutic approaches. This review highlights the regulatory mechanisms and recent advances in histone modifications in renal fibrosis, particularly histone methylation and histone acetylation. The aim is to explore the potential of histone modifications as targets for treating renal fibrosis.
Topics: Humans; Fibrosis; Histones; Renal Insufficiency, Chronic; Kidney; Acetylation; Methylation; Protein Processing, Post-Translational; Histone Code
PubMed: 38929505
DOI: 10.3390/medicina60060888 -
Animals : An Open Access Journal From... Jun 2024The present study aimed to investigate the impacts of dietary standardized ileal digestible lysine to net energy (SID Lys:NE) ratio on lipid metabolism in pigs fed...
The present study aimed to investigate the impacts of dietary standardized ileal digestible lysine to net energy (SID Lys:NE) ratio on lipid metabolism in pigs fed high-wheat diets. Thirty-six crossbred growing barrows (65.20 ± 0.38 kg) were blocked into two treatment groups, fed high-wheat diets with either a high SID Lys:NE ratio (HR) or a low SID Lys:NE ratio (LR). Each treatment group consisted of three replicates, with six pigs per pen in each replicate. The diminishing dietary SID Lys:NE ratio exhibited no adverse impacts on the carcass trait ( > 0.05) but increased the marbling score of the longissimus dorsi muscle ( < 0.05). Meanwhile, LR diets tended to increase the serum triglyceride concentration ( < 0.1). LR diets upregulated fatty acid transport protein 4 and acetyl-coA carboxylase α expression levels and downregulated the expression level of adipose triglyceride lipase ( < 0.05). LR diets improved energy metabolism via decreasing the expression levels of AMP-activated protein kinase (AMPK) α1, sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) ( < 0.05). Additionally, LR diets stimulated hepatic bile acid synthesis via upregulating the expression levels of cytochrome P450 family 7 subfamily A member 1 and cytochrome P450 family 27 subfamily A member 1, and downregulating farnesol X receptor (FXR) and small heterodimer partner (SHP) expression levels ( < 0.05). A lowered SID Lys:NE ratio affected the colonic microbial composition, characterized by increased relative abundances of , , , and , alongside a decreased in the proportion of , , , , , , , , and ( < 0.05). The alterations in microbial composition were accompanied by a decrease in colonic butyrate concentration ( < 0.1). The metabolomic analysis revealed that LR diets affected primary bile acid synthesis and AMPK signaling pathway ( < 0.05). And the mantel analysis indicated that , , , , and contributed to the alterations in body metabolism. A reduced dietary SID Lys:NE ratio improves energy metabolism, stimulates lipogenesis, and inhibits lipolysis in finishing pigs by regulating the AMPKα/SIRT1/PGC-1α pathway and the FXR/SHP pathway. and benefited bile acids synthesis, whereas , , and may contribute to the activation of the AMPK signaling pathway. Overall, body metabolism and colonic microbiota collectively controlled the lipid metabolism in finishing pigs.
PubMed: 38929443
DOI: 10.3390/ani14121824