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IScience Jun 2024The intracellular loops of G protein-coupled receptors (GPCRs) have been shown to play a key role in G protein coupling and selectivity. We recently showed that the...
The intracellular loops of G protein-coupled receptors (GPCRs) have been shown to play a key role in G protein coupling and selectivity. We recently showed that the intrinsically disordered third intracellular loop (ICL3) of β2-adrenergic receptor is dynamic and equilibrates between open and closed conformations to regulate the G protein coupling. In this study, using the extensive molecular dynamics simulations in multi-lipid bilayer models, we show that the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) stabilizes the active state of β2-adrenergic receptor by keeping ICL3 in an open conformation. This stabilization results in a tilt of the receptor within the membrane. Additionally, the ganglioside lipid, GM3 interacts with extracellular loops, impacting the ligand binding site allosterically. This demonstrates the active role of the chemistry of lipids in stabilizing specific GPCR conformations.
PubMed: 38947516
DOI: 10.1016/j.isci.2024.110086 -
IScience Jun 2024This study characterized the effect of calorie restriction (CR) on elemental content and stable isotope ratio measurements of bone "collagen" and hair keratin. Adult...
This study characterized the effect of calorie restriction (CR) on elemental content and stable isotope ratio measurements of bone "collagen" and hair keratin. Adult mice on graded CR (10-40%; 84 days) showed decreased hair N, C, and S values (significantly for N) with increasing CR, alongside a significant increase in bone "collagen" N values and a decrease in "collagen" C values. We propose this was likely due to the intensified mobilization of endogenous proteins, as well as lipids in newly synthesized "collagen". Elemental analysis of bone "collagen" revealed decreased carbon, nitrogen, and sulfur % content with increasing CR which is attributed to a change in the bone "collagen" structure with extent of CR. This complexity challenges the use of elemental indicators in the assessment of collagen quality in archaeological studies where nutritional stress may be a factor.
PubMed: 38947513
DOI: 10.1016/j.isci.2024.110059 -
IScience Jun 2024The NAD-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited...
The NAD-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited progress has been made in SIRT7 modulator discovery. Here, we applied peptide-based deacetylase platforms for SIRT7 enzymatic evaluation and successfully identified a potent SIRT7 inhibitor . We initially isolated bioactive from cockroach () extracts and then developed the synthesis of this compound Further investigation revealed that impaired SIRT7 enzymatic activities through occupation of the NAD binding pocket. attenuated DNA damage repair induced by ionizing radiation (IR) in colorectal cancer cells and exhibited a synergistic anticancer effect when used in combination with etoposide. Overall, our study not only identified as a selective SIRT7 inhibitor from insect resources, but also confirmed its potential use in combined chemo-radiotherapy by interfering in the DNA damage repair process.
PubMed: 38947512
DOI: 10.1016/j.isci.2024.110014 -
IScience Jun 2024The development of targeted drugs for the early prevention and management of chronic kidney disease (CKD) is of great importance. However, the success rates and...
The development of targeted drugs for the early prevention and management of chronic kidney disease (CKD) is of great importance. However, the success rates and cost-effectiveness of traditional drug development approaches are extremely low. Utilizing large sample genome-wide association study data for drug repurposing has shown promise in many diseases but has not yet been explored in CKD. Herein, we investigated actionable druggable targets to improve renal function using large-scale Mendelian randomization and colocalization analyses. We combined two population-scale independent genetic datasets and validated findings with cell-type-dependent eQTL data of kidney tubular and glomerular samples. We ultimately prioritized two drug targets, opioid receptor-like 1 and F12, with potential genetic support for restoring renal function and subsequent treatment of CKD. Our findings explore the potential pathological mechanisms of CKD, bridge the gap between the molecular mechanisms of pathogenesis and clinical intervention, and provide new strategies in future clinical trials of CKD.
PubMed: 38947510
DOI: 10.1016/j.isci.2024.109953 -
IScience Jun 2024Deciphering how different behaviors and ultrasonic vocalizations (USVs) of rats interact can yield insights into the neural basis of social interaction. However, the...
Deciphering how different behaviors and ultrasonic vocalizations (USVs) of rats interact can yield insights into the neural basis of social interaction. However, the behavior-vocalization interplay of rats remains elusive because of the challenges of relating the two communication media in complex social contexts. Here, we propose a machine learning-based analysis system (ARBUR) that can cluster without bias both non-step (continuous) and step USVs, hierarchically detect eight types of behavior of two freely behaving rats with high accuracy, and locate the vocal rat in 3-D space. ARBUR reveals that rats communicate via distinct USVs during different behaviors. Moreover, we show that ARBUR can indicate findings that are long neglected by former manual analysis, especially regarding the non-continuous USVs during easy-to-confuse social behaviors. This work could help mechanistically understand the behavior-vocalization interplay of rats and highlights the potential of machine learning algorithms in automatic animal behavioral and acoustic analysis.
PubMed: 38947508
DOI: 10.1016/j.isci.2024.109998 -
IScience Jun 2024The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory...
The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory mechanisms in relation to cervical cancer remain insufficiently understood. Through bioinformatics analysis, we revealed that ESM1 was highly expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and correlated with dismal clinicopathological features. The activation of ESM1 is facilitated by the presence of oncogenic HPV E6 and E7. HPV E6 and E7 enhance the expression of ESM1 by diminishing the levels of miR-205-5p, which specifically targets the 3' untranslated region of ESM1 mRNA. In addition, we demonstrated that ESM1 facilitates aerobic glycolysis of cervical cancer cells via the Akt/mTOR pathway. Suppression of ESM1 led to a reduction in the expression of HIF-1α and multiple glycolytic enzymes. Taken together, our findings provide insights into the mechanisms by which HPV infections regulate oncogenes, thereby contributing to cervical carcinogenesis.
PubMed: 38947495
DOI: 10.1016/j.isci.2024.110112 -
Heliyon Jun 2024Exserolides are isocoumarin derivatives containing lactone moiety. Recently, some isocoumarins have been demonstrated to ameliorate hyperlipidemia, a major factor for...
Exserolides are isocoumarin derivatives containing lactone moiety. Recently, some isocoumarins have been demonstrated to ameliorate hyperlipidemia, a major factor for inducing cardiovascular diseases. However, the effects and mechanisms of action of exserolides on hyperlipidemia are not known. The aim of this study is to investigate whether the marine fungus sp.-derived exserolides (compounds I, J, E, and F) exert lipid-lowering effects via improving reverse cholesterol transport (RCT) . RAW264.7 macrophages and HepG2 cells were used to establish lipid-laden models, and the levels of intracellular lipids and RCT-related proteins were determined by assay kits and Western blotting, respectively. We observed that exserolides (at a 5 μM concentration) significantly decreased intracellular cholesterol and triglyceride levels in oxidized low-density lipoprotein-laden RAW264.7 cells and markedly improved [H]-cholesterol efflux. Among the four tested compounds, exserolide J increased the protein levels of ATP-binding cassette transporter A1, peroxisome proliferator-activated receptor α (PPARα), and liver X receptor α (LXRα). Furthermore, treatment with exserolides significantly decreased oleic acid-laden lipid accumulation in HepG2 hepatocytes. Mechanistically, exserolides enhance PPARα protein levels; furthermore, compound J increases cholesterol 7 alpha-hydroxylase A1 and LXRα protein levels. Molecular docking revealed that exserolides, particularly compound J, can interact with PPARα and LXRα proteins. These data suggest that the terminal carboxyl group of compound J plays a key role in lowering lipid levels by stimulating LXRα and PPARα proteins. In conclusion, compound J exhibits powerful lipid-lowering effects . However, its hypolipidemic effects should be investigated in the future.
PubMed: 38947487
DOI: 10.1016/j.heliyon.2024.e31861 -
Heliyon Jun 2024Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair...
Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair (MMR) genes is responsible for the disease. The spectrum of tumors in LS is heterogeneous and includes cancer of the colon and rectum (CRC), endometrium, ovaries, stomach, small bowel, urinary tract, bladder, pancreas, and skin. Knowledge of the phenotypic variation of patients with LS, the type and frequency of PVs, and cascade testing studies in the Latin American population is limited. The present study aims to recognize the PVs in MMR genes, describe the phenotype in Mexican-Mestizo patients and their relatives, and identify the acceptance rate of cascade testing of relatives at risk. We included 40 carriers of a MMR gene PV and 142 relatives that developed a LS-related neoplasm. Patients' clinical data, number, and type of malignancies were obtained from their medical records. Amsterdam I-II, Bethesda criteria, and PREMM5® predictive model score were estimated. Available immunohistochemistry (IHC) reports were analyzed. Relatives at risk were determined from index cases pedigrees. The distribution of MMR gene mutations among 40 probands was: (67.5 %) (22.5 %) (7.5 %), and (2.5 %). Out of the 182 LS cases, 58 % exhibited the LS phenotype before age 50. The most common tumor was CRC, followed by endometrial cancer in women and gastric cancer in males. We found a 90.0 % concordance between the IHC and germline PV. The most frequent PV in our sample was c.676C > T, occurring in 1/6 index cases. All probands disclosed their molecular test result to their family. Out of the 451 asymptomatic relatives at risk, 28.2 % underwent germline testing. Our results highlight the importance of conducting germline genetic studies in LS since it allows the establishment of appropriate cancer screening, risk-reducing measures, and genetic cascade testing among relatives at risk. Interestingly, we observed a significantly higher prevalence of the c.676C > T variant in probably a singular characteristic of the Mexican-Mestizo population. New strategies to facilitate accurate communication between index cases and relatives should be implemented to improve the cascade testing acceptance rate.
PubMed: 38947473
DOI: 10.1016/j.heliyon.2024.e31855 -
Heliyon Jun 2024Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an...
Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an essential event in AI, the interaction between bacteria and keratinocytes in AI pathophysiology remains unclear. In this study, the NCSTN gene was suppressed using short hairpin RNA in HaCaT cells. Using RNA sequencing, real-time polymerase chain reaction, and western blotting, the expression of IL-36 cytokines was analyzed. The impact of on AI keratinocyte inflammation and underlying regulatory molecules was investigated by exposing the HaCaT cells to . By stimulating NCSTN knockdown HaCaT cells with IFN-γ, the expression and regulatory mechanism of Cathepsin S (Cat S), an IL-36γ cleavage and activating protease, were investigated. After NCSTN knockdown, the IL-36α expression increased, and the IL-36Ra expression was downregulated. NCSTN/MEK/ERK impairment-induced Krüppel-like factor 4 (KLF4) up-regulation in concert with -induced nuclear factor kappa B elevation acts synergistically to promote IL-36γ production with the subsequent IL-8 activation in HaCaT cells. NCSTN/MEK/ERK impairment was also observed in familial AI lesions. IFN-γ-induced Cat S in keratinocytes was enhanced after NCSTN knockdown. The expression of IFN-II pathway molecules was significantly upregulated in both NCSTN knockdown HaCaT cells and familial AI lesions. The Cat S expression was significantly elevated in the patient's AI lesions. Our findings suggested a synergistic relationship between and NCSTN/MAPK/KLF4 axis in IL-36γ-induced familial AI keratinocytes.
PubMed: 38947455
DOI: 10.1016/j.heliyon.2024.e31509 -
Heliyon Jun 2024L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various...
L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various ailments. This study aims to comprehensively evaluate the antioxidant, anti-inflammatory, and dermatoprotective properties of essential oil derived from , and thyme honey as well as their combined effects. To unravel the chemical composition, a rigorous GC-MS analysis was conducted. Subsequently, we examined their antioxidant potential through three distinct assays: DPPH●, hydrogen peroxide assay, and xanthine oxidase assay. The anti-inflammatory properties were scrutinized through both in vitro and experiments. Simultaneously, the dermatoprotective efficacy was investigated in vitro by evaluating tyrosinase inhibition. Our findings revealed that pulegone constitutes the predominant compound in essential oil (MPEO), constituting a remarkable 74.82 % of the composition. Significantly, when the essential oil was combined with thym honey, it exhibited superior anti-inflammatory and dermatoprotective effects across all and in vitro tests. Moreover, our in silico molecular docking analysis hinted at the potential role of cyclohexanone, 3-methyl, an element found in the MPEO, in contributing to the observed outcomes. While this study has unveiled promising results regarding the combined in vitro, and in silico biological activities of the essential oil and honey, it is imperative to delve further into the underlying mechanisms through additional experimentation and alternative experimental methods. Understanding these mechanisms in greater detail will not only enhance our comprehension of the therapeutic potential but also pave the way for the development of innovative treatments and applications rooted in the synergy of these natural compounds. Furthermore, it would be advantageous to test different possible combinations using experimental design model. Moreover, it would be better to test the effect of single compounds of MPEO to clearly elucidate their efficiency. MPEO alone or combined with thyme honey may be a useful for the development of novel biopharmaceuticals.
PubMed: 38947443
DOI: 10.1016/j.heliyon.2024.e31922