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1.
Heliyon ; 10(12): e32623, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38975173

ABSTRACT

Diabetic neuropathy (DN) represents a common and debilitating complication of diabetes, affecting a significant proportion of patients. Despite available treatments focusing on symptom management, there remains an unmet need for therapies that address the underlying pathophysiology. In pursuit of novel interventions, this study evaluated the therapeutic effects of caffeic acid-a natural phenolic compound prevalent in various foods-on diabetic neuropathy using a mouse model, particularly examining its interaction with the Insulin-like Growth Factor 1 (IGF-1) signaling pathway. Caffeic acid was administered orally at two dosages (5 mg/kg and 10 mg/kg), and a comprehensive set of outcomes including fasting blood glucose levels, body weight, sensory behavior, spinal cord oxidative stress markers, inflammatory cytokines, and components of the IGF-1 signaling cascade were assessed. Additionally, to determine the specific contribution of IGF-1 signaling to the observed benefits, IGF1R inhibitor Picropodophyllin (PPP) was co-administered with caffeic acid. Our results demonstrated that caffeic acid, at both dosages, effectively reduced hyperglycemia and alleviated sensory behavioral deficits in diabetic mice. This was accompanied by a marked decrease in oxidative stress markers and an increase in antioxidant enzyme activities within the spinal cord. Significantly lowered microglial activation and inflammatory cytokine expression highlighted the potent antioxidative and anti-inflammatory effects of caffeic acid. Moreover, increases in both serum and spinal levels of IGF-1, along with elevated phosphorylated IGF1R, implicated the IGF-1 signaling pathway as a mediator of caffeic acid's neuroprotective actions. The partial reversal of caffeic acid's benefits by PPP substantiated the pivotal engagement of IGF-1 signaling in mediating its effects. Our findings delineate the capability of caffeic acid to mitigate DN symptoms, particularly through reducing spinal oxidative stress and inflammation, and pinpoint the integral role of IGF-1 signaling in these protective mechanisms. The insights gleaned from this study not only position caffeic acid as a promising dietary adjunct for managing diabetic neuropathy but also highlight the therapeutic potential of targeting spinal IGF-1 signaling as part of a strategic treatment approach.

2.
Cell Signal ; 121: 111262, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38901722

ABSTRACT

Many solid tumors frequently overexpress Non-SMC Condensin I Complex Subunit H (NCAPH), and new studies suggest that NCAPH may be a target gene for clinical cancer therapy. Numerous investigations have shown that a variety of transcription factors, including as MYBL2, FOXP3, GATA3, and OTC1, can stimulate the transcription of NCAPH. Additionally, NCAPH stimulates many oncogenic signaling pathways, such as ß-Catenin/PD-L1, PI3K/AKT/SGK3, MEK/ERK, AURKB/AKT/mTOR, PI3K/PDK1/AKT, and Chk1/Chk2. Tumor immune microenvironment modification and tumor growth, apoptosis, metastasis, stemness, and treatment resistance all depend on these signals. NCAPH has the ability to form complexes with other proteins that are involved in glycolysis, DNA damage repair, and chromatin remodeling. This review indicates that NCAPH expression in most malignant tumors is associated with poor prognosis and low recurrence-free survival.

3.
J Environ Manage ; 364: 121452, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38889651

ABSTRACT

This study bridges the knowledge gap pertaining to the pathways of heavy metal accumulation and migration within the industrial chain of large-scale cattle farms. Two such farms in Shaanxi serve as a basis for our exploration into Zn, Cu, Cr, Pb, As, and Cd dynamics. Employing material flow analysis complemented by predictive models, we evaluate the potential ecological risks of arable soil from heavy metal influx via manure application. Our findings indicate that Zn and Cu predominate the heavy metal export from these operations, composing up to 60.00%-95.67% of their total content. Predictive models based on 2021 data reveal a potential increase in Cd soil concentration by 0.08 mg/kg by 2035, insinuating a reduced safe usage period for cattle manure at less than 50 years. Conversely, projections from 2022 data point towards a gradual Cu rise in soil, reaching risk threshold levels after 126 years. These outcomes inform limitations in cattle manure utilisation strategies, underscoring Cu and Cd content as key barriers. The study underscores the criticality of continuous heavy metal surveillance within farm by products to ensure environmental protection and sustainable agricultural practices.


Subject(s)
Farms , Manure , Metals, Heavy , Soil Pollutants , Metals, Heavy/analysis , Animals , Manure/analysis , Cattle , Risk Assessment , Soil Pollutants/analysis , Soil/chemistry , Agriculture , Environmental Monitoring
4.
Diagnostics (Basel) ; 14(12)2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38928672

ABSTRACT

Currently, brain tumors are extremely harmful and prevalent. Deep learning technologies, including CNNs, UNet, and Transformer, have been applied in brain tumor segmentation for many years and have achieved some success. However, traditional CNNs and UNet capture insufficient global information, and Transformer cannot provide sufficient local information. Fusing the global information from Transformer with the local information of convolutions is an important step toward improving brain tumor segmentation. We propose the Group Normalization Shuffle and Enhanced Channel Self-Attention Network (GETNet), a network combining the pure Transformer structure with convolution operations based on VT-UNet, which considers both global and local information. The network includes the proposed group normalization shuffle block (GNS) and enhanced channel self-attention block (ECSA). The GNS is used after the VT Encoder Block and before the downsampling block to improve information extraction. An ECSA module is added to the bottleneck layer to utilize the characteristics of the detailed features in the bottom layer effectively. We also conducted experiments on the BraTS2021 dataset to demonstrate the performance of our network. The Dice coefficient (Dice) score results show that the values for the regions of the whole tumor (WT), tumor core (TC), and enhancing tumor (ET) were 91.77, 86.03, and 83.64, respectively. The results show that the proposed model achieves state-of-the-art performance compared with more than eleven benchmarks.

5.
Materials (Basel) ; 17(12)2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38930296

ABSTRACT

Incorporating iron tailings (ITs) into asphalt represents a new method for waste-to-resource conversion. The objective of this study is to evaluate the fatigue performance of ITs as fillers in asphalt mastic and investigate the interaction and interfacial adhesion energy between asphalt and ITs. To achieve that, the particle size distributions of two ITs and limestone filler (LF) were tested through a laser particle size analyzer; the morphology and structure characteristics were obtained by scanning electronic microscopy (SEM), the mineral compositions were conducted through X-ray diffraction (XRD), and the chemical compositions were tested through X-ray Fluorescence Spectrometer (XRF). Furthermore, the fatigue properties of asphalt mastic and the interaction between asphalt binder and mineral fillers (ITs and LFs) were evaluated by Dynamic Shear Rheometer (DSR). The interfacial adhesion energy between ITs and asphalt binder were calculated through molecular dynamics simulation. In the end, the correlation between the test results and the fatigue life is established based on the gray correlation analysis, the environmental and economic benefits of iron tailings asphalt pavement are further evaluated. The results show that the particle size distribution of ITs is concentrated between 30 µm and 150 µm, and the main component is quartz. ITs have rich angularity and a higher interaction ability with asphalt. The adhesion energy of iron tailings filler to asphalt is less than that of limestone. The correlation degree of the interfacial adhesion energy and interaction between asphalt and mineral filler with asphalt mastic fatigue life is close to 0.58. Under the combined action of interaction ability and interfacial adhesion energy, the fatigue life of IT asphalt mastic meets the requirements. ITs as a partial replacement for mineral fillers in asphalt pavement have great environmental and social effectiveness.

6.
Materials (Basel) ; 17(12)2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38930322

ABSTRACT

High-entropy alloys (HEAs) have garnered significant attention for their exceptional properties, with eutectic high-entropy alloys (EHEAs) emerging as particularly notable due to their incorporation of eutectic structures comprising soft and hard phases. This study investigated the influence of shear strain on the microstructural refinement and mechanical properties of AlCoCrFeNi2.1 EHEAs, which were subjected to high-pressure torsion (HPT) at room temperature under a pressure of 6 GPa across 0.5 to 3 turns, compared to the initial material. After HPT treatment, significant grain refinement occurred due to strong shear strain, evidenced by the absence of B2 phase peaks in X-ray diffraction (XRD) analysis. Microhardness increased substantially post-HPT, reaching a saturation point at approximately 575 HV after three turns, significantly higher than that of the original sample. Moreover, the ultimate tensile strength of HPT-treated specimens reached around 1900 MPa after three revolutions, compared to approximately 1100 MPa for the as-cast alloy, with a mixed fracture mode maintained. This investigation underscores the efficacy of HPT in enhancing the mechanical properties of AlCoCrFeNi2.1 EHEAs through microstructural refinement induced by shear deformation, offering insights into the design and optimization of advanced HEAs for various engineering applications.

7.
ACS Appl Mater Interfaces ; 16(21): 27850-27865, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38760320

ABSTRACT

To meet the diverse needs of humans, smart cloth has become a potential research hotspot to replace traditional cloth. However, it is challenging to manufacture a flexible fabric with multiple functions. Here, we introduce a smart cloth based on liquid metal (LM) conductive fibers. Ga2O3 nanoparticles are obtained through ultrasonic pretreatment. Furthermore, a coordination bond is formed between thiol groups on the surface of protein fibers and Ga2O3 through a scraping method, allowing Ga2O3 particles to be grafted onto the surface of protein fibers in situ. Finally, LM conductive fibers are encapsulated using a photocuring adhesive. In addition, a wearable smart cloth integrated with multiple sensors has been developed based on LM conductive fibers. Users can not only monitor their movement trajectory and the surrounding environment in real time but also have their data supervised by family members through a client, achieving remote and continuous monitoring. The development of this wearable smart cloth provides strong support for future wearable, flexible electronic devices.

8.
Anal Chem ; 96(22): 9132-9140, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38764163

ABSTRACT

Gold nanorods (AuNRs) have been considered highly compelling materials for early cancer diagnosis and have aroused a burgeoning fascination among the biomedical sectors. By leveraging the versatile tunable optical properties of AuNRs, herein, we have developed a novel tumor-targeted dual-modal nanoprobe (FFA) that exhibits excellent bioluminescence and photoacoustic imaging performance for early tumor diagnosis. FFA has been synthesized by anchoring the recombinant bioluminescent firefly luciferase protein (Fluc) on the folate-conjugated AuNRs via the PEG linker. TEM images and UV-vis studies confirm the nanorod morphology and successful conjugation of the biomolecules to AuNRs. The nanoprobe FFA relies on the ability of the folate module to target the folate receptor-positive tumor cells actively, and simultaneously, the Fluc module facilitates excellent bioluminescent properties in physiological conditions. The success of chemical engineering in the present study enables stronger bioluminescent signals in the folate receptor-positive cells (Skov3, Hela, and MCF-7) than in folate receptor-negative cells (A549, 293T, MCF-10A, and HepG2). Additionally, the AuNRs induced strong photoacoustic conversion performance, enhancing the resolution of tumor imaging. No apparent toxicity was detected at the cellular and mouse tissue levels, manifesting the biocompatibility nature of the nanoprobe. Prompted by the positive merits of FFA, the in vivo animal studies were performed, and a notable enhancement was observed in the bioluminescent/photoacoustic intensity of the nanoprobe in the tumor region compared to that in the folate-blocking region. Therefore, this synergistic dual-modal bioluminescent and photoacoustic imaging platform holds great potential as a tumor-targeted contrast agent for early tumor diagnosis with high-performance imaging information.


Subject(s)
Contrast Media , Gold , Luminescent Measurements , Nanotubes , Photoacoustic Techniques , Photoacoustic Techniques/methods , Humans , Nanotubes/chemistry , Gold/chemistry , Animals , Contrast Media/chemistry , Mice , Mice, Nude , Optical Imaging , Neoplasms/diagnostic imaging , Female , Luciferases/chemistry , Luciferases/metabolism
9.
J Am Chem Soc ; 2024 May 16.
Article in English | MEDLINE | ID: mdl-38753624

ABSTRACT

The efficacy of photodynamic therapy is hindered by the hypoxic environment in tumors and limited light penetration depth. The singlet oxygen battery (SOB) has emerged as a promising solution, enabling oxygen- and light-independent 1O2 release. However, conventional SOB systems typically exhibit an "always-ON" 1O2 release, leading to potential 1O2 leakage before and after treatment. This not only compromises therapeutic outcomes but also raises substantial biosafety concerns. In this work, we introduce a programmable singlet oxygen battery, engineered to address all the issues discussed above. The concept is illustrated through the development of a tumor-microenvironment-responsive pyridone-pyridine switch, PyAce, which exists in two tautomeric forms: PyAce-0 (pyridine) and PyAce (pyridone) with different 1O2 storage half-lives. In its native state, PyAce remains in the pyridone form, capable of storing 1O2 (t1/2 = 18.5 h). Upon reaching the tumor microenvironment, PyAce is switched to the pyridine form, facilitating rapid and thorough 1O2 release (t1/2 = 16 min), followed by quenched 1O2 release post-therapy. This mechanism ensures suppressed 1O2 production pre- and post-therapy with selective and rapid 1O2 release at the tumor site, maximizing therapeutic efficacy while minimizing side effects. The achieved "OFF-ON-OFF" 1O2 therapy showed high spatiotemporal selectivity and was independent of the oxygen supply and light illumination.

10.
Medicine (Baltimore) ; 103(19): e37998, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38728505

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most common cancers globally, seriously endangering people health. Vitamin D was significantly associated with tumor progression and patients' prognosis. Integrative 10 machine learning algorithms were used to develop a Vitamin D-related signature (VRS) with one training cohort and 3 testing cohorts. The performance of VRS in predicting the immunology response was verified using several predicting approaches. The optimal VRS was constructed by stepCox + superPC algorithm. VRS acted as a risk factor for HCC patients. HCC patients with high-risk score had a poor clinical outcome and the AUCs of 1-, 3-, and 5-year ROC were 0.786, 0.755, and 0.786, respectively. A higher level of CD8 + cytotoxic T cells and B cells was obtained in HCC patients with low-risk score. There is higher PD1&CTLA4 immunophenoscore and TMB score in low-risk score in HCC patients. Lower TIDE score and tumor escape score was found in HCC cases with low-risk score. The IC50 value of camptothecin, docetaxel, crizotinib, dasatinib, and erlotinib was lower in HCC cases with high-risk score. HCC patients with high-risk score had a higher score of cancer-related hallmarks, including angiogenesis, glycolysis, and NOTCH signaling. Our study proposed a novel VRS for HCC, which served as an indicator for predicting clinical outcome and immunotherapy responses in HCC.


Subject(s)
Carcinoma, Hepatocellular , Immunotherapy , Liver Neoplasms , Vitamin D , Humans , Carcinoma, Hepatocellular/immunology , Liver Neoplasms/immunology , Vitamin D/therapeutic use , Male , Immunotherapy/methods , Prognosis , Female , Middle Aged , Machine Learning , Risk Factors , Biomarkers, Tumor
11.
Discov Oncol ; 15(1): 178, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38771435

ABSTRACT

OBJECTIVE: Melanoma, with its high degree of malignancy, stands as one of the most dangerous skin cancers and remains the primary cause of death from skin cancer. With studies demonstrating the potential of traditional Chinese medicine to intervene and treat melanoma, we turned our attention to celastrol. Celastrol is a triterpene compound extracted from the traditional Chinese medicine derived from Tripterygium wilfordii. Previous studies have shown that celastrol exerts inhibitory effects on various malignant tumors, including melanoma. Hence, our goal was to clarify the impact of celastrol on cell viability, apoptosis, and cell cycle progression by elucidating its effects on the PI3K/AKT/mTOR pathway. METHODS: CCK-8 and wound healing assays were used to determine the effect of celastrol on the viability and migration of B16-F10 cells. Changes in cell apoptosis, cell cycle, reactive oxygen species (ROS), and mitochondrial membrane potential were detected by flow cytometry. PI3K/AKT/mTOR pathway proteins and HIF-α mRNA expression in B16-F10 cells were detected by western blotting and qPCR. Moreover, the addition of a PI3K activator demonstrated that celastrol could inhibit the function of B16-F10 cells via the PI3K/AKT/mTOR pathway. RESULTS: Celastrol inhibited the viability and migration of B16-F10 cells. Through the inhibition of the PI3K/AKT/mTOR pathway down-regulates the expression of HIF-α mRNA, thereby causing an increase of ROS in cells and a decrease in the mitochondrial membrane potential to promote cell apoptosis and cell cycle arrest. The inhibitory effect of celastrol on B16-F10 cells was further demonstrated by co-culturing with a PI3K activator. CONCLUSION: Celastrol inhibits the function of B16-F10 cells by inhibiting the PI3K/AKT/mTOR cellular pathway and regulating the expression of downstream HIF-α mRNA.

12.
MedComm (2020) ; 5(6): e547, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38764726

ABSTRACT

Cancer is a disease with molecular heterogeneity that is closely related to gene mutations and epigenetic changes. The principal histological subtype of lung cancer is non-small cell lung cancer (NSCLC). Long noncoding RNA (lncRNA) is a kind of RNA that is without protein coding function, playing a critical role in the progression of cancer. In this research, the regulatory mechanisms of lncRNA phosphorylase kinase regulatory subunit alpha 1 antisense RNA 1 (PHKA1-AS1) in the progression of NSCLC were explored. The increased level of N6-methyladenosine (m6A) modification in NSCLC caused the high expression of PHKA1-AS1. Subsequently, high-expressed PHKA1-AS1 significantly facilitated the proliferation and metastasis of NSCLC cells, and these effects could be reversed upon the inhibition of PHKA1-AS1 expression, both in vivo and in vitro. Additionally, the target protein of PHKA1-AS1 was actinin alpha 4 (ACTN4), which is known as an oncogene. Herein, PHKA1-AS1 could enhance the protein stability of ACTN4 by inhibiting its ubiquitination degradation process, thus exerting the function of ACTN4 in promoting the progress of NSCLC. In conclusion, this research provided a theoretical basis for further exploring the potential mechanism of NSCLC metastasis and searching novel biomarkers related to the pathogenesis and progression of NSCLC.

13.
Cell Biol Int ; 2024 May 13.
Article in English | MEDLINE | ID: mdl-38741282

ABSTRACT

Polycystic ovary syndrome (PCOS) is the primary cause of female infertility with a lack of universal therapeutic regimen. Although osthole exhibits numerous pharmacological activities in treating various diseases, its therapeutic effect on PCOS is undiscovered. The present study found that application of osthole improved the symptoms of PCOS mice through preventing ovarian granulosa cells (GCs) production of more estrogen and alleviating the liberation of pro-inflammatory cytokine interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha. Meanwhile, osthole enhanced ovarian antioxidant capacity and alleviated intracellular reactive oxygen species (ROS) accumulation with a concurrent attenuation for oxidative stress, while intervention of antioxidant enzymic activity and glutathione (GSH) synthesis neutralized the salvation of osthole on GCs secretory disorder and chronic inflammation. Further analysis revealed that osthole restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and forkhead box O 1 (Foxo1) whose repression antagonized the amelioration of osthole on the insufficiency of antioxidant capacity and accumulation of ROS. Moreover, Nrf2 served as an intermedium to mediate the regulation of osthole on Foxo1. Additionally, osthole restricted the phosphorylation of IκBα and nuclear factor kappa B (NF-κB) subunit p65 by DHEA and weakened the transcriptional activity of NF-κB, but this effectiveness was abrogated by the obstruction of Nrf2 and Foxo1, whereas adjunction of GSH renewed the redemptive effect of osthole on NF-κB whose activation caused an invalidation of osthole in rescuing the aberration of GCs secretory function and inflammation response. Collectively, osthole might relieve the symptoms of PCOS mice via Nrf2-Foxo1-GSH-NF-κB pathway.

14.
Adv Sci (Weinh) ; 11(24): e2307818, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38613835

ABSTRACT

Hypercholesterolaemia is a systemic metabolic disease, but the role of organs other than liver in cholesterol metabolism is unappreciated. The phenotypic characterization of the Tsc1Dmp1 mice reveal that genetic depletion of tuberous sclerosis complex 1 (TSC1) in osteocytes/osteoblasts (Dmp1-Cre) triggers progressive increase in serum cholesterol level. The resulting cholesterol metabolic dysregulation is shown to be associated with upregulation and elevation of serum amyloid A3 (SAA3), a lipid metabolism related factor, in the bone and serum respectively. SAA3, elicited from the bone, bound to toll-like receptor 4 (TLR4) on hepatocytes to phosphorylate c-Jun, and caused impeded conversion of cholesterol to bile acids via suppression on cholesterol 7 α-hydroxylase (Cyp7a1) expression. Ablation of Saa3 in Tsc1Dmp1 mice prevented the CYP7A1 reduction in liver and cholesterol elevation in serum. These results expand the understanding of bone function and hepatic regulation of cholesterol metabolism and uncover a potential therapeutic use of pharmacological modulation of SAA3 in hypercholesterolaemia.


Subject(s)
Cholesterol , Liver , Osteoblasts , Osteocytes , Serum Amyloid A Protein , Animals , Serum Amyloid A Protein/metabolism , Serum Amyloid A Protein/genetics , Mice , Cholesterol/metabolism , Liver/metabolism , Osteocytes/metabolism , Osteoblasts/metabolism , Hypercholesterolemia/metabolism , Disease Models, Animal , Cholesterol 7-alpha-Hydroxylase/metabolism , Cholesterol 7-alpha-Hydroxylase/genetics , Male
15.
Brain Behav Immun ; 119: 431-453, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38636566

ABSTRACT

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDMϕ) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy Mϕ), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy Mϕ and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by Mϕ, plays a crucial role in lipid efflux from foamy cells. We observed that foamy Mϕ lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy Mϕ as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy Mϕ, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy Mϕ, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy Mϕ in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.


Subject(s)
ATP Binding Cassette Transporter 1 , Macrophages , Spinal Cord Injuries , Animals , ATP Binding Cassette Transporter 1/metabolism , Spinal Cord Injuries/metabolism , Mice , Male , Macrophages/metabolism , Foam Cells/metabolism , Mice, Inbred C57BL , Spinal Cord/metabolism , Mice, Knockout , Disease Models, Animal
16.
Heliyon ; 10(8): e29368, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38655323

ABSTRACT

Kidney clear cell renal cell carcinoma (KIRC) is also the most lethal subtype among all kidney cancer subtypes, posing a severe threat to public health. Therefore, it is crucial to identify new, reliable biomarkers in KIRC. Therefore, it is crucial to identify novel, reliable biomarkers associated with KIRC. We analyzed RNA sequence results from TCGA and several GEO datasets. The commonly deregulated gene, ALDOB, was found in multiple data and confirmed its important prognostic value. Subsequently, we explored the specific mechanism by which ALDOB regulates anti-tumor immunity through in vivo and in vitro experiments. We found that ALDOB may play a role in regulating tumor growth by regulating CD8+ T cell infiltration. This is consistent with the results of our immune infiltration-related analysis. In addition, we have also discovered the effect of ALDOB in previous studies on other cancer types. Finally, we concluded that ALDOB may have potential reference value for immunotherapy and can also be used as an independent predictor of prognosis in KIRC.

17.
Brain Behav ; 14(5): e3412, 2024 May.
Article in English | MEDLINE | ID: mdl-38664915

ABSTRACT

PURPOSE: Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder. Genetic and broad environmental factors are common risk factors for OCD. The purpose of this study is to explore the molecular mechanism of OCD and to find new molecular targets for the diagnosis and management of OCD. METHODS: All data were downloaded from public dataset. Key modules and candidate key mRNAs were identified based on weighted gene co-expression network analysis (WGCNA). The "limma" R package was used for differential expression analysis of mRNAs. Subsequently, functional enrichment analysis of differentially expressed mRNAs (DEmRNAs) was also carried out. In addition, a diagnostic model was constructed. Finally, the infiltration level of immune cells in OCD and its correlation with multicentric key DEmRNAs were analyzed. RESULTS: Green and red modules were selected as the hub modules. A total of 447 mRNAs were considered candidate key mRNAs according to GS > 0.2 and MM > 0.3. A total of 26 DEmRNAs in the same direction were identified in the GSE60190 and GSE78104 datasets. A total of 26 DEmRNAs were intersected with candidate key mRNAs in WGCNA to obtain 10 intersection DEmRNAs (HSPB1, ITPK1, CBX7, PPP1R10, TAOK1, PISD, MKNK2, RWDD1, PPA1, and RELN). However, only four DEmRNAs (HSPB1, TAOK1, MKNK2, and PPA1) predicted related drugs. Subsequently, receiver operating characteristic analysis shows that the diagnostic model has high diagnostic value. Moreover, six multicentric key DEmRNAs (SNRPF, SNRNP70, PRPF8, NOP56, EPRS, and CCT2) were screened by UpSet package. Finally, six multicentric key DEmRNAs were found to be associated with immune cells. CONCLUSION: The key molecules obtained in this study lay a foundation for further research on the molecular mechanism of OCD.


Subject(s)
Gene Regulatory Networks , Obsessive-Compulsive Disorder , RNA, Messenger , Signal Transduction , Humans , Obsessive-Compulsive Disorder/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction/genetics , Gene Expression Profiling
18.
Mol Neurobiol ; 2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38671329

ABSTRACT

Meditation-based interventions are novel and effective non-pharmacologic treatments for veterans with PTSD. We examined relationships between treatment response, early life trauma exposure, DNA polymorphisms, and methylation in the serotonin transporter (SLC6A4) and FK506-binding protein 5 (FKBP5) genes. DNA samples and clinical outcomes were examined in 72 veterans with PTSD who received meditation-based therapy in two separate studies of mindfulness-based stress reduction (MBSR) and Transcendental Meditation (TM). The PTSD Checklist was administered to assess symptoms at baseline and after 9 weeks of meditation intervention. We examined the SLC6A4 promoter (5HTTLPR_L/S insertion/deletion + rs25531_A/G) polymorphisms according to previously defined gene expression groups, and the FKBP5 variant rs1360780 previously associated with PTSD disease risk. Methylation for CpG sites of SLC6A4 (28 sites) and FKBP5 (45 sites) genes was quantified in DNA samples collected before and after treatment. The 5HTTLPR LALA high expression genotype was associated with greater symptom improvement in participants exposed to early life trauma (p = 0.015). Separately, pre to post-treatment change of DNA methylation in a group of nine FKBP5 CpG sites was associated with greater symptom improvement (OR = 2.8, 95% CI 1.1-7.1, p = 0.027). These findings build on a wealth of existing knowledge regarding epigenetic and genetic relationships with PTSD disease risk to highlight the potential importance of SLC6A4 and FKBP5 for treatment mechanisms and as biomarkers of symptom improvement.

19.
Nature ; 629(8011): 481-488, 2024 May.
Article in English | MEDLINE | ID: mdl-38632411

ABSTRACT

The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca2+ concentration and maintains Ca2+ homeostasis1,2. It also mediates diverse cellular processes not associated with Ca2+ balance3-5. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes6. We determined structures of CaSR in complex with G proteins from three different subfamilies: Gq, Gi and Gs. We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Gα subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα. We identified a single Gα residue that determines Gq and Gs versus Gi selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.


Subject(s)
Heterotrimeric GTP-Binding Proteins , Receptors, Calcium-Sensing , Humans , Calcium/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/chemistry , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , GTP-Binding Protein alpha Subunits, Gq-G11/chemistry , GTP-Binding Protein alpha Subunits, Gs/metabolism , GTP-Binding Protein alpha Subunits, Gs/chemistry , Models, Molecular , Protein Binding , Protein Multimerization , Receptors, Calcium-Sensing/metabolism , Receptors, Calcium-Sensing/chemistry , Heterotrimeric GTP-Binding Proteins/chemistry , Heterotrimeric GTP-Binding Proteins/metabolism , Binding Sites , Protein Structure, Secondary , Substrate Specificity
20.
Res Sq ; 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38558983

ABSTRACT

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n=58) and low (n=60) TAC troughs (N=515 AA KTRs). Targeted next generation sequencing was conducted in these two groups. Median TAC troughs in the high group were 7.7 ng/ml compared with 6.3 ng/ml in the low group, despite lower daily doses of 5 versus 12mg, respectively. Of 34,542 identified variants across 99 genes, 1,406 variants were suggestively associated with TAC troughs in univariate models (p-value <0.05), however none were significant after multiple testing correction. We suggest future studies investigate additional sources of TAC pharmacokinetic variability such as drug-drug-gene interactions and pharmacomicrobiome.

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