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1.
J Hepatocell Carcinoma ; 11: 1015-1029, 2024.
Article in English | MEDLINE | ID: mdl-38854818

ABSTRACT

Purpose: We investigated whether spleen volume (SV) changes were associated with treatment outcomes in advanced hepatocellular carcinoma (HCC) patients who received immunotherapy or first-line sorafenib. Patients and Methods: Patients with advanced HCC who underwent immunotherapy or first-line sorafenib at our institute were retrospectively analyzed. CT was used to measure SV before and within 3 months of treatment initiation. Tumor assessment followed Response Evaluation Criteria in Solid Tumors version 1.1. The association between SV change and tumor response or progression-free survival (PFS) was analyzed. The inverse probability of treatment weighting (IPTW) was used to adjust for differences in baseline characteristics. Results: The immunotherapy group comprised 143 patients (124 men, mean age, 59.8 years ± 11.2 [standard deviation]), while the sorafenib group had 57 (47 men, mean age, 59.6 years ± 9.9). SV increased in 108 (75.5%) immunotherapy and 21 (36.8%) sorafenib patients. In the immunotherapy group, patients with increased SV were more likely than those with decreased SV to have a higher disease control rate (76.9% vs 57.1%, p = 0.024) and durable clinical benefit (52.8% vs 25.7%, p = 0.005). It was also associated with extended PFS in the immunotherapy group in both the univariate (p = 0.028) and multivariate (p = 0.014) analysis. By contrast, in the sorafenib group, an increased in SV was not associated with treatment response but was presumably associated with reduced PFS (p = 0.072) in the multivariate analysis. After IPTW adjustment, the increase in SV remained a significant predictor for DCB and PFS in the immunotherapy group. Conclusion: Most patients exhibited an increase in SV after the initiation of immunotherapy, which may be used to predict response and prognosis. However, this association was not observed in patients who received sorafenib.


The study provides significant evidence that an increase in spleen volume is associated with better treatment outcomes in advanced hepatocellular carcinoma patients undergoing immunotherapy. These findings offer oncologists a new potential biomarker for optimizing treatment strategies. Specifically, increased spleen volume could be used to predict higher rates of disease control and durable clinical benefits, allowing for more personalized care.

2.
Exp Neurol ; 379: 114844, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38830500

ABSTRACT

Spinal cord injury (SCI) is a serious trauma of the central nervous system. The clearance of myelin debris is a critical step in the functional recovery following spinal cord injury (SCI). Recent studies have begun to reveal critical roles for professional phagocytes in the central nervous system, microglia, and their receptors in the control of myelin debris in neurodegenerative disease. Repeated trans-spinal magnetic stimulation (rTSMS) has been demonstrated as a noninvasive SCI treatment that enhances tissue repair and functional recovery. In this study, we investigated the role and molecular mechanism of rTSMS on microglial phagocytosis of myelin debris in a rat SCI model. In our studies, we found that rTSMS significantly promoted the motor function recovery of SCI rats associated with the inhibition the neuroinflammation and glia scar formation. Immunofluorescence results further showed that the rTSMS promotes the clearance of myelin debris by microglia in vivo and in vitro. Additionally, receptor-associated protein (RAP), a Low-density lipoprotein receptor-related protein-1 (LRP-1) inhibitor, could cancel the accelerated microglial phagocytosis of myelin debris after rTSMS in vitro experiments. Simultaneously, Elisa's results and western blotting respectively showed that rTSMS significantly decreased the levels of soluble LRP-1(sLRP-1) and the LRP-1 splicing enzyme of ADAM17. In conclusion, rTSMS could promote the clearance of myelin debris by microglia through LRP-1 to improve the functional recovery of SCI rats.

3.
Heliyon ; 10(11): e32027, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38868037

ABSTRACT

Objective: Understanding the characteristics of alveolar bone resorption in an East Asian population after maxillary incisor extraction and providing a reference for implant treatment plans. Study design: Cone-beam computerized tomography (CBCT) data of 125 East Asian patients with unilateral extraction of maxillary incisors for 3 months were collected. The alveolar bone width and height in the extraction sites were measured and compared with the corresponding contralateral sites. Results: The differences in alveolar bone width between the extraction site and contralateral site were as follows: 4.11 mm, 2.68 mm, and 2.09 mm (3 mm, 5 mm, 7 mm apical from CEJ of the contralateral tooth). Data are expressed as the median. The horizontal resorption ratio of alveolar bone was 49.94 %, 31.5 %, and 24.46 %. The difference in alveolar bone height was 0.78 mm. The vertical resorption ratio was 7.78 %. The resorption did not differ significantly between sexes and was not significantly affected by tooth positions. Conclusions: In the studied East Asian population, significant horizontal and vertical alveolar bone resorption occurs after natural healing of maxillary incisor extraction for 3 months. The closer to the alveolar ridge crest, the more significant the horizontal resorption, resulting in an "inverted triangle" shape residual alveolar bone.

4.
BMC Nurs ; 23(1): 397, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38862930

ABSTRACT

BACKGROUND: Benefit finding is the search for positive meaning from traumatic events, such as cancer. It can help caregivers have a positive experience in the caregiving process, relieve negative emotions, and reduce caregiving stress. The aim of this study was to explore benefit finding among caregivers of patients with advanced cancer in their palliative caregiving journey. METHODS: An exploratory qualitative design of phenomenology was used. Semistructured interviews were conducted with 19 caregivers of palliative care patients with advanced cancer. The Colaizzi 7-step analysis was used to analyse, summarize, and extract themes from the interview data. RESULTS: The study identified five themes of caregiver benefit finding in the caregiving process: personal growth, strengthened relationships with patients, adjustment and adaptation, perceived social support, and perceived meaning in life. Most caregivers reported a closer, more dependent relationship with the patient, and only one caregiver did not report any positive changes. CONCLUSIONS: Caregivers of palliative care patients with advanced cancer can have positive experiences in their care. Healthcare professionals should focus on supporting caregivers and helping them find positive experiences to cope with the challenges of caregiving and improve their quality of life.

5.
PLoS One ; 19(5): e0303189, 2024.
Article in English | MEDLINE | ID: mdl-38768165

ABSTRACT

OBJECTIVES: To establish a rat model that accurately replicates the clinical characteristics of male infertility (MI) with Liver Depression and Kidney Deficiency (LD & KD) and investigate the pathogenesis. METHODS: After subjecting the rats to chronic restraint stress (CRS) and adenine treatment, a series of tests were conducted, including ethological assessments, evaluations of reproductive characteristics, measurements of biochemical parameters, histopathological examinations, and analyses of urinary metabolites. Additionally, bioinformatics predictions were performed for comprehensive analysis. RESULTS: Compared to the control, the model exhibited significant manifestations of MI with LD & KD, including reduced responsiveness, diminished frequency of capturing estrous female rats, and absence of mounting behavior. Additionally, the kidney coefficient increased markedly, while the coefficients of the testis and epididymis decreased significantly. Sperm counts and viabilities decreased notably, accompanied by an increase in sperm abnormalities. Dysregulation of reproductive hormone levels in the serum was observed, accompanied by an upregulation of proinflammatory cytokines expressions in the liver and kidney, as well as exacerbated oxidative stress in the penile corpus cavernosum and testis. The seminiferous tubules in the testis exhibited a loose arrangement, loss of germ cells, and infiltration of inflammatory cells. Furthermore, utilizing urinary metabolomics and bioinformatics analysis, 5 key biomarkers and 2 crucial targets most closely linked to MI were revealed. CONCLUSION: The study successfully established a clinically relevant animal model of MI with LD & KD. It elucidates the pathogenesis of the condition, identifies key biomarkers and targets, and provides a robust scientific foundation for the prediction, diagnosis, and treatment of MI with LD & KD.


Subject(s)
Biomarkers , Disease Models, Animal , Infertility, Male , Animals , Male , Rats , Biomarkers/metabolism , Infertility, Male/metabolism , Infertility, Male/etiology , Testis/metabolism , Testis/pathology , Kidney/metabolism , Kidney/pathology , Rats, Sprague-Dawley , Liver/metabolism , Liver/pathology , Oxidative Stress , Liver Diseases/metabolism , Liver Diseases/pathology , Renal Insufficiency/metabolism , Renal Insufficiency/pathology , Renal Insufficiency/etiology
6.
Pest Manag Sci ; 2024 May 23.
Article in English | MEDLINE | ID: mdl-38779954

ABSTRACT

BACKGROUND: The litchi fruit borer Conopomorpha sinensis Bradley is a major destructive pest of litchi and longan plants in China, India and South East Asia. Given its strong olfactory-based oviposition behaviour, interfering with the chemical communication between this insect pest and its host plant may serve as a potential control strategy. However, the chemical compounds associated with its egg-laying behaviour remain poorly understood. RESULTS: In this study, we investigated the olfactory preference of female C. sinensis for oviposition on intact mature fruits of the Feizixiao (FZX) and Guiwei (GW) varieties. Results showed that female C. sinensis preferred to lay eggs on FZX compared with GW fruits, and this preference was olfactory-induced. In addition, we identified differences in the chemical composition of the volatile blend and proportions between FZX and GW fruits, with terpenes being the main volatile components contributing to this divergence. Compounds that induced electrophysiological activity in female borers were subsequently screened from FZX. d-Limonene exhibited the strongest oviposition attraction among four candidates. Furthermore, this compound served as a volatile olfactory cue for recognition and orientation in female C. sinensis. CONCLUSION: The results of this study provide a deeper understanding of the olfactory preferences of female C. sinensis for oviposition on specific litchi varieties. © 2024 Society of Chemical Industry.

7.
J Med Chem ; 67(11): 9431-9446, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38818879

ABSTRACT

Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.


Subject(s)
Brain , Drug Design , Enzyme Inhibitors , Methionine Adenosyltransferase , Methionine Adenosyltransferase/antagonists & inhibitors , Methionine Adenosyltransferase/metabolism , Humans , Animals , Structure-Activity Relationship , Rats , Brain/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Mice , Male , Rats, Sprague-Dawley , Xenograft Model Antitumor Assays
8.
Mol Immunol ; 171: 12-21, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38735126

ABSTRACT

Macrophages are critical in mediating immune and inflammatory responses, while monocyte-to-macrophage differentiation is one of the main macrophage resources that involves various matrix proteins. Matrix remodeling associated 7 (MXRA7) was recently discovered to affect a variety of physiological and pathological processes related to matrix biology. In the present study, we investigated the role of MXRA7 in monocyte-to-macrophage differentiation in vitro. We found that knockdown of MXRA7 inhibited the proliferation of THP-1 human monocytic cells. Knockdown of MXRA7 increased the adhesion ability of THP-1 cells through upregulation the expression of adhesion molecules VCAM-1 and ICAM1. Knockdown of MXRA7 alone could promoted the differentiation of THP-1 cells to macrophages. Furthermore, the MXRA7-knockdown THP-1 cells produced a more significant upregulation pattern with M1-type cytokines (TNF-α, IL-1ß and IL-6) than with those M2-type molecules (TGF-ß1 and IL-1RA) upon PMA stimulation, indicating that knockdown of MXRA7 facilitated THP-1 cells differentiation toward M1 macrophages. RNA sequencing analysis revealed the potential biological roles of MXRA7 in cell adhesion, macrophage and monocyte differentiation. Moreover, MXRA7 knockdown promoted the expression of NF-κB p52/p100, while PMA stimulation could increase the expression of NF-κB p52/p100 and activating MAPK signaling pathways in MXRA7 knockdown cells. In conclusion, MXRA7 affected the differentiation of THP-1 cells toward macrophages possibly through NF-κB signaling pathways.


Subject(s)
Cell Differentiation , Macrophages , Monocytes , Humans , Cell Differentiation/immunology , Cell Differentiation/genetics , Monocytes/metabolism , Macrophages/metabolism , Macrophages/immunology , THP-1 Cells , Cell Adhesion/physiology , Cytokines/metabolism , Cell Proliferation , Signal Transduction , Intercellular Adhesion Molecule-1/metabolism , Intercellular Adhesion Molecule-1/genetics , Gene Knockdown Techniques , NF-kappa B/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Vascular Cell Adhesion Molecule-1/genetics
9.
Pain Physician ; 27(4): 263-272, 2024 May.
Article in English | MEDLINE | ID: mdl-38805533

ABSTRACT

BACKGROUND: Flupentixol and melitracen are being investigated for their potential effectiveness in managing persistent idiopathic facial pain (PIFP), based on their mechanisms of action as dopamine receptor antagonists and noradrenaline/serotonin reuptake inhibitors, respectively. The efficacy and safety of flupentixol and melitracen (FM) tablets in treating PIFP were retrospectively analyzed at our hospital. OBJECTIVES: The aim of this study is to determine the effectiveness and safety of FM tablets in treating PIFP. STUDY DESIGN: Retrospective unicentric cohort design. SETTING: An academic university hospital. METHODS: A retrospective analysis was conducted on a cohort comprising 128 patients with a definite diagnoses of PIFP who were treated with FM tablets (flupentixol 0.5 mg and melitracen 10 mg tablet, >= 4 tablets/d) from January 2022 through May 2023 at an academic university hospital. Baseline conditions were statistically described, and Numeric Rating Scale (NRS-11) scores of pain levels before and during treatment were collected. Pain relief rates were calculated. Differences in baseline characteristics between responsive and unresponsive patients were evaluated using statistical tests. Additionally, the side effects experienced during treatment were summarized. RESULTS: Among the included 128 patients, 105 (82.0%) patients achieved pain relief (pain NRS-11 score reduction rate >= 50%). The median treatment onset time was 3 (1-7) days. NRS-11 scores of responsive patients at week 2, week 4, week 8, and week 12 were significantly lower than the baseline NRS-11 scores (P < 0.001), regardless of their Hamilton Depression Rating Scale score. Pain duration was the only factor that related to responsiveness (Wilcoxon rank sum test, P < 0.001; logistic regression, P = 0.001). No serious side effects that could affect patients' lives were observed during the first week of treatments. LIMITATIONS: Due to its retrospective nature, this study is limited by its lack of a randomized control. The lack of data on nonresponders who did not achieve significant pain relief hinders assessing overall change and the placebo effects'. Patients previously treated with antidepressants were excluded, making it hard to determine if FM tablets were a better treatment for PIFP. Additionally, the small sample size in a single center may be influenced by chance variation in pain relief. CONCLUSIONS: FM tablets showed its potential in the management of PIFP with considerable efficacy and safety. Early administration of FM tablets after a PIFP diagnosis may result in a high possibility of pain relief.


Subject(s)
Facial Pain , Flupenthixol , Humans , Retrospective Studies , Male , Female , Middle Aged , Facial Pain/drug therapy , Adult , Flupenthixol/therapeutic use , Flupenthixol/adverse effects , Flupenthixol/administration & dosage , Tablets , Aged , Treatment Outcome
11.
Adv Mater ; : e2401589, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38744437

ABSTRACT

Constructing an anti-counterfeiting material with non-interference dual optical modes is an effective way to improve information security. However, it remains challenging to achieve multistage secure information encryption due to the limited stimulus responsiveness and color tunability of the current dual-mode materials. Herein, a dual-mode hydrogel with both independently tunable structural and fluorescent colors toward multistage information encryption, is reported. In this hydrogel system, the rigid lamellar structure of poly(dodecylglyceryl itaconate) (pDGI) formed by shear flow-induced self-assembly provides the restricted domains wherein monomers undergo polymerization to form a hydrogel network, producing structural color. The introduction of fluorescent monomer 6-acrylamidopicolinate (6APA) as a complexation site provides the possibility of fluorescent color formation. The hydrogel's angle-dependent structural color can be controlled by adjusting the crosslinking density and water content. Additionally, the fluorescence color can be modulated by adjusting the ratio of lanthanide ions. Information of dual-mode can be displayed separately in different channels and synergistically overlayed to read the ultimate message. Thus, a multistage information encryption system based on this hydrogel is devised through the programed decryption process. This strategy holds tremendous potential as a platform for encrypting and safeguarding valuable and authentic information in the field of anti-counterfeiting.

12.
J Cancer Res Clin Oncol ; 150(5): 239, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38713252

ABSTRACT

PURPOSE: Multiple myeloma (MM) is an incurable hematological malignancy characterized by clonal proliferation of malignant plasma B cells in bone marrow, and its pathogenesis remains unknown. The aim of this study was to determine the role of kinesin family member 22 (KIF22) in MM and elucidate its molecular mechanism. METHODS: The expression of KIF22 was detected in MM patients based upon the public datasets and clinical samples. Then, in vitro assays were performed to investigate the biological function of KIF22 in MM cell lines, and subcutaneous xenograft models in nude mice were conducted in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay were used to determine the mechanism of KIF22-mediated regulation. RESULTS: The results demonstrated that the expression of KIF22 in MM patients was associated with several clinical features, including gender (P = 0.016), LDH (P < 0.001), ß2-MG (P = 0.003), percentage of tumor cells (BM) (P = 0.002) and poor prognosis (P < 0.0001). Furthermore, changing the expression of KIF22 mainly influenced the cell proliferation in vitro and tumor growth in vivo, and caused G2/M phase cell cycle dysfunction. Mechanically, KIF22 directly transcriptionally regulated cell division cycle 25C (CDC25C) by binding its promoter and indirectly influenced CDC25C expression by regulating the ERK pathway. KIF22 also regulated CDC25C/CDK1/cyclinB1 pathway. CONCLUSION: KIF22 could promote cell proliferation and cell cycle progression by transcriptionally regulating CDC25C and its downstream CDC25C/CDK1/cyclinB1 pathway to facilitate MM progression, which might be a potential therapeutic target in MM.


Subject(s)
CDC2 Protein Kinase , Cyclin B1 , DNA-Binding Proteins , Kinesins , Multiple Myeloma , cdc25 Phosphatases , Animals , Female , Humans , Male , Mice , Middle Aged , CDC2 Protein Kinase/metabolism , CDC2 Protein Kinase/genetics , cdc25 Phosphatases/metabolism , cdc25 Phosphatases/genetics , Cell Line, Tumor , Cell Proliferation , Cyclin B1/metabolism , Cyclin B1/genetics , Disease Progression , Gene Expression Regulation, Neoplastic , Kinesins/metabolism , Kinesins/genetics , Mice, Inbred BALB C , Mice, Nude , Multiple Myeloma/pathology , Multiple Myeloma/metabolism , Multiple Myeloma/genetics , Prognosis , Signal Transduction
13.
Curr Opin Immunol ; 87: 102427, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38781720

ABSTRACT

The essential and redundant functions of human type I and II interferons (IFNs) have been delineated over the last three decades by studies of patients with inborn errors of immunity or their autoimmune phenocopies, but much less is known about type III IFNs. Patients with cells that do not respond to type III IFNs due to inherited IL10RB deficiency display no overt viral disease, and their inflammatory disease phenotypes can be explained by defective signaling via other interleukine10RB-dependent pathways. Moreover, patients with inherited deficiencies of interferon-stimulated gene factor 3 (ISGF-3) (STAT1, STAT2, IRF9) present viral diseases also seen in patients with inherited deficiencies of the type I IFN receptor (IFNAR1/2). Finally, patients with autoantibodies neutralizing type III IFNs have no obvious predisposition to viral disease. Current findings thus suggest that type III IFNs are largely redundant in humans. The essential functions of human type III IFNs, particularly in antiviral defenses, remain to be discovered.


Subject(s)
Interferon Lambda , Interferons , Virus Diseases , Humans , Interferons/metabolism , Interferons/immunology , Virus Diseases/immunology , Animals , Signal Transduction/immunology , STAT2 Transcription Factor/metabolism , STAT2 Transcription Factor/genetics , STAT2 Transcription Factor/immunology , Interferon-Stimulated Gene Factor 3, gamma Subunit/genetics , Interferon-Stimulated Gene Factor 3, gamma Subunit/immunology , Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism , STAT1 Transcription Factor/metabolism , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/immunology , Interleukin-10 Receptor beta Subunit/genetics , Interleukin-10 Receptor beta Subunit/immunology , Interleukin-10 Receptor beta Subunit/metabolism
14.
J Hepatocell Carcinoma ; 11: 787-800, 2024.
Article in English | MEDLINE | ID: mdl-38737384

ABSTRACT

Background: Anti-programmed death-1 (PD1) antibodies have changed the treatment landscape for hepatocellular carcinoma (HCC) and exhibit promising treatment efficacy. However, the majority of HCCs still do not respond to anti-PD-1 therapy. Methods: We analyzed the expression of CXCL9 in blood samples from patients who received anti-PD-1 therapy and evaluated its correlation with clinicopathological characteristics and treatment outcomes. Based on the results of Cox regression analysis, a nomogram was established for predicting HCC response to anti-PD-1 therapy. qRT‒PCR and multiple immunofluorescence assays were utilized to analyze the proportions of N1-type neutrophils in vitro and in tumor samples, respectively. Results: The nomogram showed good predictive efficacy in the training and validation cohorts and may be useful for guiding clinical treatment of HCC patients. We also found that HCC cell-derived CXCL9 promoted N1 polarization of neutrophils in vitro and that AMG487, a specific CXCR3 inhibitor, significantly blocked this process. Moreover, multiple immunofluorescence (mIF) showed that patients with higher serum CXCL9 levels had greater infiltration of the N1 phenotype of tumor-associated neutrophils (TANs). Conclusion: Our study highlights the critical role of CXCL9 as an effective biomarker of immunotherapy efficacy and in promoting the polarization of N1-type neutrophils; thus, targeting the CXCL9-CXCR3 axis could represent a novel pharmaceutical strategy to enhance immunotherapy for HCC.

15.
Front Immunol ; 15: 1393852, 2024.
Article in English | MEDLINE | ID: mdl-38711526

ABSTRACT

Different eukaryotic cell organelles (e.g., mitochondria, endoplasmic reticulum, lysosome) are involved in various cancer processes, by dominating specific cellular activities. Organelles cooperate, such as through contact points, in complex biological activities that help the cell regulate energy metabolism, signal transduction, and membrane dynamics, which influence survival process. Herein, we review the current studies of mechanisms by which mitochondria, endoplasmic reticulum, and lysosome are related to the three major malignant gynecological cancers, and their possible therapeutic interventions and drug targets. We also discuss the similarities and differences of independent organelle and organelle-organelle interactions, and their applications to the respective gynecological cancers; mitochondrial dynamics and energy metabolism, endoplasmic reticulum dysfunction, lysosomal regulation and autophagy, organelle interactions, and organelle regulatory mechanisms of cell death play crucial roles in cancer tumorigenesis, progression, and response to therapy. Finally, we discuss the value of organelle research, its current problems, and its future directions.


Subject(s)
Genital Neoplasms, Female , Mitochondria , Organelles , Humans , Female , Genital Neoplasms, Female/pathology , Genital Neoplasms, Female/metabolism , Mitochondria/metabolism , Mitochondria/pathology , Organelles/metabolism , Cell Survival , Animals , Lysosomes/metabolism , Endoplasmic Reticulum/metabolism , Autophagy , Energy Metabolism , Signal Transduction
16.
Int J Mol Sci ; 25(9)2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38732130

ABSTRACT

Parkinson's disease (PD), as a neurologically implemented disease with complex etiological factors, has a complex and variable pathogenesis. Accompanying further research, neuroinflammation has been found to be one of the possible factors in its pathogenesis. Microglia, as intrinsic immune cells in the brain, play an important role in maintaining microenvironmental homeostasis in the brain. However, over-activation of neurotoxic microglia in PD promotes neuroinflammation, which further increases dopaminergic (DA) neuronal damage and exacerbates the disease process. Therefore, targeting and regulating the functional state of microglia is expected to be a potential avenue for PD treatment. In addition, plant extracts have shown great potential in the treatment of neurodegenerative disorders due to their abundant resources, mild effects, and the presence of multiple active ingredients. However, it is worth noting that some natural products have certain toxic side effects, so it is necessary to pay attention to distinguish medicinal ingredients and usage and dosage when using to avoid aggravating the progression of diseases. In this review, the roles of microglia with different functional states in PD and the related pathways inducing microglia to transform into neuroprotective states are described. At the same time, it is discussed that abscisic acid (ABA) may regulate the polarization of microglia by targeting them, promote their transformation into neuroprotective state, reduce the neuroinflammatory response in PD, and provide a new idea for the treatment of PD and the selection of drugs.


Subject(s)
Abscisic Acid , Microglia , Neuroinflammatory Diseases , Parkinson Disease , Microglia/drug effects , Microglia/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/pathology , Humans , Abscisic Acid/metabolism , Abscisic Acid/pharmacology , Animals , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/etiology , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use
17.
Br J Cancer ; 130(11): 1744-1757, 2024 May.
Article in English | MEDLINE | ID: mdl-38582810

ABSTRACT

BACKGROUND: Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood. METHODS: Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects. RESULTS: Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis. CONCLUSION: Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.


Subject(s)
Carcinoma, Squamous Cell , Dynamins , Ferroptosis , Glutamine , Mitochondria , Mitochondrial Dynamics , Mouth Neoplasms , Neoplastic Stem Cells , Ferroptosis/drug effects , Humans , Mouth Neoplasms/pathology , Mouth Neoplasms/metabolism , Mouth Neoplasms/genetics , Mouth Neoplasms/drug therapy , Animals , Dynamins/antagonists & inhibitors , Dynamins/genetics , Dynamins/metabolism , Mice , Glutamine/metabolism , Mitochondria/metabolism , Mitochondria/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/drug effects , Cell Line, Tumor , Mitochondrial Dynamics/drug effects , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/drug therapy , Citric Acid Cycle/drug effects , Amino Acid Transport System ASC/metabolism , Amino Acid Transport System ASC/genetics , Amino Acid Transport System ASC/antagonists & inhibitors , Ketoglutaric Acids/metabolism , Quinazolinones/pharmacology , Minor Histocompatibility Antigens/metabolism , Minor Histocompatibility Antigens/genetics , Piperazines/pharmacology , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/drug therapy
18.
HGG Adv ; 5(3): 100300, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38678364

ABSTRACT

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

19.
Int J Impot Res ; 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38653801

ABSTRACT

Visceral adipose tissue (VAT) is regarded as an important risk factor for obesity-related diseases. The results of the association between VAT and total testosterone (TT) are controversial and whether this association is nonlinear is still unknown. 3971 male participants who were aged 20-59 years from the National Health and Nutrition Examination Surveys 2011-2016 were included. VAT area was measured by dual-energy x-ray absorptiometry. TT in serum was assessed utilizing the isotope dilution liquid chromatography-tandem mass spectrometry technique. Linear regression models assessed the associations between VAT area and TT. A restricted cubic spline model was employed to investigate nonlinear relationships. A two-piecewise linear regression model was applied to determine the threshold effect. Subgroup analyses were conducted. The weighted methods were utilized in all analyses. VAT area was inversely associated with TT in the crude and adjusted models. In the fully adjusted model, VAT area was associated with TT (ß = -0.59, 95% confidence interval [CI] = -0.74, -0.43) and compared to the first tertile of VAT area, the second and the third tertile had a lower TT level, the ß and 95% CI = -65.49 (-83.72, -47.25) and -97.57 (-121.86, -73.27) respectively. We found these inverse associations were nonlinear. The cutoff point of the VAT area was 126 cm2. When the VAT area was <126 cm2, VAT area was significantly associated with a lower TT level (ß = -1.55, 95% CI = -1.93 to -1.17, p < 0.0001). However, when the VAT area was ≥126 cm2, this association was less apparent (ß = -0.26, 95% CI = -0.52 to 0.01, p = 0.06). No significant interactions among different ages (<50 or ≥50 years), marital, and physical activity status were found. These findings underscore the potential for VAT area as a modifiable indicator for improving testosterone deficiency.

20.
Prev Med Rep ; 41: 102707, 2024 May.
Article in English | MEDLINE | ID: mdl-38576516

ABSTRACT

Objectives: Abdominal obesity is recognized as a significant determinant of Arteriosclerotic cardiovascular disease (ASCVD), with sagittal abdominal diameter (SAD) being considered a more precise indicator of visceral fat. Nevertheless, the association between SAD and ASCVD remains unexplored in large-scale general-population studies. Methods: The study included 11,211 participants aged 20 to 80 from the National Health and Nutrition Examination Survey. Logistic regression models were utilized to evaluate the association between the SAD-to-height ratio (SADHtR) and ASCVD. Subgroup analyses based on age categories, sex, diabetes, and hypertension were conducted to assess result robustness. Results: The median SADHtR value was 0.13 (0.12-0.15), and 1,006 cases (7.46 %) of ASCVD were recorded. Multivariable models showed that each standard deviation increase in SADHtR was positively associated with higher odds of ASCVD (OR 1.48, 95 % CI 1.36-1.62 in model 1; OR 1.41, 95 % CI 1.28-1.54 in model 2; OR 1.18, 95 % CI 1.08-1.30 in model 3). Comparing the first quartile of SADHtR to the second to fourth quartiles, positive associations with ASCVD were observed in models 1 and 2. However, in model 3, only the fourth quartile of SADHtR remained statistically significant (OR 1.58, 95 % CI 1.17-2.15), with all p-values for the trend being less than 0.05. No interactions were found in the subgroup analyses. Conclusion: This study demonstrates a positive association between SADHtR and ASCVD in the general adult population of the United States. Our findings indicate that SADHtR, especially when ≥ 0.155, could be a valuable metric for assessing the risk of ASCVD.

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