Current molecular medicine最新文献

Natural killer (NK) cells are among the most important cells in innate immune defense. In contrast to T cells, the effector function of NK cells does not require prior stimulation and is not MHC restricted. Therefore, chimeric antigen receptor (CAR)-NK cells are superior to CAR-T cells. The complexity of the tumor microenvironment (TME) makes it necessary to explore various pathways involved in NK cell negative regulation. CAR-NK cell effector function can be improved by inhibiting the negative regulatory mechanisms. In this respect, the E3 ubiquitin ligase tripartite motif containing 29 (TRIM29) is known to be involved in reducing NK cell cytotoxicity and cytokine production. Also, targeting TRIM29 may enhance the antitumor efficacy of CAR-NK cells. The present study discusses the negative effects of TRIM29 on NK cell activity and proposes genomic deletion or suppression of the expression of TRIM29 as a novel approach to optimize CAR-NK cell-based immunotherapy.

Background: Dietary chemicals and their gut-metabolized products are explored for their anti-proliferative and pro-cell death effects. Dietary and metabolized chemicals are different from ruminants such as goats over humans.

Methods: Loss of cell viability and induction of death due to goat urine DMSO fraction (GUDF) derived chemicals were assessed by routine in vitro assays upon MCF-7 breast cancer cells. Intracellular metabolite profiling of MCF-7 cells treated with goat urine DMSO fraction (GUDF) was performed using an in-house designed vertical tube gel electrophoresis (VTGE) assisted methodology, followed by LC-HRMS. Next, identified intracellular dietary chemicals such as ellagic acid were evaluated for their inhibitory effects against transducers of the c-Raf signaling pathway employing molecular docking and molecular dynamics (MD) simulation.

Results: GUDF treatment upon MCF-7 cells displayed significant loss of cell viability and induction of cell death. A set of dietary and metabolized chemicals in the intracellular compartment of MCF-7 cells, such as ellagic acid, 2-hydroxymyristic acid, artelinic acid, 10-amino-decanoic acid, nervonic acid, 2,4-dimethyl-2-eicosenoic acid, 2,3,4'- Trihydroxy,4-Methoxybenzophenone and 9-amino-nonanoic acid were identified. Among intracellular dietary chemicals, ellagic acid displayed a strong inhibitory affinity (-8.7 kcal/mol) against c-Raf kinase. The inhibitory potential of ellagic acid was found to be significantly comparable with a known c-Raf kinase inhibitor sorafenib with overlapping inhibitory site residues (ARG450, GLU425, TRP423, VA403).

Conclusion: Intracellular dietary-derived chemicals such as ellagic acid are suggested for the induction of cell death in MCF-7 cells. Ellagic acid is predicted as an inhibitor of c-Raf kinase and could be explored as an anti-cancer drug.

An increasing volume of studies has reported that long non-codingRNAs (lncRNAs) are involved in the carcinogenesis of many different cancers. Especially in gastrointestinal tumors, lncRNAs are found to participate in various physiological and pathological processes. LncRNAs can regulate gene expression at multiple levels, including transcriptional, post-transcription, translational, and post-translational levels. Long intergenic non-protein coding RNA 665(LINC00665), a novel cancer-related lncRNA, is frequently dysregulated in multiple gastrointestinal tumors, including gastric and colorectal cancers, hepatocellular carcinoma, and so on. In this review, we analyzed the expression and prognostic value of LINC00665 in human gastrointestinal tumors, systematically summarized the current literature about the clinical significance of this lncRNA, and explored the regulatory mechanisms of LINC00665 as a competing endogenous RNA (ceRNA) in tumor progression. Consequently, we concluded that LINC00665 might act as a prognostic biomarker and a potential target for gastrointestinal tumor diagnosis and treatment.

Objective: Circular RNAs (circRNAs) have been extensively implicated in osteoarthritis (OA) progression. Therefore, this study explores the impact of hsa_circ_0004662 on OA progression and the related molecular mechanism.

Methods: Human articular chondrocyte injury was induced by IL-1β to construct the OA model in vitro. Hsa_circ_0004662 and microRNA (miR)-424-5p expression in chondrocytes was evaluated with qRT-PCR. Vascular endothelial growth factors A (VEGFA) expression was examined with qRT-PCR and western blot after hsa_circ_0004662 knockdown or miR-424-5p overexpression in chondrocytes. Subsequent to loss- and gain-of-function assays in IL-1β-induced chondrocytes, the proliferation and apoptosis of chondrocytes were assessed with CCK-8 assay and flow cytometry, respectively. The expression of MMP13, Aggrecan, and apoptosis-related proteins Bax and Bcl-2 was measured with western blot. The binding of miR-424-5p to hsa_circ_0004662 and VEGFA was assessed with a dual-luciferase reporter gene assay.

Results: Hsa_circ_0004662 was up-regulated, but miR-424-5p was down-regulated in IL-1β-induced chondrocytes. Mechanistically, both hsa_circ_0004662 and VEGFA bound to miR-424-5p, and hsa_circ_0004662 enhanced VEGFA expression by downregulating miR-424-5p. Hsa_circ_0004662 knockdown elevated cell proliferation, decreased apoptosis and MMP13 and Bax expression, and increased Aggrecan and Bcl- 2 expression in IL-1β-induced chondrocytes, which was counteracted by further miR- 424-5p down-regulation or VEGFA overexpression.

Conclusion: Hsa_circ_0004662 facilitates OA progression via the miR-424-5p/ VEGFA axis.

Background: Radiofrequency ablation (RFA) is an important treatment strategy for patients with advanced hepatocellular carcinoma (HCC). However, its therapeutic effect is unsatisfactory and recurrence often occurs after RFA treatment. The octamer-binding transcription factor OCT1 is a novel tumour-promoting factor and an ideal target for HCC therapy.

Objective: This study aimed to expand the understanding of HCC regulation by OCT1.

Methods: The expression levels of the target genes were examined using qPCR. The inhibitory effects of a novel inhibitor of OCT1 (NIO-1) on HCC cells and OCT1 activation were examined using Chromatin immunoprecipitation or cell survival assays. RFA was performed in a subcutaneous tumour model of nude mice.

Results: Patients with high OCT1 expression in the tumour tissue had a poor prognosis after RFA treatment (n = 81). The NIO-1 showed antitumor activity against HCC cells and downregulated the expression of the downstream genes of OCT1 in HCC cells, including those associated with cell proliferation (matrix metalloproteinase-3) and epithelial-mesenchymal transition-related factors (Snail, Twist, N-cadherin, and vimentin). In a subcutaneous murine model of HCC, NIO-1 enhanced the effect of RFA treatment on HCC tissues (n = 8 for NIO-1 and n = 10 for NIO-1 + RFA).

Conclusion: This study demonstrated the clinical importance of OCT1 expression in HCC for the first time. Our findings also revealed that NIO-1 aids RFA therapy by targeting OCT1.

Background: The developmental biology for the nonalcoholic fatty liver disease and coronary heart disease are known but elaborative ideas of triglycerides phenomenon in the embryo-genesis of the liver and the heart are still not clear.

Objective: The aim of the study was to relate different triglycerides like LXRα, LPL, LDL R, PPARG-, SREBP-1C expression in the high fat fed mice with the normal fed diet mice in the process of developmental and embryo-genesis biology.

Methods: Tissue preparation was done by ripalysis. Different protein content was obtained via western blot for the 6 samples namely a-17.5 days mice embryo heart; b- 0th day or the birthday mice infant heart; c-1 week mice infant heart; d-2 weeks mice infant heart; e-3 weeks mice infant heart; f-Adult mice heart. Protein lysates from the heart tissues of the mice was obtained via homegenization and centrifugation. Hematoxylin and Eosin (H and E) was done to see the fat droplets in the liver tissues at the different developmental stages.

Result: LXRα,SREBP-1C expression in 17.5 days mice embryo heart and 0th day or the birthday mice infant heart is highly expressed in the high fat diet. LDL-R in the high fat diet mice is increased in 2 weeks mice infant heart but in17.5 days mice embryo heart and in 0th day or the birthday mice infant heart it is low expression but from 1week mice infant heart to the adult mice heart the expression is in decreasing trend. Similarly LPL is highly expressed in17.5 days mice embryo heart and 1 week mice infant heart and thus low expression in decreasing order until adult mice heart.Thus, these results collectively shows that maternal HF diet increases expression of proteins such as LPL, LDLr in the embryo phase and thus getting normal expressions in the adult phase that facilitate Triglycerides (TAG) hydrolysis across the liver and the heart. Also,maternal high fat diet increases the SREBP1c expression, leading to stimulation of LPL Expression.

Conclusion: In summary, using a pregnant mice model, we found that maternal high fat diet increases the fetal fat accumulation. Elevated placental LPL activity and expression of genes that facilitate placental lipid transport suggest that enhanced placental lipid transport may play a key role in maternal nutrition and obesity-induced fetal fat accumulation.

Background: It is well recognized that both smoke and Candida infection are crucial risk factors for oral mucosal diseases. The nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and its downstream effectors, interleukin (IL)-1β and IL-18, are pivotal to the host defense against Candida and other pathogens.

Methods: The present study was designed to explore the effects of cigarette smoke and C. albicans on the NLRP3 inflammasome and its downstream signal pathway via in vitro cell model. Oral epithelial cells (Leuk-1 cells) were exposed to cigarette smoke extract (CSE) for 3 days and/or challenged with C. albicans.

Results: Microscopically, Leuk-1 cells exerted a defense response to C. albicans by markedly limiting the formation of germ tubes and microcolonies. CSE clearly eliminated the defense response of Leuk-1 cells. Functionally, CSE repressed NLRP3 inflammasome, and IL-1β and IL-18 activation induced by C. albicans in Leuk-1 cells.

Conclusion: Our results suggested that in oral epithelial cells, the NLRP3 inflammasome might be one of the target pathways by which CSE attenuates innate immunity and leads to oral disorders.

Backgrounds: Glaucoma is the second leading cause of blindness. Apoptosis of retinal ganglion cells (RGCs) is an important mechanism of glaucomatous optic injury. Rho kinase expression is significantly increased in apoptotic RGCs. This study aimed to investigate the role of RhoA, a Rho GTPase, on the survival of RGCs and further to explore its potential therapeutic applications.

Methods: RGCs were treated with siRhoA for 24 hours in vitro. Knockdown of RhoA was confirmed with quantitative RT-PCR. Oxidative stress was induced by treating the RGCs with 200 μM of H₂O₂ for 1 hour, and apoptosis of RGCs was quantified with TUNEL assay in situ, and with flow cytometry. The mRNA expression levels of RhoA, Nogo receptor, caspase 3 and Bcl-2 were evaluated by quantitative RT-PCR, and the protein levels of RhoA, ROCK1, ROCK2, Nogo receptor, caspase 3 and Bcl-2 were evaluated by Western blot. We found siRhoA treatment efficiently downregulated the expression of RhoA in RGCs and protected against H₂O₂-induced injury in RGCs in vitro. Apoptosis of RGC cells under oxidative stress was quantified in situ using TUNEL assay and confirmed with flow cytometry (FCM).

Results: With the knockdown of RhoA, the expression of ROCK1, ROCK2, Nogo Receptor, Casepase-3 were decreased, while the expression of Bcl-2 was increased in both mRNA and protein level. Our data indicated that siRhoA prevented H₂O₂-induced apoptosis in RGC cells by modulating the RhoA/ROCK pathway.

Conclusion: The results suggested that siRhoA may exert potentially effective neuroprotection for RGCs by reducing injury.

In this review we have brought forward various nuclear imaging modalities used in the diagnosis, staging, and management of thyroid cancer. Thyroid cancer is the most common endocrine malignancy, accounting for approximately 3% of all new cancer diagnoses. Nuclear imaging plays an important role in the evaluation of thyroid cancer, and the use of radioiodine imaging, FDG imaging, and somatostatin receptor imaging are all valuable tools in the management of this disease. Radioiodine imaging involves the use of Iodine-123 [I-123] or Iodine-131 [I-131] to evaluate thyroid function and detect thyroid cancer. I-123 is a gamma-emitting isotope that is used in thyroid imaging to evaluate thyroid function and detect thyroid nodules. I-131 is a beta-emitting isotope that is used for the treatment of thyroid cancer. Radioiodine imaging is used to detect the presence of thyroid nodules and evaluate thyroid function. FDG imaging is a PET imaging modality that is used to evaluate the metabolic activity of thyroid cancer cells. FDG is a glucose analogue that is taken up by cells that are metabolically active, such as cancer cells. FDG PET/CT can detect primary thyroid cancer and metastatic disease, including lymph nodes and distant metastases. FDG PET/CT is also used to monitor treatment response and detect the recurrence of thyroid cancer. Somatostatin receptor imaging involves the use of radiolabeled somatostatin analogues to detect neuroendocrine tumors, including thyroid cancer. Radiolabeled somatostatin analogues, such as Indium-111 octreotide or Gallium-68 DOTATATE, are administered to the patient, and a gamma camera is used to detect areas of uptake. Somatostatin receptor imaging is highly sensitive and specific for the detection of metastatic thyroid cancer. A comprehensive search of relevant literature was done using online databases of PubMed, Embase, and Cochrane Library using the keywords "thyroid cancer," "nuclear imaging," "radioiodine imaging," "FDG PET/CT," and "somatostatin receptor imaging" to identify relevant studies to be included in this review. Nuclear imaging plays an important role in the diagnosis, staging, and management of thyroid cancer. The use of radioiodine imaging, thyroglobulin imaging, FDG imaging, and somatostatin receptor imaging are all valuable tools in the evaluation of thyroid cancer. With further research and development, nuclear imaging techniques have the potential to improve the diagnosis and management of thyroid cancer and other endocrine malignancies.

Objective: To observe the short-term effect of sequentially combined multimodal artificial liver treatment (SCMALT) on HBV-related acute-on-chronic liver failure (HBV-ACLF).

Methods: HBV-ACLF patients 155 cases undergoing artificial liver treatment were analyzed, and they were sorted into the SCMALT group and the conventional-modal artificial liver treatment (CALT) group. The clinical data of all patients were recorded and the serum levels of interleukin-8 (IL-8), chemokine interferon-inducible protein-10 (IP-10), and interleukin-6 (IL-6) were detected. The changes in the 30-day survival rate, cytokine level, model for end-stage liver disease (MELD) score, and complications of artificial liver treatment were analyzed.

Results: After being followed up for 30 days, 104 patients survived and 51 died. At the end of the whole-course treatment, the decreases in IL-6, IP-10, and IL-8 levels and MELD scores in the SCMALT group were greater than in the CALT group. Cox regression suggested WBC (OR=1.066, 95% CI 1.012-1.123, P=0.017), AT-III activity (OR=0.935, 95% CI 0.907-0.964, p=0.000) at baseline, artificial liver treatment mode (OR=0.362, 95% CI 0.164-0.800, p=0.012), number of artificial liver treatments (OR=0.656.95% CI 0.436-0.986, p=0.043), spontaneous peritonitis (OR=0.337, 95% CI 0.165-0.689, p=0.003), and hepatic encephalopathy (OR=0.104, 95% CI 0.028-0.388, p=0.001) were independent influencing factors of 30-day survival rate. SCMALT can significantly prolong the survival period of the patient. No obvious difference was shown in the proportions of bleeding and circulation instability between the two groups (p>0.05).

Conclusion: Compared with the CALT, SCMALT can more effectively remove inflammatory mediators and reduce the MELD score in HBV-ACLF patients, which can obviously ameliorate the prognosis, with less effect on the platelet count.