The regulatory role and mechanism of mast cells in tumor microenvironment.

Mast cells (MCs) have emerged as pivotal contributors to both the defensive immune response and immunomodulation. They also exhibit regulatory functions in modulating pathological processes across various allergic diseases. The impact of MC presence within tumor tissues has garnered considerable attention, yielding conflicting findings. While some studies propose that MCs within tumor tissues promote tumor initiation and progression, others advocate an opposing perspective. Notably, evidence emphasizes the dual role of MCs in cancer, both as promoters and suppressors, is crucial for optimizing cancer treatment strategies. These conflicting viewpoints have generated substantial controversy, underscoring the need for a comprehensive understanding of MC's role in tumor immune responses.

Small-molecule exhibits anti-tumor activity by targeting the RNA m6A reader IGF2BP3 in ovarian cancer.

Based on its absence in normal tissues and its role in tumorigenesis and tumor progression, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader of N6-methyladenosine (M6A) on RNA, represents a putative valuable and specific target for some cancer therapy. In this study, we performed bioinformatic analysis and immunohistochemistry (IHC) to find that IGF2BP3 was highly expressed in tumor epithelial cells and fibroblasts of ovarian cancer (OC), and was associated with poor prognosis, metastasis, and chemosensitivity in OC patients. In particular, we discovered that knockdown IGF2BP3 expression inhibited the malignant phenotype of OC cell lines by decreasing the protein levels of c-MYC, VEGF, CDK2, CDK6, and STAT1. To explore the feasibility of IGF2BP3 as a therapeutic target for OC, a small molecular AE-848 was designed and screened by molecular operating environment (MOE), which not only could duplicate the above results of knockdown assay but also reduced the expression of c-MYC in M2 macrophages and tumor-associated macrophages and promoted the cytokine IFN-γ and TNF-α secretion. The pharmacodynamic models of two kinds of OC bearing animals were suggested that systemic therapy with AE-848 significantly inhibited tumor growth by reducing the expression of tumor-associated antigen (c-MYC/VEGF/Ki67/CDK2) and improving the anti-tumor effect of macrophages. These results suggest that AE-848 can inhibit the growth and progression of OC cells by disrupting the stability of the targeted mRNAs of IGF2BP3 and may be a targeted drug for OC treatment.

Double-endpoint Genotoxicity Quantification and PAHs Characterization of Drinking Water Source alongside Polluted Yinghe River with High Tumor Mortality.

The etiology for the high tumor mortality in heavy polluted Yinghe river basin is still unclear and polycyclic aromatic hydrocarbons (PAHs) belong to the priority pollutants in water based on the former surveillance data. In order to explore the potential genotoxicants contributing to the double-endpoint genotoxicity of polluted drinking water source, 12 groundwater and 3 surface water samples were collected from 3 villages and the nearby rivers alongside Yinghe river basin, respectively and their comprehensive genotoxicity was estimated with a bioassay group of SOS/umu test and micronucleus (MN) test (MNT). Some groundwater samples showed positive genotoxicity and all surface water samples were highly genotoxic. Eight groundwater samples showed DNA genotoxic effect with the average 4-NQO equivalent concentration (TEQ(4-NQO)) of 0.067 µg/L and 0.089 µg/L in wet and dry season, respectively. The average MN ratios of groundwater samples were 14.19‰ and 17.52‰ in wet and dry season, respectively. Groundwater samples showed different genotoxic effect among 3 villages. The total PAHs concentrations in all water samples ranged from 8.98 to 25.17 ng/L with an average of 14.97±4.85 ng/L. BaA, CHR, BkF, BaP and DBA were the main carcinogenic PAHs contributing to the genotoxicity of water samples. In conclusion, carcinogenic PAHs are possibly related to the high tumor mortality in the target area. Characterization of carcinogenic PAHs to genotoxicity of drinking water source may shed light on the etiology study for high tumor mortality in Yinghe river basin.

Early-onset hearing loss reorganizes the visual and auditory network in children without cochlear implantation.

The present study investigates the effect of early-onset hearing loss on the reorganization of visual and auditory networks in children without cochlear implants. Eleven congenitally deaf children and 12 age-matched hearing children were included in the study. Bilateral transverse temporal cortices and bilateral lateral occipital cortices were defined as auditory and visual seeds, respectively (as verified using an independent component analysis). The four seed-based connectivity maps were computed for each participant. As a result, group analysis showed that the primary auditory cortex was less connected with the motor cortex, whereas the visual cortex showed strengthened connectivity with motor and speech cortices in congenitally deaf children compared with the controls. Moreover, we found that the differences in functional connectivity between deaf and control children were not because of morphometric changes. Our results provide neural evidence for the sensorimotor coupling model of speech development.

The molecular mechanism underlying the induction of hepatic MRP3 expression and function by omeprazole.

Previous work has indicated that there is increased protein expression of multidrug resistance-associated protein 3 (MRP3) in the liver samples of patients treated with omeprazole compared with those who were not. However, evidence is still lacking to show the mechanisms underlying that induction. This study aimed to assess changes in the fold-induction of MRP3 mRNA and protein expression over controls in omeprazole-treated HepG2 cells after transient transfection of human MRP3 siRNA, or after pretreatment with actinomycin D (Act-D). Furthermore, MRP3 siRNA knock-down or MRP-specific inhibition (indomethacin) was used to determine whether the MRP3 protein induced by omeprazole possessed an enhanced efflux transport. The results demonstrated that omeprazole induced MRP3 mRNA and protein expression in a concentration- and time-dependent manner. Moreover, that induction was almost completely abolished by the addition of human MRP3 siRNA and also by pretreatment with Act-D, respectively. In addition, the decay rate of MRP3 mRNA in vehicle- and omeprazole-treated cells was similar in the presence of Act-D, suggesting transcriptional up-regulation of MRP3 mRNA expression by omeprazole. Most importantly, omeprazole induced MRP3 efflux transport activity, as measured by the 5-carboxyfluorescein assay in the absence and presence of human MRP3 siRNA or indomethacin. It is concluded that omeprazole can induce MRP3 mRNA and protein expression and enhance MRP3 efflux transport activity through transcriptional up-regulation, and that omeprazole can also induce other MRP transporters.

Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: role of autophagy.

The present study aimed to test the hypothesis that berberine, a plant-derived anti-oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction (MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague-Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC-3B, Beclin-1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high-dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post-MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC-3B II and Beclin-1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho-Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho-Akt signalling pathways.

Comparison of 4-hydroxynonenal-induced p53-mediated apoptosis in prostate cancer cells LNCaP and DU145.

AIM OF THE STUDY: To explore the mechanism of oxidative stress in the development of prostate cancer, here we compared 4-hydroxynonenal (4-HNE)- treated LNCaP (hormone-sensitive) and DU145 (hormone insensitive) cells with significant differences in sensitivity to androgen. MATERIAL AND METHODS: The prostate cancer cell line LNCaP and late cell line DU145 were treated with different concentrations of 4-HNE. The cell proliferation, apoptosis and mitochondrial transmembrane potential were detected at different time points, and expression of related molecules in cell proliferation and apoptosis signal pathway was analyzed by Western blot, and the over-expression of glutathione S-transferase (GSTA-4) was used to validate the changes of the effects of 4-HNE on the two kinds of cells. RESULTS: LNCaP cells showed greater antiproliferative and proapoptotic activities of HNE in a time- and dose-dependent manner corresponding to the activation of p53-mediated intrinsic apoptotic signaling, but JNK activation was not observed. In contrast, HNE-treated DU145 cells showed less apoptosis and proliferation was not inhibited; instead there was sustained activation of JNK, but activation of p53, p-p53, p21, Bax and caspase-3 was not observed. In addition, their effect of induction of apoptosis can be inhibited by overexpression of GSTA-4. CONCLUSIONS: These studies suggest that 4-HNE promotes prostate cancer cell apoptosis through the p53 signaling pathway; the differences of sensitivity to 4-HNE in LNCaP and DU145 cells may be related to the androgen sensitivity of prostate cancer cells; and the 4-HNE-induced p53-mediated apoptosis signal is regulated by GSTA-4.

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction.

INTRODUCTION: Elevated midkine (MK) expression may contribute to ventricular remodeling and ameliorate cardiac dysfunction after myocardial infarction (MI). Ex vivo modification of signaling mechanisms in mesenchymal stem cells (MSCs) with MK overexpression may improve the efficacy of cell-based therapy. This study sought to assess the safety and efficacy of MSCs with MK overexpression transplantation in a rat model of MI. METHODS: A pLenO-DCE vector lentivirus encoding MK was constructed and infected in MSCs. MSC migration activity and cytoprotection was examined in hypoxia-induced H9C2 cells using transwell insert in vitro. Rats were randomized into five groups: sham, MI plus injection of phosphate buffered saline (PBS), MSCs, MSCs-green fluorescent protein (MSCs-GFP) and MSCs-MK, respectively. Survival rates were compared among groups using log-rank test and left ventricular function was measured by echocardiography at baseline, 4, 8 and 12 weeks. RESULTS: Overexpression of MK partially prevented hypoxia-induced MSC apoptosis and exerted MSC cytoprotection to anoxia induced H9C2 cells. The underlying mechanisms may be associated with the increased mRNA and protein levels of vascular endothelial growth factor (VEGF), transformation growth factor-ß (TGF-ß), insulin-like growth factor 1 (IGF-1) and stromal cell-derived factor 1 (SDF-1a) in MSCs-MK compared with isolated MSCs and MSCs-GFP. Consistent with the qPCR results, the culture supernatant of MSCs-MK had more SDF-1a (9.23 ng/ml), VEGF (8.34 ng/ml) and TGF-ß1 (17.88 ng/ml) expression. In vivo, a greater proportion of cell survival was observed in the MSCs-MK group than in the MSCs-GFP group. Moreover, MSCs-MK administration was related to a significant improvement of cardiac function compared with other control groups at 12 weeks. CONCLUSIONS: Therapies employing MSCs with MK overexpression may represent an effective treatment for improving cardiac dysfunction and survival rate after MI.

Antiepileptics topiramate and levetiracetam alleviate behavioral deficits and reduce neuropathology in APPswe/PS1dE9 transgenic mice.

BACKGROUND: The close relationship between epileptic seizure and Alzheimer's disease (AD) has been demonstrated in the past decade. Valproic acid, a traditional first-line antiepileptic drug, exerted protective effects in transgenic models of AD. It remains uncertain whether new antiepileptic drugs could reverse neuropathology and behavioral deficits in AD transgenic mice. AIMS: APPswe/PS1dE9 transgenic mice were used in this study, which over express the Swedish mutation of amyloid precursor protein together with presenilin 1 deleted in exon 9. 7-month-old APPswe/PS1dE9 transgenic mice were treated daily with 20 mg/kg topiramate (TPM) and 50 mg/kg levetiracetam (LEV) for 30 days by intraperitoneal injection to explore the effects of TPM and LEV on the neuropathology and behavioral deficits. RESULTS: The results indicated that TPM and LEV alleviated behavioral deficits and reduced amyloid plaques in APPswe/PS1dE9 transgenic mice. TPM and LEV increased Aß clearance and up-regulated Aß transport and autophagic degradation. TPM and LEV inhibited Aß generation and suppressed γ-secretase activity. TPM and LEV inhibited GSK-3ß activation and increased the activation of AMPK/Akt activation. Further, TPM and LEV inhibited histone deacetylase activity in vivo. CONCLUSIONS: Therefore, TPM and LEV might have the potential to treat AD effectively in patient care.

Over-expressed and truncated midkines promote proliferation of BGC823 cells in vitro and tumor growth in vivo.

AIM: To determine whether midkine (MK) and its truncated form (tMK) contribute to gastric tumorigenesis using in vitro and in vivo models. METHODS: Human MK and tMK plasmids were constructed and expressed in BGC823 (a gastric adenocarcinoma cell line) to investigate the effect of over-expressed MK or tMK on cell growth and turmorigenesis in nude mice. RESULTS: The growth of MK-transfected or tMK-transfected cells was significantly increased compared with that of the control cells, and tMK-transfected cells grew more rapidly than MK-transfected cells. The number of colony formation of the cells transfected with MK or tMK gene was larger than the control cells. In nude mice injected with MK-transfected or tMK-transfected cells, visible tumor was observed earlier and the tumor tissues were larger in size and weight than in control animals that were injected with cells without the transfection of either genes. CONCLUSION: Over-expressed MK or tMK can promote human gastric cancer cell growth in vitro and in vivo, and tMK has greater effect than MK. tMK may be a more promising gene therapeutic target compared with MK for treatment of malignant tumors.

[Synergy effect of dissolved oxygen in photodegradation of propisochlor in aqueous solution].

The synergetic effect of dissolved oxygen (DO) in the photodegradation of propisochlor aqueous solution was investigated in the presence of UV. With the increase of dissolved oxygen concentration, from 0 to 7.5 mg/L, photodegradation of propisochlor was accelerated. After the concentration of 7.5 mg/L, the rate and efficiency of photodegradation stopped increasing and began to decrease when the concentration became higher. During the photolysis process, dissolved oxygen was consumed. It suggested that the oxygen took an active part in the photolysis. It was found by analysis that the pohtolysis products under different dissolved oxygen concentrations were almost the same, but the production of several products was different. Singlet oxygen (1O2) as the resonance intermediate in the photolysis systems was confirmed by electron spin resonance spin trapping experiments.