Rheum khorasanicum. Hydroalcoholic root extract induces cell death in human colorectal adenocarcinoma: An in vitro and in silico study.

Colorectal cancer (CRC) is the second greatest cause of cancer-related death in the world and chemotherapy, as an important part of CRC treatment, has some drawbacks, including systemic toxicity. Therefore, it is crucial to discover new and more effective CRC treatment plans. Rheum khorasanicum (R. khorasanicum) is a medicinal plant with high flavonoids, stilbenes, and anthraquinone contents, so it can be a potential source of antioxidants and can be used for therapeutic purposes and trigger apoptosis in cancer cells. In this study, we investigated the effects of hydroalcoholic root extract of R. khorasanicum treatment on inducing mitochondrial apoptosis of HT-29 and Caco-2 human colorectal adenocarcinoma cells. Firstly, the total phenolic and flavonoid content was determined. Then, the cytotoxic effects of R. khorasanicum on cells of three different types, including HT-29 and Caco-2 colon cancer cells as well as normal 3T3 cells were assessed using the MTT assay. To investigate the characteristics of cellular death, flow cytometry, and western blotting were performed. The results of this study indicated considerable phenolic (356.4±9.4 GAE/gDW) and flavonoid (934.55±17.1 QE/gDW) contents in R. khorasanicum. MTT assay's finding indicated that 100, 60, and 30µg/mL concentrations of R. khorasanicum reduce cell viability in HT-29 and Caco-2 cell lines significantly (P<0.05). It has been also revealed that R. khorasanicum extract induces apoptosis rather than necrosis in these cell lines. Moreover, Bcl-2 expression was significantly reduced in both HT-29 and Caco-2 cell lines, while Bax and cleaved caspase-3 expression soared considerably in the groups under R. khorasanicum treatment (P<0.05). In conclusion, our findings have suggested that high phenol and flavonoid contents of R. khorasanicum root extract possibly play an important role in cell cytotoxicity and apoptosis induction in HT-29 and Caco-2 colon cancer cells.

[Pediatric very early onset inflammatory bowel disease: Role of pathology]. / Maladies inflammatoires intestinales pédiatriques de survenue très précoce : place de l'anatomie pathologique.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are a heterogeneous group of multifactorial pathologies, often polygenic, due to a dysregulated immune response in a genetically susceptible host. In children under 6 years of age, a significant proportion of IBD, named "very early onset inflammatory bowel diseases" (VEO-IBD), are monogenic disorders in more than one third of cases. Over 80 genes have been linked to VEO-IBD and pathological descriptions are sparce. In this clarification, we describe the clinical aspects of monogenic VEO-IBD and the main causative genes, as well as the various histological patterns observed in intestinal biopsies. The management of a patient with VEO-IBD should be a coordinated effort by a multidisciplinary team including pediatric gastroenterologists, immunologists, geneticists, and of course pediatric pathologists.

NCAPG2 contributes to the progression of malignant melanoma through regulating proliferation and metastasis.

Malignant melanoma is a highly aggressive cutaneous neoplasm with increasing incidence worldwide. Non-SMC condensin II complex subunit G2 (NCAPG2) exerts import biological function in the pathogenesis of several tumors. In this study, the functional roles of NCAPG2 knockdown in malignant melanoma were revealed in in vitro and in vivo experiments. In vitro study demonstrated that NCAPG2 depletion could inhibit proliferation and migration and promote apoptosis of malignant melanoma cells. Our in vivo date further confirmed that NCAPG2 knockdown attenuated tumor growth of malignant melanoma. Interestingly, NCAPG2 drove tumor development of malignant melanoma through activating the signal transducer and activator of transcription 3 (STAT3). In conclusion, this study elaborated the tumor-promoting effects of NCAPG2 on malignant melanoma, and NCAPG2 may be a potential therapeutic target for malignant melanoma therapy.

FYCO1 regulates migration, invasion, and invadopodia formation in HeLa cells through CDC42/N-WASP/Arp2/3 signaling pathway.

FYCO1, an autophagy adaptor, plays an essential role in the trafficking toward the plus-end of microtubules and the fusion of autophagosomes. Autophagic dysfunction is involved in numerous disease states, including cancers. Previous studies have implicated FYCO1 as one of the critical genes involved in the adenoma to carcinoma transition, but the biological function and mechanism of FYCO1 in carcinogenesis remain unclear. This study aims to elucidate the role and mechanism of up- and downregulation of FYCO1 in mediating tumor effects in HeLa cells. Functionally, FYCO1 promotes cellular migration, invasion, epithelial-mesenchymal transition, invadopodia formation, and matrix degradation, which are detected through wound healing, transwell, immunofluorescence, and Western blot approaches. Interestingly, the data show that although FYCO1 does not affect HeLa cell proliferation, cell cycle distribution, nor vessels' formation, FYCO1 can block the apoptotic function. FYCO1 inhibits cleavage of PARP, caspase3, and caspase9 and increases Bcl-2/Bax ratio. Then, we used CK666, an Arp2/3 specific inhibitor, to confirm that FYCO1 may promote the migration and invasion of HeLa cells through the CDC42/N-WASP/Arp2/3 signaling pathway. Taken together, these results provide a new insight that FYCO1, an autophagy adaptor, may also be a new regulator of tumor metastasis.

SET8, a novel regulator to ameliorate vascular calcification via activating PI3K/Akt mediated anti-apoptotic effects.

Previous studies have shown that the apoptosis of vascular smooth muscle cells (VSMCs) underlies the mechanism of pathological calcification in patients with chronic kidney disease (CKD). SET domain-containing protein 8 (SET8) is an efficient protein that modulates apoptosis in hepatocellular carcinoma cells, esophageal squamous cells, and neuronal cells by regulating pathological processes, such as cell cycle progression and transcription regulation. However, whether SET8 is involved in high phosphorus-induced vascular calcification by mediating apoptosis remains unclear. Here, we report that SET8 is located both in the nucleus and cytoplasm and is significantly downregulated in calcification models. SET8 deficiency promoted apoptosis of VSMCs, as indicated by the increased Bax/Bcl-2 and cleaved caspase-3/total caspase-3 ratios. Mechanistically, the PI3K/Akt pathway was mediated by SET8, and inhibition of the PI3K/Akt signaling pathway by administering LY294002 or transfecting the Akt phosphorylation-inactivated mutation plasmid increased apoptosis and calcification. Akt phosphorylation constitutively activated mutations can reduce the apoptosis and calcification of VSMCs. Furthermore, exogenous overexpression of SET8 reversed the effect of PI3K/Akt inhibition on VSMC apoptosis and calcification. In summary, our research suggests that SET8 overexpression ameliorates high phosphorus-induced calcification of VSMCs by activating PI3K/Akt mediated anti-apoptotic effects.

Nisin induces apoptosis in cervical cancer cells via reactive oxygen species generation and mitochondrial membrane potential changes.

Nisin, an antimicrobial peptide produced by Lactococcus lactis, is widely used as a safe food preservative and has recently attracted the attention of researchers as a potential anticancer agent. The cytotoxicity of nisin against human cervical cancer cell lines (HeLa), human ovarian carcinoma cell lines (OVCAR-3 and SK-OV-3), and human umbilical vein endothelial cells (HUVECs) was evaluated using an MTT assay. The apoptotic effect of nisin was identified by Annexin-V/propidium iodide assay, which was further confirmed by western blotting analysis, mitochondrial membrane potential (ΔΨm) analysis, and reactive oxygen species (ROS) assay. The MTT assay showed concentration-dependent cytotoxicity of nisin towards cancer cell lines, with IC50 values of 11.5-23 µM, but less toxicity against normal endothelial cells. Furthermore, the treatment of cervical cancer cells with 12 µM nisin significantly (P < 0.05) increased the Bax/Bcl-2 ratio (4.9 fold), reduced ΔΨm (70%), and elevated ROS levels (1.7 fold). These findings indicate that nisin may have anticancer and apoptogenic activities through mitochondrial dysfunction and oxidative stress damage in cervical cancer cells.

Cholecalciferol induces apoptosis via autocrine metabolism in epidermoid cervical cancer cells.

The anti-cancer effects of vitamin D are of fundamental interest. Cholecalciferol is sequentially hydroxylated endogenously to calcidiol and calcitriol. Here, SiHa epidermoid cervical cancer cells were treated with cholecalciferol (10-2600 nmol/L). Cell count and viability were assayed using Crystal Violet and Trypan Blue, respectively. Apoptosis was assessed using flow cytometry for early and late biomarkers along with brightfield microscopy and transmission electron microscopy. Autocrine vitamin D metabolism was analysed by reverse transcription-quantitative PCR and immunoblotting for activating enzymes: 25-hydroxylases (CYP2R1 and CYP27A1) and 1α-hydroxylase (CYP27B1), the catabolic 24-hydroxylase (CYP24A1), and the vitamin D receptor (VDR). Data were analysed using one-way ANOVA and Bonferroni post-hoc test, and p < 0.05 was considered significant. After cholecalciferol, cell count (p = 0.011) and viability (p < 0.0001) decreased, apoptotic biomarkers were positive, mitochondrial membrane potential decreased (p = 0.0145), and phosphatidylserine externalisation (p = 0.0439), terminal caspase activity (p = 0.0025), and nuclear damage (p = 0.004) increased. Microscopy showed classical features of apoptosis. Gene and protein expression were concordant. Immunoblots revealed increased CYP2R1 (p = 0.021), VDR (p = 0.04), and CYP24A1 (p = 0.0274) and decreased CYP27B1 (p = 0.031). The authors conclude that autocrine activation of cholecalciferol to calcidiol may mediate VDR signalling of growth inhibition and apoptosis in SiHa cells.

A-kinase anchoring protein 5 anchors protein kinase A to mediate PLN/SERCA to reduce cardiomyocyte apoptosis induced by hypoxia and reoxygenation.

The A-kinase anchoring protein 5 (AKAP5) has a variety of biological activities. This study explored whether AKAP5 was involved in cardiomyocyte apoptosis induced by hypoxia and reoxygenation (H/R) and its possible mechanism. H9C2 cells were used to construct an H/R model in vitro, followed by AKAP5 overexpression. Flow cytometry was performed to determine the rate of cardiomyocyte apoptosis. Phosphorylation of phospholamban (PLN), sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), and apoptosis-related proteins was determined by western blotting. Immunofluorescence staining and immunoprecipitation were performed to detect the distribution and interaction between AKAP5, protein kinase A (PKA), and PLN. After H/R induction, H9C2 cells exhibited significantly reduced AKAP5 protein expression. Upregulation of AKAP5 promotes cell survival and significantly reduces lactate dehydrogenase (LDH) levels and apoptosis rates in H9C2 cells. In addition, the overexpression of AKAP5 was accompanied by the activation of the PLN/SERCA2a signaling pathway and a reduction in apoptosis. Immunofluorescence staining and immunoprecipitation revealed that AKAP5 co-localized and interacted with PLN and PKA. Interestingly, St-Ht31, an inhibitory peptide that disrupts AKAP interactions with regulatory subunits, inhibits the effect of AKAP5 overexpression on H/R-induced apoptosis in H9C2 cardiomyocytes. AKAP5 overexpression alleviated H/R-induced cardiomyocyte apoptosis possibly by anchoring PKA to mediate the PLN/SERCA pathway, suggesting that AKAP5 is a potential therapeutic target for the prevention and treatment of ischemia-reperfusion injury.

Staurosporine-induced cleavage of apoptosis-inducing factor in human fibrosarcoma cells is independent of matrix metalloproteinase-2.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein which mediates staurosporine (STS) - induced cell death. AIF cleavage and translocation to the cytosol is thought to be calpain-1-dependent as calpain inhibitors reduce AIF proteolysis; however, many calpain inhibitors also inhibit matrix metalloproteinase-2 (MMP-2) activity, an intracellular and extracellular protease implicated in apoptosis. Here we investigated whether MMP-2 activity is affected in response to STS and if it contributes to AIF cleavage. Human fibrosarcoma HT1080 cells were treated with STS (0.1 µM, 0.25-24 h). A significant increase in cellular MMP-2 activity was seen by gelatin zymography after a 6 h STS treatment, prior to induction of cell necrosis. Western blot showed the time-dependent appearance of two forms of AIF (∼60 and 45 kDa) in the cytosol which were significantly increased at 6 h. Surprisingly, knocking down MMP-2 or inhibiting its activity with MMP-2 preferring inhibitors ARP-100 or ONO-4817, or inhibiting calpain activity with ALLM or PD150606, did not prevent the STS-induced increase in cytosolic AIF. These results show that although STS rapidly increases MMP-2 activity, the cytosolic release of AIF may be independent of the proteolytic activities of MMP-2 or calpain.

Doxorubicin-induced apoptosis enhances monocyte infiltration and adverse cardiac remodeling in diabetic animals.

Diabetic cancer patients were treated with doxorubicin (DOX), a potent chemotherapeutic drug that induces cardiac toxicity; however, molecular mechanisms of cardiac toxicity in this specific disease progression in patients and animal models are completely unknown. Therefore, we designed a study to understand the effects of DOX-induced cardiac toxicity in diabetic animals and the involved pathophysiological mechanisms. C57BL/6 J mice were divided into four DOX- and diabetic (streptozotocin; STZ) - treated groups; control, STZ, DOX, and DOX+STZ. At day 14, animals were sacrificed, echocardiography was used to examine heart function, and heart and blood samples were collected to investigate apoptotic mechanisms (caspase 3, BAX, B-Cell leukemia/lymphoma 2 (Bcl2)), inflammation, and cardiac remodeling. Our data shows a significant (p < 0.05) increase in glucose levels, apoptotic markers, and monocyte infiltration at the site of apoptosis and triggered inflammatory immune response (tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)), in DOX+STZ animals compared with control and experimental groups. We also observed significant (p < 0.05) increase in myofibrillar area, fibrosis, and significantly decreased (p < 0.05) cardiac function in DOX-treated diabetic animals compared with controls. In conclusion, our data suggest that DOX induces significantly increased apoptosis, fibrosis, and structural alterations in diabetic hearts compared with non-diabetic animals.

Colchicine attenuates renal ischemia-reperfusion-induced liver damage: implication of TLR4/NF-κB, TGF-ß, and BAX and Bcl-2 gene expression.

Ischemia-reperfusion injury (IRI) is typically associated with a vigorous inflammatory and oxidative stress response to hypoxia and reperfusion that disturbs the function of the organ. The remote effects of renal IRI on the liver, however, require further study. Renal damage associated with liver disease is a common clinical problem. Colchicine, a polymerization inhibitor of microtubules, has been used as an anti-inflammatory and anti-fibrotic drug for liver diseases. The goal of the current study was to investigate the possible protective mechanisms of colchicine on liver injury following renal IRI. Forty rats were divided randomly into four groups: sham group, colchicine-treated group, IRI group, and colchicine-treated + IRI group. Treatment with colchicine significantly reduced hepatic toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) transcription factor, myeloid differentiation factor 88 (MyD88), and tumor necrosis factor-alpha (TNF-α) contents; downregulated BCL2 associated X apoptosis regulator (BAX) gene expression, transforming growth factor-ß (TGF-ß) content, and upregulated hepatic B cell lymphoma 2 (Bcl-2) gene expression as compared with the IRI group. Finally, hepatic histopathological examinations have confirmed the biochemical results. Renal IRI-induced liver damage in rats was alleviated by colchicine through its anti-inflammatory, anti-apoptotic, and anti-fibrotic actions.

Delta-tocotrienol enhances the anti-tumor effects of interferon alpha through reactive oxygen species and Erk/MAPK signaling pathways in hepatocellular carcinoma cells.

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN-α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining δ-tocotrienol and IFN-α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN-α therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

Anti-cancer potential of cannabis terpenes in a Taxol-resistant model of breast cancer.

Chemotherapeutic resistance can limit breast cancer outcomes; therefore, the exploration of novel therapeutic options is warranted. Isolated compounds found in cannabis have previously been shown to exhibit anti-cancer effects, but little is known about their effects in resistant breast cancer. Our study aimed to evaluate the effects of terpenes found in cannabis in in vitro chemotherapy-resistant model of breast cancer. We aimed to identify whether five terpenes found in cannabis produced anti-cancer effects, and whether their effects were improved upon co-treatment with cannabinoids and flavonoids also found in cannabis. Nerolidol and ß-caryophyllene produced the greatest cytotoxic effects, activated the apoptotic cascade, and reduced cellular invasion. Combinations with the flavonoid kaempferol potentiated the cytotoxic effects of ocimene, terpinolene, and ß-myrcene. Combinations of nerolidol and Δ9-tetrahydrocannabinol or cannabidiol produced variable responses ranging from antagonism and additivity to synergy, depending on concentrations used. Our results indicate that cannabis terpenes, alone or combined with cannabinoids and flavonoids, produced anti-cancer effects in chemotherapy-resistant breast cancer cell lines. This study is a first step in the identification of compounds that could have therapeutic potential in the treatment of resistant breast cancer.

Crosstalk among apoptosis, inflammation, and autophagy in relation to melatonin protective effect against contrast-induced nephropathy in rats.

Contrast medium (CM) is a chemical substance that is used for imaging anatomical boundaries and to explore normal and abnormal physiological findings; the use of CM was associated with kidney injury and acute renal failure. Melatonin (M) possesses antioxidant, anti-inflammatory, and antiapoptotic effects in addition to autophagy modulation. This study aimed to investigate the protective effect of M against contrast-induced nephropathy (CIN) and its impact on the crosstalk between inflammasome, apoptosis, and autophagy in CIN. Male albino rats received M (10, 20, and 40 mg/kg/day, intraperitoneally) for 3 days. One hour after the last administration, rats were subjected to CIN induction (10 mg/kg indomethacin, double doses of l-NAME 10 mg/kg, i.v., and meglumine diatrizoate 60% 6 mL/kg, i.v.). CIN-induced kidney damage was evidenced through elevated kidney function biomarkers and induced renal histopathological changes. Pretreatment with M caused a significant decrease in nephrotoxicity biomarkers and histopathological alterations. Moreover, CIN-induced oxidative stress, NLRP3 inflammasome, and apoptosis were attenuated by M. Furthermore, M modulates autophagy in CIN rats. M inhibits CIN-induced NLRP3-inflammasome activation and apoptosis as well as enhances autophagy.

Paeonol inhibits inflammatory response and protects chondrocytes by upregulating sirtuin 1.

Paeonol is the bioactive component in Paeonia lactiflora Pall., Cynanchum paniculatum and Paeonia × suffruticosa Andr. Paeonol has been previously demonstrated to inhibit the release of tumor necrosis factor α (TNF-α) and interluekin 6 (IL-6) in chondrocytes. Sirtuin 1 (SIRT1) is downregulated in degraded cartilage and paeonol could induce nuclear accumulation of SIRT1. Therefore, the present study aims to investigate the possible role of paeonol in chondrocyte inflammation and cartilage protection in osteoarthritis (OA) as well as its regulation of SIRT1. Primary chondrocytes from rat knee joints were transfected with short hairpin (sh) - SIRT1 and (or) paeonol prior to IL-1ß exposure, and then inflammatory response, apoptosis, and extracellular matrix (ECM) degradation in the cells were evaluated concurrent with the activation of the nuclear factor κß (NF-κß) signaling pathway. Increased levels of TNF-α, IL-17, IL-6, matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 along with decreased tissue inhibitor of metalloproteinases 1 and type II collagen levels were found in IL-1ß-stimulated chondrocytes. Chondrocyte apoptosis was elevated and the NF-κß signaling pathway was activated in response to IL-1ß treatment. Paeonol enhanced SIRT1 expression to inactivate the NF-κß signaling pathway, thereby ameliorating inflammatory cytokine secretion, ECM degradation, and chondrocyte apoptosis. In conclusion, the results of the present study confirm the potential of paeonol as a candidate OA drug.

Formononetin protects against concanavalin-A-induced autoimmune hepatitis in mice through its anti-apoptotic and anti-inflammatory properties.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that seriously threatens the health of humans globally. Formononetin (FMN) is a natural herb extract with multiple biological functions. In this study, an experimental model of AIH was established in mice through the use of concanavalin A (ConA). To investigate the effects of FMN on ConA-induced hepatitis, the mice were pretreated with 50 or 100 mg/kg body mass of FMN. The results show that FMN alleviated ConA-induced liver injury of mice in a dose-dependent manner. Moreover, pretreatment with FMN inhibited the apoptosis of hepatocytes in the ConA-treated mice through downregulating the expression of pro-apoptotic proteins (Bax, cleaved caspase 9, and cleaved caspase 3) and upregulating the expression of anti-apoptotic protein (Bcl-2). It was also found that the levels of proinflammatory cytokines were greatly reduced in the serum and liver tissues of mice pretreated with FMN. Further studies showed that FMN reduced the level of phosphorylated nuclear factor kappa B (p-NF-κB) p65 and enhanced the level of IκBα (inhibitor of NF-κB), suggesting that FMN inhibits the activation of the NF-κB signaling pathway. In addition, FMN inhibited activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Therefore, FMN could be a promising agent for the treatment of AIH.

Bovine lactoferrin and lactoferrin peptides affect endometrial and cervical cancer cell lines.

Cervical, uterine, and ovarian cancers are the most common malignancies of the female genital tract worldwide. Despite advances in prevention, early diagnosis, effective screening, and treatment programs, mortality remains high. Consequently, it is important to search for new treatments. The activity of bovine lactoferrin (bLF) and LF peptides against several types of cancer has been studied; however, only a few studies report the effect of bLF and LF peptides against cervical and endometrial cancers. In this study, we explored the effect of bLF as well as LF chimera and its constituent peptides LFcin17-30 and LFampin265-284 on the viability of cervical (HeLa, SiHa) and endometrial (KLE, HEC-1A) cancer cell lines. Cell proliferation was quantified with an MTT assay, cell morphological changes and damage were determined by Giemsa and phalloidin-TRITC and DAPI staining, and apoptotic and necrotic cells were identified by Alexa Fluor® 488 Annexin V and propidium iodide staining. Additionally, the effect of combinations of bLF and LF peptides with cisplatin was assessed. bLF and LF peptides inhibited the proliferation of uterine cancer cells and caused cellular morphological changes and damage to cell monolayers. bLF induced apoptosis, LFcin17-30 and LFampin265-284 induced apoptosis and necrosis, and LF chimera induced necrosis. Additionally, bLF and LF chimera showed an additive interaction with cisplatin against uterine cancer cells.

Isovitexin attenuates tumor growth in human colon cancer cells through the modulation of apoptosis and epithelial-mesenchymal transition via PI3K/Akt/mTOR signaling pathway.

Isovitexin, a biologically active flavone C-glycosylated derivative, has a variety of biological activities. We aimed to identify the effect of isovitexin (Isov) on colon cancer. Human colonic epithelial cells (HCECs) and cancer cells were treated with Isov and Cell Counting Kit-8 (CCK8) was used to detect cell proliferation and calculate the half-inhibitory concentration (IC50). The biological activity of cancer cells was assessed. The tumor size and volume were recorded. Protein expression levels were analyzed by western blotting. Isov inhibited cancer cell proliferation but had little cytotoxicity on HCECs. Isov significantly attenuated cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and induced cell apoptosis., This trend was blocked by insulin-like growth factor-1 (IGF-1) treatment. The expression levels of phosphorylated phosphatidylinositol 3-kinasep (p-PI3K), phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and B cell lymphoma-2 (Bcl-2) decreased when treated with Isov, while the levels of Bcl2-associated X (Bax) and caspase-3 significantly increased. After Isov treatment, the tumor volume and weight were decreased, and the levels of p-PI3K, p-Akt, p-mTOR, and Bcl-2 significantly decreased in tumor tissues. Our findings demonstrated that Isov inhibited cancer cell migration, invasion, and EMT. Isov may be a new potential treatment for colon cancer.

Dexmedetomidine upregulates the expression of miR-493-5p, inhibiting growth and inducing the apoptosis of lung adenocarcinoma cells by targeting RASL11B.

Numerous studies have indicated that microRNAs (miRNAs) play critical roles in the development and progression of cancer. However, how changes to the expression levels of miRNAs in response to dexmedetomidine affects the progression of lung cancer remains poorly understood. In this study, we treated the lung adenocarcinoma cell line-A549 with dexmedetomidine and then examined the changes to the expression levels of miRNAs. We found that one of the most significantly upregulated miRNAs was miR-493-5p, which has an important role in the growth and apoptosis of lung adenocarcinoma (LUAD) cells. In addition, bioinformatics searches and luciferase reporter assays revealed that miR-493-5p targets RASL11B, which has a high degree of similarity to RAS. Finally, database searches revealed that RASL11B is associated with survival of LUAD cells. In conclusion, dexmedetomidine causes changes to the expression levels of miRNAs in LUAD, including significant upregulation of miR-493-5p. MiR-493-5p targets RASL11B, thereby inhibiting cell growth and inducing apoptosis in LUAD.

The S1PR1 agonist SEW2871 promotes the survival of skin flap.

Skin flap transfer is an important method to repair and reconstruct various tissue defects; however, avascular necrosis largely affects the success of flap transfer. The sphingosine 1-phosphate receptor 1 (S1PR1) agonist SEW2871 has been proven to ameliorate ischemic injury; however, its effect on flap survival has not been reported. In this study, an experimental skin flap model was established in rats to investigate the roles of SEW2871. The results indicated that SEW2871 greatly increased the survival of the skin flap, alleviated pathological injury, promoted the angiogenesis, and inhibited cells apoptosis in skin flap tissues. SEW2871 activated S1PR1 downstream signaling pathways, including heat shock protein 27 (HSP27), extracellular regulated protein kinases (ERK), and protein kinase B (Akt). In addition, SEW2871 promoted the expression of S1PR1. These findings may provide novel insights for skin flap transfer.