SOX4 induces drug resistance of colorectal cancer cells by downregulating CYLD through transcriptional activation of microRNA-17.

Exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells. Drug tolerance can reduce the benefits obtained from canonical treatment and reduce the survival rate of patients. Regulation of SRY-related HMG box transcription factor 4 (SOX4) has been proved to affect drug sensitivity. The current study aimed to explore the role of SOX4 in drug resistance of colorectal cancer (CRC) cells as well as the related molecular mechanisms. Expression patterns of SOX4, microRNA-17 (miR-17), and CYLD in both CRC tissues and cells were determined with their relationship analyzed by bioinformatics analysis, dual-luciferase reporter gene assay, and ChIP. Loss- and gain-function assays were performed to ascertain the effect of SOX4, miR-17, and CYLD on biological cellular processes and drug resistance to 5-FU. SOX4 and miR-17 were found to be highly expressed while CYLD was poorly expressed in CRC tissues and cells. Silencing of SOX4 resulted in the suppression of cellular proliferation, invasion, migration as well as a reduction in CRC drug resistance. Mechanically, CYLD was specifically targeted by miR-17, while SOX4 upregulated the expression of miR-17. Functionally, SOX4 triggered drug resistance of CRC cells to 5-FU through the miR-17/CYLD axis. Taken together, the key findings of the present study provides evidence suggesting that SOX4 elevates miR-17 to decrease CYLD, thus inducing chemotherapy resistance of CRC cells.

Correction to Multifunctional Alginate Hydrogel Protects and Heals Skin Defects in Complex Clinical Situations.

[This corrects the article DOI: 10.1021/acsomega.0c01108.].

Multifunctional Alginate Hydrogel Protects and Heals Skin Defects in Complex Clinical Situations.

Skin defects, soft tissue damage, and fractures often occur simultaneously in severe trauma. Under current medical technology, fractures can be quickly fixed by internal or external repair techniques, and early functional exercises can be performed. However, skin defects heal over a long time and can even be difficult to heal. Functional exercise may cause cutting of fresh granulation to break and impair wound healing. Functional exercise and wound healing seem to contradict each other. In this study, an alginate hydrogel was developed. With self-healing characteristics, the hydrogel tightly adhered to the wound and could self-heal breaks in the gel caused by functional exercises. These characteristics enable this hydrogel to be used in complex clinical situations to solve sports rehabilitation and skin defect repair problems. In addition, this hydrogel can slowly release strontium ions, promote angiogenesis and collagen deposition in the wound, and quickly heal the wound.

Ursolic acid protects against cisplatin­induced ototoxicity by inhibiting oxidative stress and TRPV1­mediated Ca2+­signaling.

Cisplatin (CDDP) is widely used in clinical settings for the treatment of various cancers. However, ototoxicity is a major side effect of CDDP, and there is an associated risk of irreversible hearing loss. We previously demonstrated that CDDP could induce ototoxicity via activation of the transient receptor potential vanilloid receptor 1 (TRPV1) pathway and subsequent induction of oxidative stress. The present study investigated whether ursolic acid (UA) treatment could protect against CDDP­induced ototoxicity. UA is a triterpenoid with strong antioxidant activity widely used in China for the treatment of liver diseases. This traditional Chinese medicine is mainly isolated from bearberry, a Chinese herb. The present results showed that CDDP increased auditory brainstem response threshold shifts in frequencies associated with observed damage to the outer hair cells. Moreover, CDDP increased the expression of TRPV1, calpain 2 and caspase­3 in the cochlea, and the levels of Ca2+ and 4­hydroxynonenal. UA co­treatment significantly attenuated CDDP­induced hearing loss and inhibited TRPV1 pathway activation. In addition, UA enhanced CDDP­induced growth inhibition in the human ovarian cancer cell line SKOV3, suggesting that UA synergizes with CDDP in vitro. Collectively, the present data suggested that UA could effectively attenuate CDDP­induced hearing loss by inhibiting the TRPV1/Ca²+/calpain­oxidative stress pathway without impairing the antitumor effects of CDDP.

H89 dihydrochloride hydrate and calphostin C lower the body temperature through TRPV1.

The transient receptor potential vanilloid (TRPV1) serves as a negative regulator of body temperature, and during fever conditions its expression can lead to a decrease in temperature. TRPV1 is regulated by a variety of enzymes; however, it is currently unclear whether the regulation of TRPV1 phosphorylation may serve a role in the increase in TRPV1 expression during fever. In the present study, using an in vivo experimental method, rat brain ventricles were injected with the protein kinase A (PKA) antagonist, H89, and the protein kinase C (PKC) antagonist, calphostin C, and fever was induced using lipopolysaccharide (LPS) in order to detect the expression of TRPV1 and phosphorylated (p­)TRPV1, the intracellular Ca2+ concentration [(Ca2+)i] of hypothalami and rat body temperature. The results demonstrated that following the generation of fever using LPS, the expressions of TRPV1 and p­TRPV1, and hypothalamic [Ca2+]i markedly increased. In addition, following an injection with the PKA or PKC antagonist, the temperature increased further due to the inhibition of p­TRPV1. Thus, it was hypothesized that PKA and PKC may be involved in TRPV1 phosphorylation, resulting in a temperature reduction during LPS­induced fever conditions.

Pomegranate peel extract attenuates D-galactose-induced oxidative stress and hearing loss by regulating PNUTS/PP1 activity in the mouse cochlea.

Oxidative stress is considered to be a major contributor to age-related hearing loss (ARHL). Here, we investigated whether pomegranate peel extract (PPE) protected against hearing loss by decreased oxidative stress in the cochlea of D-galactose-induced accelerated aging mice. The aging mice exhibited an increase in hearing threshold shifts and hair cells loss, which were improved in the PPE-treated aging mice. The aging mice also exhibited an increase in 4-hydroxynonenal, the expression of protein phosphatase 1 nuclear targeting subunit (PNUTS), p53 and caspase-3, and a decrease in protein phosphatase 1 (PP1) and MDM2 in the cochlea. PPE treatment reversed the changes in aforementioned molecules. Our results suggested that PPE can protect against ARHL, the underlying mechanisms may involve in the inhibition of oxidative damage of cochlea, possibly by regulating PNUTS/PP1 pathway. The results from the present study provide a new therapeutic strategy to use PPE for prevention of ARHL.

Mechanism of alpha-lipoic acid in attenuating kanamycin-induced ototoxicity.

In view of the theory that alpha-lipoic acid effectively prevents cochlear cells from injury caused by various factors such as cisplatin and noise, this study examined whether alpha-lipoic acid can prevent kanamycin-induced ototoxicity. To this end, healthy BALB/c mice were injected subcutaneously with alpha-lipoic acid and kanamycin for 14 days. Auditory brainstem response test showed that increased auditory brainstem response threshold shifts caused by kanamycin were significantly inhibited. Immunohistochemical staining and western blot analysis showed that the expression of phosphorylated p38 mitogen-activated protein kinase and phosphorylated c-Jun N-terminal kinase in mouse cochlea was significantly decreased. The experimental findings suggest that phosphorylated p38 and phosphorylated c-Jun N-terminal kinase mediated kanamycin-induced ototoxic injury in BALB/c mice. Alpha-lipoic acid effectively attenuated kanamycin ototoxicity by inhibiting the kanamycin-induced high expression of phosphorylated p38 and phosphorylated c-Jun N-terminal kinase.

[Effects of salvia miltiorrhiza injection on gentamicin-induced expression of nitric oxide synthase isoforms in guinea pig cochlea].

OBJECTIVE: To investigate the effects of salvia miltiorrhiza injection (SM) on gentamicin (GM)-induced expression of nitric oxide synthase (NOS) isoforms in guinea pig cochlea, and to explore the protective mechanism of SM on GM-induced ototoxicity. METHODS: 40 guinea pigs were randomly assigned to 4 groups: control group, GM group, SM group and GM plus SM group. Expression of NOS isoforms in the guinea pig cochlea was detected by the SABC method of immunohistochemistry and microscope image analysis technique. Auditory threshold was tested by auditory brainstem response (ABR) measurement. RESULTS: Inducible NOS (iNOS/NOS II) expression and ABR threshold in GM plus SM group were both significantly declined as compared with those in GM group (P < 0.01). Moreover, change of iNOS expression was in high correlation with that of ABR threshold ([r] > 0.7, P < 0.01). While expression of neuronal NOS (nNOS/NOS I) and endothelial NOS (eNOS / NOS III) showed no significant differences in all groups. CONCLUSION: SM had no effect on the expression of nNOS and eNOS, but could inhibit iNOS high-expression induced by GM to reduce excessive generation of NO, therefore SM could protect against GM ototoxicity.