Evaluation and Application of Frailty Index in Colorectal Cancer: A Comprehensive Review.

Colorectal cancer (CRC) is a common malignant tumor that primarily affects the elderly population. Surgery is one of the main treatment modalities for CRC. Frailty is a prevalent characteristic among the elderly and a leading cause of mortality. The frailty index (FI) is a comprehensive tool for assessing patients' frailty status, quantifying indicators such as weight loss, fatigue, and nutritional status, to reflect the degree of frailty. In recent years, the FI has undergone modifications to more accurately evaluate the risk of surgical complications and prognosis in CRC patients. This review summarizes the methods for frailty assessment, the development and modifications of the FI, and compiles the research findings and applications of the FI in predicting surgical complications, postoperative recovery, and survival rates in CRC patients. Furthermore, limitations in the current modified frailty index (mFI) and future research directions are discussed. This review provides essential references for further understanding the role of frailty in CRC patients and the clinical application of the mFI.

Puerarin inhibits cisplatin-induced ototoxicity in mice through regulation of TRPV1-dependent calcium overload.

Puerarin (PUE), a flavonoid derivative with vasodilatory effects found in the traditional Chinese medicine kudzu, has anti-sensorineural hearing loss properties. However, the mechanism of its protective effect against ototoxicity is not well understood. In this study, we used in vitro and in vivo methods to investigate the protective mechanism of puerarin against cisplatin (CDDP)-induced ototoxicity. We established an ototoxicity model of CDDP in BALB/c mice and assessed the degree of hearing loss and cochlear cell damage. We used bioinformatics analysis, molecular docking, histological analysis, and biochemical and molecular biology to detect the expression of relevant factors. Our results show that puerarin improved CDDP-induced hearing loss and reduced hair cell loss. It also blocked CDDP-induced activation of TRPV1 and inhibited activation of IP3R1 to prevent intracellular calcium overload. Additionally, puerarin blocked CDDP-stimulated p65 activation, reduced excessive ROS production, and alleviated cochlear cell apoptosis. Our study provides new evidence and potential targets for the protective effect of puerarin against drug-induced hearing loss. Puerarin ameliorates cisplatin-induced ototoxicity and blocks cellular apoptosis by inhibiting CDDP activated TRPV1/IP3R1/p65 pathway, blocking induction of calcium overload and excessive ROS expression.

Genome-Wide CRISPR/Cas9 Library Screening Identified that DUSP4 Deficiency Induces Lenvatinib Resistance in Hepatocellular Carcinoma.

Background: Lenvatinib is in a first-line therapy for advanced hepatocellular carcinoma (HCC). However, drug resistance is one of the principal obstacles for treatment failure. The molecular mechanism of Lenvatinib resistance has not been well investigated. Materials and methods: A genome-wide CRISPR/Cas9 knockout screening system was established and bioinformatic analysis was used to identify critical genes associated with Lenvatinib resistance. Cell proliferation assays, colony formation assays and cell migration assays were performed to investigate the effect of drug resistance associated genes, particularly DUSP4, on cancer cell malignant behavior during Lenvatinib treatment. In vivo experiments were conducted by using a xenograft mouse model. Results: We identified six genes that were associated with Lenvatinib resistance in HCC, including DUSP4, CCBL1, DHDH, CNTN2, NOS3 and TNF. DUSP4 was found to be significantly decreased at the mRNA and protein levels in Lenvatinib resistant HCC cells. DUSP4 knockout enhanced HCC cell survival, cell proliferation and migration during Lenvatinib treatment in vitro and in vivo, accompanied by regulation of p-ERK and p-MEK levels. This finding implied that DUSP4 deficiency induced Lenvatinib resistance. Interestingly, DUSP4 deficiency induced Lenvatinib resistance was abrogated by the MEK inhibitor Selumetinib, implying that MEK phosphorylation and DUSP4-inhibition dependent ERK activation were required for drug resistance. Finally, we found that DUSP4 deficiency was associated with HCC prognosis and response to Lenvatinib based on clinical data. Conclusions: DUSP4 deficiency mediates Lenvatinib resistance by activating MAPK/ERK signaling and combination therapy using Lenvatinib and MEK inhibitors may be a promising therapeutic strategy for overcoming Lenvatinib resistance.

Remote ischaemic perconditioning reduces the infarct volume and improves the neurological function of acute ischaemic stroke partially through the miR-153-5p/TLR4/p65/IkBa signalling pathway.

Remote ischemic perconditioning (RIPerC) could improve neuronal damage and inhibit inflammation and apoptosis. We conducted an in-depth exploration of the protective mechanism of RIPerC in cerebral ischaemia injury. In this study, a middle cerebral artery occlusion (MCAO) mouse model was built. According to whether to undergo RIPerC treatment and the duration of cerebral infarction, mice were divided into 5 groups: Sham group, MCAO 3.0 h group, MCAO 4.5 h group, MCAO 3.0 h + RIPerC group, and MCAO 4.5 h + RIPerC group. Overexpressed or silenced miR-153-5p was transfected into the cells to analyse the effects of oxygen-glucose deprivation (OGD) treatment on Neuro-2a cell viability, apoptosis, and related gene expressions by performing quantitative real-time polymerase chain reaction (qRT-PCR), MTT assay, flow cytometry, and Western blot. Bioinformatics analysis, qRT-PCR, dual-luciferase experiment, and RNA immunoprecipitation (RIP) were used to screen and verify the miRNA and downstream mRNA-targeted Toll-like receptor 4 (TLR4). The rescue test further verified the effects of the above target genes and miR-153-5p on the apoptosis of OGD-injured cells, apoptosis-related proteins, and the p65/IkBa pathway. The plasma levels of miR-153-5p in 68 patients with ischaemic stroke were detected within 6 hours of onset, and the patients were followed up for 3 months. We found that, in in vivo studies, RIPerC treatment inhibits cerebral infarction volume and neurological damage, and promotes the expression of miR-153-5p in the MCAO animal model. The expression of miR-153-5p in OGD cells was inhibited, and its upregulation protected Neuro-2a cells. TLR4 was predicted to be the target gene of miR-153-5p and could offset the effect of miR-153-5p mimic on OGD cell protection after up-regulating TLR4. TLR4 overexpression promoted the activation of OGD on the p65/IkBa pathway. Compared with the high plasma miR-153-5p group, the 3-month overall survival rate of patients with ischaemic stroke in the low plasma miR-153-5p group was significantly lower (c2 = 5.095, p = 0.024). In conclusion, RIPerC intervention inhibits the damage caused by cerebral ischaemia partially through the miR-153-5p/TLR4/p65/IkBa signalling pathway.

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.

MiR-328-3p inhibits cell proliferation and metastasis in colorectal cancer by targeting Girdin and inhibiting the PI3K/Akt signaling pathway.

MiR-328-3p has been reported to be downregulated and serve as a tumor suppressor in several cancers. Previous studies only have reported the downregulation of miR-328-3p in CRC. However, the roles of miR-328-3p in CRC growth and metastasis were unknown. In this study, we demonstrated that miR-328-3p overexpression inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). The PI3K/Akt signaling pathway was also inactivated by miR-328-3p overexpression. MiR-328-3p knockdown showed the opposite effects. In addition, we confirmed that miR-328-3p directly bound to 3'UTR of Girdin and negatively regulated its expression. Girdin knockdown or treatment with PI3K inhibitor LY294002 blocked the effects of miR-328-3p inhibitor on cell proliferation, metastasis, and the PI3K/Akt signaling pathway. Moreover, pre-miR-328 decreased numbers of liver metastatic nodules, and reduced the levels of p-Akt, p-Girdin, and Girdin in metastatic tissues in liver. In conclusion, miR-328-3p may inhibit proliferation and metastasis of CRC cells by targeting Girdin and inactivating the PI3K/Akt signaling pathway. MiR-328-3p may be a novel target in cancer therapy.

MiR-346-5p promotes colorectal cancer cell proliferation in vitro and in vivo by targeting FBXL2 and activating the ß-catenin signaling pathway.

MiR-346-5p is overexpressed in several cancers, including colorectal cancer (CRC). However, the effects of miR-346-5p on CRC progression have not yet been clarified. In our study, miR-346-5p levels in four CRC cell lines and normal human colon epithelial cells were determined by real-time PCR. SW620 and HCT116 cells were selected and then transfected with miR-346-5p mimic, miR-346-5p inhibitor, or specific siRNAs targeting F-box/LRR-repeat protein 2 (FBXL2). Cell proliferation, cell cycle distribution and cell cycle regulators were examined by CCK-8 assay, flow cytometry, and western blot. The binding of miR-346-5p on 3' untranslated region (UTR) of FBXL2 were verified by dual-luciferase reporter assay. CRC cells were co-transfected with miR-346-5p inhibitor and siFBXL2 to investigate the involvement of FBXL2. Interaction of FBXL2 with forkhead box M1 (FoxM1) was examined by co-immunoprecipitation (Co-IP) assay. The effect of miR-346-5p knockdown on CRC tumorigenesis in vivo was investigated. Here, we found that miR-346-5p overexpression promoted, while miR-346-5p knockdown inhibited cell proliferation and G1-S transition. Inhibition of FBXL2 showed similar effects as miR-346-5p overexpression. Moreover, we verified that FBXL2 was a direct target of miR-346-5p. FBXL2 interacted with FoxM1, and then negatively regulated both FoxM1 and nuclear ß-catenin levels. Additionally, FBXL2 knockdown reversed the effects of miR-346-5p inhibitor. In xenograft models, miR-346-5p knockdown significantly inhibited tumor growth, increased FBXL2 expression, and downregulated the levels of FoxM1 and nuclear ß-catenin. In conclusion, miR-346-5p may promote CRC growth by targeting FBXL2 and activating the ß-catenin signaling pathway. MiR-346-5p may be a novel target in cancer therapy.

Detection of deteriorating patients after Whipple surgery by a modified early warning score (MEWS).

BACKGROUND: The modified early warning score (MEWS) was set up to supply prompt recognition of clinically deteriorating patients before they undergo a severe and life-threatening event. The study aimed to describe the probable usefulness of the MEWS in identifying deteriorating post-Whipple patients in hospital wards. METHODS: We performed a study to analyze the relationship between the vital parameters and postoperative severe adverse events of patients after Whipple surgery in Guangdong Provincial People's Hospital from 2000 to 2017. In the retrospective study, a total of 13,651 sets of vital parameters in 236 Whipple postoperative patients were included. Subsequently, we applied a MEWS scoring system and explored the accuracy of the MEWS in evaluating the patients' final events versus advanced mathematical models. We then put the MEWS into the ward warning system and confirmed the accuracy of the MEWS based on the results of prospective studies again. RESULTS: We assessed the ability of the MEWS to predict postoperative complications with an accuracy rate of 90.86-91.23%, a sensitivity of 83.04-90.88%, and a specificity of 90.85-95.73%. CONCLUSIONS: The MEWS model was applied to identify post-Whipple patients at risk of complication. Once the MEWS ≥2, interventions were needed to minimize the adverse events. Our data suggest that the MEWS is comparable to the advanced mathematical models, but MEWS is more accessible to perform and more generally applicable.

Resistin-Induced Endoplasmic Reticulum Stress Contributes to the Impairment of Insulin Signaling in Endothelium.

Background: Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of obesity, insulin resistance and cardiovascular diseases (CVDs). Impairment of insulin vascular action may represent a mechanism linking insulin resistance and CVDs. The present study tested the hypothesis that adipocyte-derived resistin inhibits insulin-stimulated endothelial NO production through the induction of ER stress. Methods and Results: Human umbilical vein endothelial cells (HUVC) were incubated with tunicamycin (an inducer of ER stress, 1-20 µg/mL) or resistin (10-100 ng/mL) for 1 h. Either tunicamycin or resistin increased GRP78 (an ER stress marker) expression associated with the impairment of insulin-stimulated Akt/eNOS phosphorylation, which were prevented by TUDCA (an ER stress suppressor). Resistin increased reactive oxygen species (ROS) production, antioxidant treatment inhibited resistin-induced GRP78 expression and impairment of insulin Akt/eNOS signaling, suggesting that ROS may involve resistin-induced ER stress. Resistin also increased JNK phosphorylation, which was prevented by TUDCA. JNK inhibitor SP600125 relieved the resistin inhibitory effects on endothelial insulin Akt/eNOS signaling. In ex vivo experiments, the incubation of aortic rings with resistin impaired insulin- but not acetylcholine-induced vasodilation, which was restored by TUDCA. LNAME (a NOS inhibitor) abolished insulin-induced vasorelaxation in the control or the resistin-treated aortic rings. In addition, resistin increased the mRNA expressions of proinflammatory cytokines tumor nuclear factor (TNF)α and interleukin (IL)-1ß, which were also prevented by TUDCA. Conclusion: Our results support the ideal that ER stress may play an important role for resistin impairment of vascular insulin signaling and insulin action. The mitigation of ER stress may represent a new strategy for prevention and treatment of CVDs in obesity and insulin resistant-related diseases.

Macrophage Depletion Lowered Blood Pressure and Attenuated Hypertensive Renal Injury and Fibrosis.

Monocyte/macrophage recruitment is closely associated with the degree of hypertensive renal injury. We investigated the direct role of macrophages using liposome-encapsulated clodronate (LEC) to deplete monocytes/macrophages in hypertensive renal injury. C57BL/6 mice were treated with a pressor dose of angiotensin (Ang, 1.4 mg/kg/day) II plus LEC or the PBS-liposome for 2 weeks. Ang II mice developed hypertension, albuminuria, glomerulosclerosis, and renal fibrosis. LEC treatment reduced systolic blood pressure (SBP), albuminuria, and protected against renal structural injury in Ang II mice. Ang II significantly increased renal macrophage infiltration (MOMA2+ cells) and the expression of renal tumor necrosis factor α and interleukin ß1, which were significantly reduced in Ang II/LEC mice. Ang II increased renal oxidative stress and the expression of profibrotic factors transforming growth factor (TGF) ß1 and fibronectin. Ang II also inhibited the phosphorylation of endothelial nitric oxide synthase [phospho-endothelial nitric oxide synthesis (eNOS), ser1177]. LEC treatment reduced renal oxidative stress and TGFß1 and fibronectin expressions, and increased phospho-eNOS expression in the Ang II mice. In Dahl rats of salt-sensitive hypertension, LEC treatment for 4 weeks significantly attenuated the elevation of SBP induced by high salt intake and protected against renal injury and fibrosis. Our results demonstrate that renal macrophages play a critical role in the development of hypertension and hypertensive renal injury and fibrosis; the underlying mechanisms may be involved in the reduction in macrophage-driven renal inflammation and restoration of the balance between renal oxidative stress and eNOS. Therefore, macrophages should be considered as a potential therapeutic target to reduce the adverse consequences of hypertensive renal diseases.

S1P1 receptor inhibits kidney epithelial mesenchymal transition triggered by ischemia/reperfusion injury via the PI3K/Akt pathway.

Ischemia/reperfusion (I/R) is a major cause of acute kidney injury (AKI), along with delayed graft function, which can trigger chronic kidney injury by stimulating epithelial to mesenchymal transition (EMT) in the kidney canaliculus. Sphingosine 1-phosphate receptor 1 (S1P1) is a G protein-coupled receptor that is indispensable for vessel homeostasis. This study aimed to investigate the influence of S1P1 on the mechanisms underlying I/R-induced EMT in the kidney using in vivo and in vitro models. Wild-type (WT) and S1P1-overexpressing kidney canaliculus cells were subject to hypoxic conditions followed by reoxygenation in the presence or absence of FTY720-P, a potent S1P1 agonist. In vivo, bilateral arteria renalis in wild-type mice and mice with silenced S1P1 were clamped for 30 min to obtain I/R models. We found that hypoxia/reoxygenation (H/R) significantly enhanced the expressions of EMT biomarkers and down-regulated S1P1 expression in wild-type canaliculus cells. In contrast, FTY720-P treatment or overexpression of S1P1 significantly suppressed EMT in wild-type canaliculus cells. Furthermore, after 48-72 h, a significant upregulation of EMT biomarker expression was triggered by I/R in mice with silenced S1P1, while the expressions of these markers did not change in wild-type mice. A kt activity was increased with H/R-induced EMT, suggesting that the protective influence of FTY720-P was due to its inhibition of PI3K/Akt. Therefore, the results of this study provide evidence that down-regulation of S1P1 expression is essential for the generation and progression of EMT triggered by I/R. S1P1 exhibits a prominent inhibitory effect on kidney I/R-induced EMT in the kidney by affecting the PI3K/Akt pathway.

Deguelin induces PUMA-mediated apoptosis and promotes sensitivity of lung cancer cells (LCCs) to doxorubicin (Dox).

As a natural agent for chemotherapy, deguelin remarkably suppresses proliferation in numerous solid cancers. Nevertheless, the molecular mechanisms of its suppression are still insufficient. In our research, it was revealed that deguelin induced cell death of lung cancer cells (LCCs) by triggering expression of PUMA. Deguelin triggered PUMA induction independently of p53 via suppression of PI3K/AKT pathway, therefore stimulating Foxo3a to bind with PUMA promoter and stimulate its transcription. Subsequent to activation, PUMA motivated Bax as well as the intrinsic mitochondrial cell death pathway. Removal of PUMA from LCC cells led to deguelin resistance, suggesting deguelin-induced cell death was modulated by PUMA. Furthermore, we demonstrated that deguelin enhanced the chemotherapeutic sensitivity of doxorubicin in vitro and in vivo, which were associated with potentiated PUMA induction. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of deguelin in lung cancer cells and provide the rationale for clinical evaluation.

Effect of Self-efficacy Intervention on Quality of Life of Patients With Intestinal Stoma.

Colorectal carcinoma is one of the most common malignancies worldwide and the most prevalent cause of cancer mortality in China. The Miles operation and permanent colostomy are effective treatment. However, these affect the quality of life of patients as they alter normal defecation. Self-efficacy is used to define an individuals' assessments of their ability to perform a specific behavior successfully. It is regarded as an important belief that can predict health behaviors. The aim of this study was to explore the effect of a self-efficacy intervention on the quality of life of patients with a permanent colostomy. Forty-eight patients in treatment for permanent colostomy surgery were divided into the control and intervention groups. The control group received routine nursing; the intervention group was exposed to a 3-month self-efficacy intervention, as well as routine nursing. The two groups completed the Chinese version of a self-efficacy questionnaire at 10 days, 1 month, and 3 months after surgery. Three months after surgery, the two groups also completed a quality-of-life questionnaire. There were significant differences in the quality of life between the two groups. The self-efficacy intervention nursing method improved self-efficacy and the quality of life of patients with intestinal stoma and is worthy of clinical utilization and application.

Oral nicotine aggravates endothelial dysfunction and vascular inflammation in diet-induced obese rats: Role of macrophage TNFα.

Obesity and cigarette smoke are major cardiovascular (CV) risk factors and, when coexisting in the same individuals, have additive/synergistic effects upon CVD. We studied the mechanisms involved in nicotine enhancement of CVD in Sprague Dawley rats with diet-induced obesity. The rats were fed either a high fat (HFD) or normal rat chow diet with or without nicotine (100 mg/L in drinking water) for 20 weeks. HFD rats developed central obesity, increased systolic blood pressure (SBP), aortic superoxide (O2-) production, and impaired endothelial nitric oxide synthase (eNOS) and endothelium-dependent relaxation to acetylcholine (EDR). Nicotine further increased SBP, O2- and impaired eNOS and EDR in obese rats. In the peritoneal macrophages from obese rats, tumor necrosis factor (TNF) α, interleukin 1ß and CD36 were increased, and were further increased in nicotine-treated obese rats. Using PCR array we found that 3 of 84 target proinflammatory genes were increased by 2-4 fold in the aorta of obese rats, 11 of the target genes were further increased in nicotine-treated obese rats. HUVECs, incubated with conditioned medium from the peritoneal macrophages of nicotine treated-obese rats, exhibited reduced eNOS and increased NADPH oxidase subunits gp91phox and p22phox expression. Those effects were partially prevented by adding anti-TNFα antibody to the conditioned medium. Our results suggest that nicotine aggravates the CV effects of diet-induced obesity including the oxidative stress, vascular inflammation and endothelial dysfunction. The underlying mechanisms may involve in targeting endothelium by enhancement of macrophage-derived TNFα.

FoxO3a plays a key role in the protective effects of pomegranate peel extract against amikacin-induced ototoxicity.

The use of amikacin (AMK) in present treatment strategies results in severe ototoxicity; however, the underlying molecular mechanisms of this toxicity remain unclear. In this study, we investigated the effectiveness of orally administered pomegranate peel extract (PPE), a strong antioxidant, as a protective agent against AMK-induced ototoxicity. To this end, PPE was orally administered to adult BALB/c mice for 5 days, and the mice were then concurrently treated with AMK (500 mg/kg/day for 15 consecutive days). Auditory threshold shifts induced by AMK were significantly attenuated. The results of immunohistochemical staining and western blot analysis revealed that PPE exerted its protective effects by by downregulating the phosphorylation of Forkhead box O3a (FoxO3a), an important transcription factor which is involved in the responses to oxidative stress. The results also showed that PPE treatment inhibited mitogen-activated protein kinase phosphorylation, prevented the activation of pro-apoptotic protein caspase-3, decreased the levels of apoptosis-inducing Bax protein, and increased the levels of the anti-apoptotic mediator, Bcl-2, induced by AMK in the mouse cochlea. Taken together, our experimental findings suggest that phosphorylated FoxO3a mediates AMK-induced apoptosis in BALB/c mice cochlea. PPE effectively attenuated oxidative stress and ototoxicity by regulating FoxO3a, and may thus prove to be beneficial in protecting auditory cells from ototoxic drugs.

Puerarin protects against endothelial dysfunction and end-organ damage in Ang II-induced hypertension.

Puerarin, a major isoflavonoid compound from Chinese herb Kudzu roots, has been widely used for the treatment of hypertensive and cardiovascular diseases in China. Here, we investigated puerarin's beneficial effects on the cardiovascular system in angiotensin (Ang) II-induced hypertensive rats. Sprague-Dawley rats were treated with Ang II for 5 days or with puerarin for 10 days followed by Ang II and puerarin for 5 days. Endothelium-dependent relaxation (EDR) to acetylcholine was determined using an organ chamber bath. Ang II increased the systolic blood pressure (SBP: 178 ± 5 mmHg vs. 112 ± 3 mmHg in control, p < 0.05), aortic (30%, p < 0.05), and left ventricular (LV) weight (23%); puerarin reduced SBP (160 ± 2 mmHg, p < 0.05), aortic, and left ventricular weight in Ang II-infused rats. Puerarin also reduced aortic medial thickness and myocardial cell surface area in Ang II-infused rats. Compared with control rats, Ang II infused rats exhibited an impaired EDR with reduction in the protein expression of phosphor-eNOS at Ser 1177 and an increase in the expression of gp91phox (85%), p22phox (113%), transforming growth factor ß1 (145%) and vascular cell adhesion molecule 1 (82%). Puerarin improved EDR and reversed the changes in Ang II-induced protein expression of above molecules. Our results demonstrate that in Ang II-induced hypertensive rats, puerarin protects against endothelial dysfunction and end organ damage with a mild reduction in SBP, and that the cardiovascular beneficial effects of puerarin may be in part attributed to its anti-oxidant and upregulation of phosphor-eNOS.

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension.

The cardioprotective benefits of aldehyde dehydrogenase 2 (ALDH2) are well established, although the regulatory role of ALDH2 in vascular remodeling in pulmonary arterial hypertension (PAH) is largely unknown. ALDH2 potently regulates the metabolism of aldehydes such as 4-hydroxynonenal (4-HNE), the endogenous product of lipid peroxidation. Thus, we hypothesized that ALDH2 ameliorates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting 4-HNE accumulation and regulating downstream signaling pathways, thereby ameliorating pulmonary vascular remodeling. We found that low concentrations of 4-HNE (0.1 and 1µM) stimulated cell proliferation by enhancing cyclin D1 and c-Myc expression in primary HPASMCs. Low 4-HNE concentrations also enhanced cell migration by activating the nuclear factor kappa B (NF-κB) signaling pathway, thereby regulating matrix metalloprotein (MMP)-9 and MMP2 expression in vitro. In vivo, Alda-1, an ALDH2 agonist, significantly stimulated ALDH2 activity, reducing elevated 4-HNE and malondialdehyde levels and right ventricular systolic pressure in a monocrotaline-induced PAH animal model to the level of control animals. Our findings indicate that 4-HNE plays an important role in the abnormal proliferation and migration of HPASMCs, and that ALDH2 activation can attenuate 4-HNE-induced PASMC proliferation and migration, possibly by regulating NF-κB activation, in turn ameliorating vascular remodeling in PAH. This mechanism might reflect a new molecular target for treating PAH.

[Effect of cisplatin on apoptosis of spiral ganglion cell and expression of caspase-3 in mouse cochlea].

OBJECTIVE: To establish a mice model of cisplatin-induced ototoxicity, and to investigate the effect of cisplatin on apoptosis of spiral ganglion cell and expression of caspase-3 in mouse cochlea. METHODS: Terminal deoxynucleotidyl transferase-mediated nick end labeling method (TUNEL) was used to monitor the apoptosis of spiral ganglion cell. Envision method of immunohistochemistry was applied to detect the expression of caspase-3 in cochlea. Auditory brainstem response (ABR) was measured to observe the change of hearing. RESULTS: The weight and hearing of mice in different dose of cisplatin groups were declined significantly as compared with those of control group (P < 0.05, P < 0.01), and the TUNEL positive cell number and expression of caspase-3 were greater remarkably with the more cisplatin injected. CONCLUSION: A mouse model of cisplatin-induced ototoxicity can be established. Cisplatin can lead to the apoptosis of spiral ganglion cells, and caspase-3 has participated in this apoptosis process, which approves further that apoptosis might be one of the mechanisms of cisplatin ototoxicity.