Cardiomyocyte-specific Peli1 contributes to the pressure overload-induced cardiac fibrosis through miR-494-3p-dependent exosomal communication.

Cardiac fibrosis is an essential pathological process in pressure overload (PO)-induced heart failure. Recently, myocyte-fibroblast communication is proven to be critical in heart failure, in which, pathological growth of cardiomyocytes (CMs) may promote fibrosis via miRNAs-containing exosomes (Exos). Peli1 regulates the activation of NF-κB and AP-1, which has been demonstrated to engage in miRNA transcription in cardiomyocytes. Therefore, we hypothesized that Peli1 in CMs regulates the activation of cardiac fibroblasts (CFs) through an exosomal miRNA-mediated paracrine mechanism, thereby promoting cardiac fibrosis. We found that CM-conditional deletion of Peli1 improved PO-induced cardiac fibrosis. Moreover, Exos from mechanical stretch (MS)-induced WT CMs (WT MS-Exos) promote activation of CFs, Peli1-/- MS-Exos reversed it. Furthermore, miRNA microarray and qPCR analysis showed that miR-494-3p was increased in WT MS-Exos while being down regulated in Peli1-/- MS-Exos. Mechanistically, Peli1 promoted miR-494-3p expression via NF-κB/AP-1 in CMs, and then miR-494-3p induced CFs activation by inhibiting PTEN and amplifying the phosphorylation of AKT, SMAD2/3, and ERK. Collectively, our study suggests that CMs Peli1 contributes to myocardial fibrosis via CMs-derived miR-494-3p-enriched exosomes under PO, and provides a potential exosomal miRNA-based therapy for cardiac fibrosis.

Disturbing NLRP3 acetylation and inflammasome assembly inhibits androgen receptor-promoted inflammatory responses and prostate cancer progression.

Chronic inflammation is one of the definite factors leading to the occurrence and development of tumors, including prostate cancer (PCa). The androgen receptor (AR) pathway is essential for PCa tumorigenesis and inflammatory response. However, little is known about the AR-regulated NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome pathway in human PCa. In this study, we explored the expression of inflammatory cytokine and AR in high-grade PCa and observed that NLRP3 inflammasome-associated genes were upregulated in high-grade PCa compared with that in low-grade PCa and benign prostatic hyperplasia and were associated with AR expression. In addition, we identified circAR-3-a circRNA derived from the AR gene-which is involved in the AR-regulated inflammatory response and cell proliferation by activating the NLRP3 inflammatory pathway. While circAR-3 overexpression promoted cell proliferation and the inflammatory response, its depletion induced opposite effects. Mechanistically, we noted that circAR-3 mediated the acetylation modification of NLRP3 by KAT2B and then promoted NLRP3 inflammasome complex subcellular distribution and assembly. Disturbing NLRP3 acetylation or blocking inflammasome assembly with an inhibitor suppressed the progression of PCa xenograft tumors. Our findings provide the first evidence that targeting NLRP3 acetylation or inflammasome assembly may be effective in inhibiting PCa progression.

Identification and Mutation Analysis of Nonconserved Residues on the TIM-Barrel Surface of GH5_5 Cellulases for Catalytic Efficiency and Stability Improvement.

Exploring the potential functions of nonconserved residues on the outer side of α-helices and systematically optimizing them are pivotal for their application in protein engineering. Based on the evolutionary structural conservation analysis of GH5_5 cellulases, a practical molecular improvement strategy was developed. Highly variable sites on the outer side of the α-helices of the GH5_5 cellulase from Aspergillus niger (AnCel5A) were screened, and 14 out of the 34 highly variable sites were confirmed to exert a positive effect on the activity. After the modular combination of the positive mutations, the catalytic efficiency of the mutants was further improved. By using CMC-Na as the substrate, the catalytic efficiency and specific activity of variant AnCel5A_N193A/T300P/D307P were approximately 2.0-fold that of AnCel5A (227 ± 21 versus 451 ± 43 ml/s/mg and 1,726 ± 19 versus 3,472 ± 42 U/mg, respectively). The half-life (t1/2) of variant AnCel5A_N193A/T300P/D307P at 75°C was 2.36 times that of AnCel5A. The role of these sites was successfully validated in other GH5_5 cellulases. Computational analyses revealed that the flexibility of the loop 6-loop 7-loop 8 region was responsible for the increased catalytic performance. This work not only illustrated the important role of rapidly evolving positions on the outer side of the α-helices of GH5_5 cellulases but also revealed new insights into engineering the proteins that nature left as clues for us to find. IMPORTANCE A comprehensive understanding of the residues on the α-helices of the GH5_5 cellulases is important for catalytic efficiency and stability improvement. The main objective of this study was to use the evolutionary conservation and plasticity of the TIM-barrel fold to probe the relationship between nonconserved residues on the outer side of the α-helices and the catalytic efficiency of GH5_5 cellulases by conducting structure-guided protein engineering. By using a four-step nonconserved residue screening strategy, the functional role of nonconserved residues on the outer side of the α-helices was effectively identified, and a variant with superior performance and capability was constructed. Hence, this study proved the effectiveness of this strategy in engineering GH5_5 cellulases and provided a potential competitor for industrial applications. Furthermore, this study sheds new light on engineering TIM-barrel proteins.

Cd-Based Metal-Organic Framework for Selective Turn-On Fluorescent DMSO Residual Sensing.

Dimethyl sulfoxide (DMSO) is a universally used solvent in various synthetic reactions, and trace amounts of DMSO residual are often seen on the surface of chemical product. It is difficult to quickly determine whether the residual DMSO is washed completely. This work reports a CdII metal-organic framework (MOF) SXU-4 which can detect trace amounts of DMSO in various solvents. Fluorescence experiments reveal its turn-on fluorescence effect toward DMSO with high selectivity and sensitivity, indicating that it can be used as an effective luminescent probe for rapid chemical product purity detection by testing the washing solution. Crystallographically characterized DMSO loaded SXU-4 (DMSO@SXU-4), in combination with computational results uncover that the enhanced DMSO-MOF conjugation through multiple DMSO-MOF supramolecule interactions and charge rearrangement are the main causes of fluorescence intensification.

Recent advances in the contribution of circRNAs to cisplatin chemotherapy resistance in cancers.

Worldwide, cancer is a serious threat to the health of citizens of every country, with the incidence and mortality increasing year by year. Cisplatin is the first-line anticancer drug commonly used in clinics and is widely used for the treatment of solid tumors including lung, gastric, liver, bladder, and ovarian cancer. Although cisplatin-based chemotherapy has a high clinical response efficacy, patients will inevitably develop drug resistance after repeated use, leading to severe restrictions of its application. Circular RNAs (circRNAs) are a promising class of non-coding RNAs capable of promoting or suppressing cancer via functioning as miRNAs sponges. Recently, an increasing amount of evidence shows that circRNAs are closely related to the cisplatin resistance of cancers. Therefore, standing at the perspective of the cisplatin chemotherapy resistance, this paper reviews the research progress of circRNAs related to cisplatin resistance of various cancers.

Effect of IL-15-Mediating IFN-γ on HTR-8/SVneo Cells and a Preeclampsia Mouse Model Induced by Lipopolysaccharides.

OBJECTIVE: Determine the effect of interleukin (IL)-15 on HTR-8/SVneo cells and a preeclampsia (PE) mouse model induced by LPS. METHODS: Transwell and Annexin-V-FITC/PI assays were performed in HTR-8/SVneo cells transfected with IL-15 activation plasmid/siRNA prior to LPS treatment. Additionally, pregnant mice were injected with LPS and IL-15 siRNA followed by measurement of systolic blood pressure (SBP), urine protein, and serum NO. HE staining was used to observe the morphological changes of the placenta and kidney. Glycogen accumulation was detected using Best's carmine. qRT-PCR, Western blotting, and ELISA were performed to detect mRNA and protein expression. RESULTS: LPS increased IL-15 and IFN-γ expression in HTR-8/SVneo cells, and IL-15 positively regulated IFN-γ expression in LPS-induced HTR-8/SVneo cells. Moreover, LPS promoted apoptosis and reduced the invasion and migration of HTR-8/SVneo cells, which was, further, promoted by IL-15 overexpression but attenuated by IL-15 inhibition. Furthermore, LPS increased SBP and urine protein but decreased serum NO in mice, and these factors were reversed by IL-15 siRNA. Downregulation of IL-15 also mitigated kidney injury and improved pregnancy outcomes in LPS-induced PE mice. A significantly thicker junctional zone (JZ) and thinner labyrinth layer were found in placentas of PE mice treated with IL-15 siRNA, along with increased glycogen trophoblast cells in the JZ. Moreover, decreased IFN-γ and NKp46 were found in placentas of PE mice treated with IL-15 siRNA. CONCLUSION: IL-15 inhibition reduced cell apoptosis and increased the invasive and migratory abilities of LPS-induced HTR-8/SVneo cells, thereby alleviating the PE-like phenotype and improving pregnancy outcome.

Suicide Prevention for Local Public and Volunteer Relief Workers in Disaster-Affected Areas.

OBJECTIVES: Local workforces play a critical role in disaster relief and reconstruction. However, the mental health of local relief workers might be affected by disasters, threatening the sustainability of local workforces. In this study, we tried to address this concern by investigating the well-being of local relief workers and its association with suicidal ideation. DESIGN: A retrospective study was conducted. Surveys were designed to collect data from a purposive sample of local disaster relief workers who survived a disaster. Binary logistic regression analysis was performed to test hypotheses. SETTING AND PARTICIPANTS: The study sample was from a population of local relief workers in the worst quake-hit regions in China in 2008. The respondents were local relief workers from a town in these regions. All of the 83 local relief workers were invited 11 months after the earthquake, and 70 joined the study, resulting in a response rate of 84.3%. MAIN OUTCOME MEASURES: The dependent variable was postdisaster suicidal ideation. The independent variables were bereavement, depression and posttraumatic stress, daily work hours, job burnout, work-family conflict, and work engagement. RESULTS: Approximately 21.4% of participants reported suicidal ideation after the earthquake in comparison with 7.1% before the earthquake. One potential risk factor was an interaction effect of job burnout and work-family conflict (odds ratio [OR] = 3.738; 95% confidence interval [CI], 1.086-12.868). Potential protective factors included daily work hours (OR = 0.317; 95% CI, 0.106-0.952) and work engagement (OR = 0.297; 95% CI, 0.091-0.969). CONCLUSIONS: Findings suggest that for local relief workers who are also disaster survivors, meaningful engagement such as participation in disaster relief could be salutary to their mental health, but overwork and interference with personal life could be harmful and increase the risk of suicidal ideation. Discretion is needed in managing local workforces, particularly with long work hours and work-family balance.

Vitrification-enabled enhancement of proton conductivity in hydrogen-bonded organic frameworks.

Hydrogen-bonded organic frameworks (HOFs) are versatile materials with potential applications in proton conduction. Traditional approaches involve incorporating humidity control to address grain boundary challenges for proton conduction. This study finds vitrification as an alternative strategy to eliminate grain boundary effect in HOFs by rapidly melt quenching the kinetically stable HOF-SXU-8 to glassy state HOF-g. Notably, a remarkable enhancement in proton conductivity without humidity was achieved after vitrification, from 1.31 × 10-7 S cm-1 to 5.62× 10-2 S cm-1 at 100 °C. Long term stability test showed negligible performance degradation, and even at 30 °C, the proton conductivity remained at high level of 1.2 × 10-2 S cm-1. Molecule dynamics (MD) simulations and X-ray total scattering experiments reveal the HOF-g system is consisted of three kinds of clusters, i.e., 1,5-Naphthalenedisulfonic acid (1,5-NSA) anion clusters, N,N-dimethylformamide (DMF) molecule clusters, and H+-H2O clusters. In which, the H+ plays an important role to bridge these clusters and the high conductivity is mainly related to the H+ on H3O+. These findings provide valuable insights for optimizing HOFs, enabling efficient proton conduction, and advancing energy conversion and storage devices.

TREM2 as an independent predictor of poor prognosis promotes the migration via the PI3K/AKT axis in prostate cancer.

OBJECTIVE: Prostate adenocarcinoma (PRAD) is one of the most common cancers, with high morbidity and mortality. Triggering receptors expressed on myeloid cells 2 (TREM2) is upregulated in various malignancies, however its effect on PRAD remains unknown. This study aimed to investigate the prognostic value of TREM2 in PRAD. METHODS: PRAD samples were collected from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), Oncomine, and the Human Protein Atlas (HPA) to analyze the differences in TREM2 expression between normal and tumor tissues. The influence of TREM2 on the clinicopathological characteristics and its prognostic value were evaluated using the Kaplan-Meier curve, Cox regression analysis, ROC (receiver operating characteristic) plot, and nomogram. Gene Ontology (GO), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) were conducted to screen biological functions and pathways. The relationship between TREM2 and tumor microenvironment (TME) characteristics was explored. The TREM2 expression in PRAD specimens and cell lines was assessed by immunohistochemistry staining and western blot. TREM2-specific siRNAs were used to evaluate the effects of TREM2 on cell function. RESULTS: TREM2 was upregulated and positively associated with poor clinicopathologic characteristics. Overexpression of TREM2 is an independent biomarker for the prognosis of PFI (progression-free interval). Moreover, TREM2 expression was positively correlated with various TME characteristics. Knockdown of TREM2 inhibited the migration of PRAD cell lines via the PI3K/AKT axis. CONCLUSION: High TREM2 expression may represent a novel diagnostic and prognostic biomarker and serve as a potential target gene for PRAD therapy.

SF3B4 promotes Twist1 expression and clear cell renal cell carcinoma progression by facilitating the export of KLF 16 mRNA from the nucleus to the cytoplasm.

Splicing factor 3B subunit 4 (SF3B4) plays important functional roles not only in pre-mRNA splicing, but also in the regulation of transcription, translation, and cell signaling, and its dysregulation contributes to various diseases including Nager syndrome and tumorigenesis. However, the role of SF3B4 and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) remain obscure. In the present study, we found that the expression of SF3B4 was significantly elevated in ccRCC tissues and negatively correlated with the overall survival of ccRCC patients. Upregulation of SF3B4 promotes migration and invasion of ccRCC cells in vitro and in vivo. The promoting effect of SF3B4 on cell migration and invasion is mediated by Twist1, a key transcription factor to mediate EMT. Interestingly, SF3B4, a component of the pre-mRNA spliceosome, is able to promote KLF16 expression by facilitating the transport of KLF16 mRNA into the cytoplasm. Mechanistically, SF3B4 promotes the export of KLF16 mRNA from the nucleus to the cytoplasm and thus enhances KLF16 expression, and in turn elevated KLF16 directly binds to the Twist1 promoter to activate its transcription, leading to EMT and ccRCC progression. Our findings provide evidence that the SF3B4-KLF16-Twist1 axis plays important functional roles in the development and progression of ccRCC, and manipulating this pathway may be a novel therapeutic target for the treatment of ccRCC.

Confirmatory factor analysis of the stagnation scale--a traditional Chinese medicine construct operationalized for mental health practice.

BACKGROUND: Traditional Chinese medicine stagnation ("yu") syndrome is characterized by a cluster of mind/body obstruction-like symptoms. Previous studies have operationalized the concept as a psychological construct through scale development, producing a three-factor 16-item inventory with good psychometric properties. PURPOSE: The study aimed to further validate the Stagnation Scale by confirmatory factor analysis (CFA) and examine self-appraisal of stagnation as an illness. METHOD: A cross-sectional questionnaire survey was conducted on a random community sample of 755 adults recruited by cluster sampling in Hong Kong. RESULTS: CFA revealed a good fit of the three-factor model (CFI = .95; RMSEA = .077; SRMR = .043). ROC analysis suggested a cutoff score at 50 on stagnation total score for predicting self-appraisal of an illness condition, with false positive and negative rates at 25.8% and 23.3%, respectively. Overall, 6.2% participants self-appraised to suffer stagnation symptoms to a degree of an illness, and for it, 1.9% participants intended to seek treatment. Stagnation showed positive correlations with physical distress, depression, and anxiety (r = .59-.76, p < .01) and negative correlation with age (r = -.22, p < .01). CONCLUSION: The Stagnation Scale appeared to be robust in factorial and construct validity. With prevalence of illness by self-appraisal at 6.2% and intention for treatment at 1.9%, stagnation is a fairly common condition associated with treatment-seeking behaviors.

Therapeutic Potential of Superoxide Dismutase Fused with Cell- Penetrating Peptides in Oxidative Stress-Related Diseases.

Superoxide dismutase (SOD) is a well-known cellular antioxidant enzyme. However, exogenous SOD cannot be used to protect tissues from oxidative damage due to the low permeability of the cell membrane. Cell-penetrating peptides (CPPs) are a class of short peptides that can cross the cell membrane. Recombinant fusion protein that fuses SOD protein with CPP (CPP-SOD) can cross various tissues and organs as well as the blood-brain barrier. CPP-SODs can relieve severe oxidative damage in various tissues caused by radiation, ischemia, inflammation, and chemotherapy by clearing the reactive oxygen species, reducing the expression of inflammatory factors, and inhibiting NF-κB/MAPK signaling pathways. Therefore, the clinical application of CPP-SODs provides new therapeutic strategies for a variety of oxidative stress-related disorders, such as Parkinson's disease, diabetes, obesity, cardiac fibrosis, and premature aging.

Silybin B exerts protective effect on cisplatin-induced neurotoxicity by alleviating DNA damage and apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Silybum marianum is a traditional Chinese medicine that has been used for treating liver disease. Silybin consisting of silybin A and silybin B, is a member of Silybum marianum, and exerts a therapeutic effect on many diseases. However, the protective effect of silybin on cisplatin-induced neurotoxicity and the stereoisomer contributing to the effect remain unknown. AIM OF THE STUDY: The present study aimed to study the effect of silybin on cisplatin-induced neuronal injury, compare the difference of protective effect between silybin A and silybin B, and the potential mechanism. MATERIALS AND METHODS: High performance liquid chromatography (HPLC) was used to separate silybin A and silybin B. X-ray crystallographic analysis in combination with experimental and calculated ECD were performed to identify the structure of silybin A and silybin B. The toxicity of the silybin or cisplatin against murine hippocampal neuronal HT22 cells was determined through MTT assay. The cell cycle and cell apoptosis were measured by PI staining and Annexin V-FITC/PI staining, respectively, and then subjected to flow cytometry. Western blot analysis was conducted to quantify the expression of proteins related to apoptosis and DNA damage. Immunofluorescence was used to evaluate the expression of DNA damage marker. In vivo experiment, the behavioral analysis was determined through pole test, swimming test and Morris water maze test. The index of superoxide dismutase (SOD), reduced glutathione (GSH), total antioxidant capacity (T-AOC) and lipid peroxidation (LPO) were examined to evaluate the antioxidant capacity in mice brain. Nissl staining and Tunel assay were used to detect the neuronal viability and apoptosis in hippocampus. RESULTS: We successfully separated and identified silybin A and silybin B. We found both silybin A and silybin B alleviated cisplatin-induced apoptosis and cell cycle arrest in HT22 cells, and silybin B was more effective. We chose silybin B for further mechanism investigation, and found silybin B alleviated DNA damage by enhancing phosphorylation of ATR and decreasing expression of γ-H2AX. In the in vivo experiment, we observed that silybin B markedly improved the behavioral abnormalities in cisplatin-treated mice, reduced LPO level while increased SOD, GSH and T-AOC in mice brain tissue. Nissl staining and Tunel assay showed that silybin B alleviated cisplatin-induced hippocampal damage. CONCLUSIONS: These results suggest that silybin B might serve as a promising drug candidate in mitigating cisplatin-induced neural injury in the brain and thereby improving the chemotherapeutic outcomes.

The role of holistic care culture in mitigating burnout and enhancing engagement: a study among elderly service workers in Hong Kong.

OBJECTIVES: Elderly service work is a labor intensive and emotion demanding occupation. Workers in this field are prone to burnout, a form of emotional exhaustion at work. While their job well-being is associated with a number of job demands, little research has been done in exploring job resources to promote their well-being. Holistic care culture (HCC) was proposed as an organizational culture of holistic caring. This study explored the role of HCC in predicting job well-being and moderating the impact of perceived stress on job well-being. METHOD: A large-scale questionnaire survey was conducted among 992 elderly service workers of a major social service organization in Hong Kong, with a 93% response rate. Participants completed a standardized self-report questionnaire. RESULTS: Structural equation modeling found HCC negatively predicted burnout (ß = -0.32, p < 0.01) and positively predicted engagement (ß = 0.36, p < 0.01). HCC showed significant moderating on the relationship between perceived stress and job well-being in expected directions. The model explained 53.7% and 35.8% of variance in burnout and engagement. CONCLUSION: Findings from this study provides supportive evidence for HCC as a moderator to ameliorate burnout and facilitate engagement among elderly service workers. Further studies of rigorous design on HCC are recommended. Implication of this study for organizational practice was discussed.

Sustaining engagement through work in postdisaster relief and reconstruction.

After the devastating 2008 earthquake in China, grass-roots government officials were the main local force in postquake relief and reconstruction. Like other survivors, many officials were severely bereaved. Their psychological well-being was at stake. We conducted 25 semistructured interviews to investigate sources of stress at work and their coping experiences. We coded interviews using the content analysis method. Misunderstandings and assaults from survivors, prolonged heavy workload, and grief and bereavement were major sources of stress at work. Finding meaning in the work, emotion regulation, and goal and time management were main coping strategies. The challenge and importance of the work, combined with support and recognition at work, fostered an empowering work environment. Few interviewees reported fatigue, whereas the majority displayed dedication to work, indicating a status of work engagement more than burnout among grass-roots officials. Implications of a meaning-oriented empowerment approach to stress management for disaster relief forces are drawn.

[Expression and clinical significance of constitutive androstane receptor in placental syntrophoblast of intrahepatic cholestasis of pregnancy].

OBJECTIVE: To explore the expression and clinical significance of constitutive androstane receptor (CAR) in placenta syntrophoblast from patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: Placenta were collected from women with ICP who delivered from April 2009 to March 2010 in First Affiliated Hospital of Chongqing Medical University. According to the severity of ICP, patients were classified into mild ICP group (n = 10) and severe ICP group (n = 10). Ten healthy pregnant women who delivered in the same period were chosen as control group. The location of CAR protein in placenta was studied by immunohistochemical streptavidin-biotin complex (SABC) method. CAR mRNA level was determined by reverse transcription (RT)-PCR technique and CAR protein expression level was determined by western blot. RESULTS: (1) CAR was located in the placenta syncytiotrophoblastic cells in control group and mild ICP group, showed light tan when stained, and was mainly in the cytoplasm. In severe ICP group, CAR was also located in placenta syncytiotrophoblastic cells but mainly in the nucleolus, showed dark tan when stained. (2) The mRNA expressions of CAR in control group, mild ICP group, severe ICP group were 0.06 ± 0.03, 0.07 ± 0.03 and 0.56 ± 0.03, respectively. CAR in severe ICP group was significantly higher than those in control group and mild ICP group (P < 0.05). The difference of mRNA between control group and mild ICP group was not statistically significant (P > 0.05). (3) The CAR protein levels in control group, mild ICP group, severe ICP group were 0.74 ± 0.03, 0.79 ± 0.03 and 1.02 ± 0.04, respectively. CAR protein expression in the severe ICP group was significantly higher than the other two groups (P < 0.05). And there was no statistical significance between mild group and control group (P > 0.05). CONCLUSION: In ICP women, especially severe ICP patients, the CAR expression in placenta syncytiotrophoblastic cells increased appreciably, which may be involved in the maintenance of placenta barrier function and protection in ICP pathogenesis.

Protection against chemotherapy- and radiotherapy-induced side effects: A review based on the mechanisms and therapeutic opportunities of phytochemicals.

BACKGROUND: Although great achievements have been made in the field of cancer therapy, chemotherapy and radiotherapy remain the mainstay cancer therapeutic modalities. However, they are associated with various side effects, including cardiocytotoxicity, nephrotoxicity, myelosuppression, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, mucositis, and alopecia, which severely affect the quality of life of cancer patients. Plants harbor a great chemical diversity and flexible biological properties that are well-compatible with their use as adjuvant therapy in reducing the side effects of cancer therapy. PURPOSE: This review aimed to comprehensively summarize the molecular mechanisms by which phytochemicals ameliorate the side effects of cancer therapies and their potential clinical applications. METHODS: We obtained information from PubMed, Science Direct, Web of Science, and Google scholar, and introduced the molecular mechanisms by which chemotherapeutic drugs and irradiation induce toxic side effects. Accordingly, we summarized the underlying mechanisms of representative phytochemicals in reducing these side effects. RESULTS: Representative phytochemicals exhibit a great potential in reducing the side effects of chemotherapy and radiotherapy due to their broad range of biological activities, including antioxidation, antimutagenesis, anti-inflammation, myeloprotection, and immunomodulation. However, since a majority of the phytochemicals have only been subjected to preclinical studies, clinical trials are imperative to comprehensively evaluate their therapeutic values. CONCLUSION: This review highlights that phytochemicals have interesting properties in relieving the side effects of chemotherapy and radiotherapy. Future studies are required to explore the clinical benefits of these phytochemicals for exploitation in chemotherapy and radiotherapy.

Protective Effect of Penetratin Analogue-Tagged SOD1 on Cisplatin-Induced Nephrotoxicity through Inhibiting Oxidative Stress and JNK/p38 MAPK Signaling Pathway.

Copper/zinc superoxide dismutase (SOD1) can clear cisplatin- (CP-) induced excessive reactive oxygen species (ROS), but exogenous SOD1 cannot enter cells because of its low biomembrane permeability. Cell-penetrating peptides (CPPs) can rapidly cross plasma membranes. This study is aimed at identifying an efficient and stable CPP-SOD1 and investigating its effects on CP-induced nephrotoxicity. We recombined SOD1 with 14 different CPPs and purified them using an NTA-Ni2+ column. In in vitro experiments, CPPs-SOD1 cell membrane penetration ability and JNK/p38 MAPK signaling pathway were evaluated using Western blotting. ROS production, mitochondrial membrane potential (MMP), and cell apoptosis were determined using flow cytometry and immunofluorescence staining in VERO and HK-2 cells. For in vivo experiments, mice were administered PSF-SOD1 for 2 h before cotreatment with a single CP injection for an additional 4 days. Blood and kidney samples were collected for renal function assessment (creatinine, urea nitrogen, histopathology, TUNEL assay, and JNK/p38 MAPK signaling pathway). Compared with TAT-SOD1, we found that PSF-SOD1 is more efficient at crossing the cell membrane and is stable after transduction into cells. Pretreatment with PSF-SOD1 inhibited CP-induced apoptosis, ROS generation, and JNK/p38 MAPK activation and restored CP-induced MMP loss in VERO and HK-2 kidney cells. Treatment of mice with PSF-SOD1 inhibited CP-induced serum creatinine, blood urea nitrogen elevation, and JNK/p38 MAPK activation. H&E staining and TUNEL assay indicated that kidney tissue damage was alleviated following PSF-SOD1 pretreatment. Overall, PSF-SOD1 ameliorated CP-induced renal damage by partially reducing oxidative stress and cell apoptosis by regulating JNK/p38 MAPK signaling pathway and might be a better cytoprotective agent than TAT-SOD1.