Marein Alleviates Doxorubicin-Induced Cardiotoxicity through FAK/AKT Pathway Modulation while Potentiating its Anticancer Activity.

Doxorubicin (DOX) is an effective anticancer agent, yet its clinical utility is hampered by dose-dependent cardiotoxicity. This study explores the cardioprotective potential of Marein (Mar) against DOX-induced cardiac injury and elucidates underlying molecular mechanisms. Neonatal rat cardiomyocytes (NRCMs) and murine models were employed to assess the impact of Mar on DOX-induced cardiotoxicity (DIC). In vitro, cell viability, oxidative stress were evaluated. In vivo, a chronic injection method was employed to induce a DIC mouse model, followed by eight weeks of Mar treatment. Cardiac function, histopathology, and markers of cardiotoxicity were assessed. In vitro, Mar treatment demonstrated significant cardioprotective effects in vivo, as evidenced by improved cardiac function and reduced indicators of cardiac damage. Mechanistically, Mar reduced inflammation, oxidative stress, and apoptosis in cardiomyocytes, potentially via activation of the Focal Adhesion Kinase (FAK)/AKT pathway. Mar also exhibited an anti-ferroptosis effect. Interestingly, Mar did not compromise DOX's efficacy in cancer cells, suggesting a dual benefit in onco-cardiology. Molecular docking studies suggested a potential interaction between Mar and FAK. This study demonstrates Mar's potential as a mitigator of DOX-induced cardiotoxicity, offering a translational perspective on its clinical application. By activating the FAK/AKT pathway, Mar exerts protective effects against DOX-induced cardiomyocyte damage, highlighting its promise in onco-cardiology. Further research is warranted to validate these findings and advance Mar as a potential adjunctive therapy in cancer treatment.

Analysis of vasoactive and oxidative stress indicators for evaluating the efficacy of continuous positive airway pressure, and relation of vasoactive and oxidative stress indicators and cardiac function in obstructive sleep Apnea Syndrome patients.

Background: Obstructive Sleep Apnea Syndrome (OSAS) is a breathing disorder during sleep. The work was to evaluate the relationship between vasoactive and oxidative stress indicators and cardiac function in Obstructive Sleep Apnea Syndrome (OSAS) patients. Methods: OSAS patients (n=120) were treated with CPAP from May 2021 to June 2022. According to the clinical efficacy, the patients were divided into effective and ineffective groups. Vasoactive factors and oxidative stress indices were compared between the two groups to evaluate their clinical efficacy. The changes in cardiac function indices in the two groups were tested, and the correlation between vasoactive factors and oxidative stress indices and cardiac function was analysed. Results: The effective rate of CPAP was 63.33% (76/120). Ang II, ET-1, and MDA levels were lower, and the SOD level was higher in the effective group than in the ineffective group after treatment. The AUC of the four indicators was all greater than 0.75. LPWT and IVST values of the effective group were lower than the ineffective group. A positive correlation was identified between the levels of Ang II, ET-1, and MDA with LPWT, between levels of ET-1 and MDA with IVST, and a negative correlation between SOD with LPWT and IVST. Conclusions: CPAP treatment can effectively improve vascular activity and reduce the oxidative stress response in OSAS patients, and the combined detection of vasoactive factors and oxidative stress indicators is valuable for evaluating the efficacy of CPAP and is related to the cardiac function of patients.

Neuroprotective effect of ketamine and sevoflurane against TNF-α induced cognitive impairment.

In the present study, neuroprotective effect of sevoflurane in combination with ketamine was investigated on TNF-α induced necroptosis of neurons and cognitive impairment in the rat model. The results demonstrated that exposure to TNF-α/z-VAD led to a significant decrease in viability of HT-22 neuronal cells. However, incubation of HT-22 cells with ketamine plus sevoflurane inhibited decrease in viability induced by TNF-α/z-VAD exposure. The increase in production of ROS by TNF-α/z-VAD exposure in HT-22 cells was effectively suppressed on pre-treatment with ketamine plus sevoflurane. Moreover, suppression of TNF-α/z-VAD induced ROS production in HT-22 cells by ketamine plus sevoflurane pretreatment was higher in comparison to ketamine or sevoflurane treatment alone. Treatment of HT-22 cells with ketamine plus sevoflurane suppressed TNF-α/z-VAD induced increase in RIP1 and p-MLKL protein expression. Ketamine plus sevoflurane treatment effectively reversed decrease in movement speed as well as total distance traveled in TNF-α injected rats. The number of neurons in rat hippocampus injected with TNF-α showed a significant decrease more specifically in carbonic anhydrase-3 region. However, no significant change in the density of neurons was observed in the hippocampus of rats pretreated with ketamine plus sevoflurane by TNF-α injection. The increase in expression of p-MLKL and p-RIP3 by TNF-α injection was effectively reversed in rats on treatment with ketamine plus sevoflurane. In silico studies revealed that ketamine interacts with p-MLKL protein in different confirmations with the binding affinities ranging from -9.7 to -8.4 kcal/mol. It was found that ketamine binds to p-MLKL protein by interacting with alanine (ALA A:295), proline (PRO A:306), glutamine (GLN A: 307) and isoleucine (ILE A:293) amino acid residues. In summary, ketamine plus sevoflurane combination alleviates TNF-α/z-VAD induced decrease in viability of HT-22 cells in vitro and rat hippocampus neurons in vivo. Moreover, ketamine plus sevoflurane combination prevented TNF-α injection induced cognitive impairment in rats. Therefore, sevoflurane plus ketamine combination can be developed as a potential therapeutic regimen for treatment of isoflurone induced cognitive impairment.

HSF1 inhibits microglia activation to attenuate neuroinflammation via regulating miR-214-3p and NFATc2 in Parkinson's disease.

Parkinson's disease (PD) is characterized by microglia activation that leads to neuroinflammation. Heat shock transcription factor 1 (HSF1) is known to exert neuroprotective effects on neurodegenerative diseases. This study sought to analyse the role and mechanism of HSF1 in PD-induced neuroinflammation. The PD mouse models were established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animal behaviour capacities and neuronal damage were assessed via behavioural tests, tyrosine hydroxylase (TH) staining, and immunofluorescence. Levels of HSF1, miR-214-3p, nuclear factor of activated T cells 2 (NFATc2), and neuroinflammatory factors were detected via RT-qPCR, Western blotting, and ELISA.Binding relationships between HSF1 and miR-214-3p, miR-214-3p, and NFATc2 were tested via dual-luciferase or chromatin immunoprecipitation assays. Functional rescue experiments were designed to confirm the roles of miR-214-3p and NFATc2. HSF1 expression in brain tissues was downregulated upon MPTP treatment. HSF1 overexpression reduced motor deficits and loss of dopaminergic neurons, increased TH-positive neurons, and repressed neuroinflammation and micro-glia activation. Mechanically, HSF1 bound to the miR-214-3p promoter to increase its expression and inhibited NFATc2 transcription. miR-214-3p downregulation or NFATc2 overexpression reversed the inhibition of HSF1 overexpression on neuroinflammation and microglia activation. Overall, our findings unveiled the therapeutic role of HSF1 in PD-induced neuroinflammation and microglia activation via regulating miR-214-3p and NFATc2.

Effects of schedule exercise therapy on chronic insomnia.

Schedule exercise therapy (SET) is a novel nonpharmacological intervention for the treatment of chronic insomnia disorder (CID). The aim of this study was to explore the effects of SET on CID. Methods: One hundred and eighteen CID were recruited and randomized into medication (MED) or medication combined with SET (MSET) groups. Over 12 observational weeks, sleep and mood status were evaluated using the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Self-rating Depression Scale (SDS), and Self-rating Anxiety Scale (SAS). At the end of the observational period, the rates of clinically effective hypnotic use were calculated. At 12 weeks, the PSQI progressively decreased for all subjects combined (P < .001) as well as ISI (P < .001), ESS (P < .001), SDS (P < .001), and SAS (P < .001). The decreases in PSQI (P < .05), ISI (P < .05), SDS (P < .01), and SAS (P < .05) in the MSET group were significantly larger than those in the MED group, but not the same as those in the ESS group (P > .05). At the trial endpoint, the clinically effective rate was significantly higher (P < .05) and the hypnotic usage rate was lower (P < .05) in the MSET group than in the MED group. SET may be an effective treatment for insomnia in patients with CID.

CRNDE inducing cisplatin resistance through SRSF1/TIA1 signaling pathway in ovarian cancer.

BACKGROUND: CRNDE is known to be an important predictive factor of prognosis in many tumors; however, its role in cisplatin resistance is still unknown in ovarian cancer. The aim of the current research was to investigate the association between CRNDE and cisplatin resistance. MATERIALS AND METHODS: QRT-PCR and in situ hybridization assay were employed to detect the expression of CRNDE in ovarian cancer cells and tissues; CCK8 assay, AnnexinV-FITC apoptosis assay and Trans-well assay, to determine the cell proliferation, apoptosis and invasion; and RNA-pull down assay, mass spectrometry analysis, gene microarray to search the targeted gene of CRNDE and SRSF1. Association of CRNDE with SRSF1 was determined in ovarian cancer cells and nude mice. RESULTS: It was found that CRNDE and SRSF1 expression were higher in the cisplatin resistant ovarian cancer cells than their control cells. High expression of CRNDE and SRSF1 led to cisplatin resistance. While inhibition of CRNDE or SRSF1 sensitized ovarian cancer to cisplatin in vitro and in vivo. Moreover, as indicated in RIP assay, SRSF1 was potentially the targeted gene of CRNDE, and CRNDE promoting SRSF1 expression to induce cisplatin resistance; as indicated in gene microassay, there was significantly positive correlation between SRSF1 and TIA1, and SRSF1 promoting TIA1 expression. CONCLUSION: In conclusion, CRNDE induced cisplatin resistance in ovarian cancer through SRSF1/TIA1 signaling pathway; thus, CRNDE inhibitor or SRSF1 inhibitor combined with cisplatin might act as a novel promising approach to ovarian cancer.

In Silico Studies, Biological Activities, and Anti-human Pancreatic Cancer Potential of 6-Hydroxy-4-methylcoumarin and 2,5-Dihydroxyacetophenone as Flavonoid Compounds.

Coronavirus is one of the RNA viruses with the largest genome; It is a group of viruses known to infect humans very little until the end of the 20th century, generally causing infection in animals (bird, cat, pig, mouse, horse, bat). It is the causative agent of 15-30% of seasonal lower and upper respiratory tract infections, and may rarely cause gastrointestinal and nervous system infections. We have obtained results for the collagenase and elastase enzymes were at the micromolar level. We obtained IC50 results for the collagenase enzyme for 6-hydroxy-4-methylcoumarin 257.22 ± 34.07 µM and for 2,5-dihydroxyacetophenone 74.46 ± 8.61 µM. 6-Hydroxy-4-methylcoumarin and 2,5-dihydroxyacetophenone were considered good inhibitors for elastase enzyme. Additionally, these compounds significantly decreased human pancreatic cancer cell viability from low doses. In addition, 100 µM dose of all compounds caused significant reductions in human pancreatic cancer cell viability. IC50 results (IC50: 10-50 µM) were better than control. In the otherwords, the docking results suggest that both compounds tend to have lower efficacy on the main protease targets of SARS-CoV-2 than standard compounds, (NL-1 and NL-2). The reason for this is that the standard compounds interact strongly and more frequently with the target proteins, and the surface areas they cover on the active surface are much larger than the small ligand molecules studied.

Nutritional screening and nutritional interventions in patients following gastrointestinal surgery in a general surgical ward: a best practice implementation project.

OBJECTIVES: The aim of this implementation project was to improve nutritional screening and nutritional interventions for patients scheduled for gastrointestinal surgery in a general surgical ward. INTRODUCTION: Malnutrition is common in hospitalized surgical patients and has many adverse outcomes affecting the patients' quality of life. Improving nutritional risk screening and nutritional support could reduce the incidence of malnutrition and its adverse outcomes. METHODS: The project used the JBI audit and feedback method to implement evidence into practice. JBI Practical Application of Clinical Evidence System and Getting Research into Practice audit tools were used for promoting change in general surgical wards. Six audit criteria were created based on an evidence summary, including using screening tool, patients' and caregivers' education, nurses' education on nutritional screening and support, preoperative nutrition support and postoperative early food intake. A baseline audit was conducted, followed by nursing information system improvement, education, multidisciplinary meetings targeted at clinicians and two cycles of follow-up audits. RESULTS: Results from the baseline and follow-up audits showed improvement for all the criteria. Compliance for criteria 1-3 increased from 0 to 100%, and that for criterion 4 increased from 32 to 100%. These four criteria sustained 100% in follow-up cycle 2. Compliance for criterion 5 increased from 8 to 50% in follow-up cycle 1 audit, but decreased to 0% in follow-up cycle 2 audit, and similarly for criterion 6, compliance increased from 45 to 56% in follow-up cycle 1 audit, but decreased to 48% in follow-up cycle 2 audit. CONCLUSION: The objectives related to nutritional risk screening, nurse knowledge, patients and families were successfully realized and sustained positive results. This project demonstrated that a nursing information system and long-term patient education are essential strategies to achieve and sustain positive results. The objectives related to preoperative nutritional support and postoperative early enteral food intake were challenges and represented barriers. In future, a multiple-pronged strategy will be implemented to achieve overall success and change according to best practice.

The Optimal Time of Ovarian Reserve Recovery After Laparoscopic Unilateral Ovarian Non-Endometriotic Cystectomy.

Background: Laparoscopic ovarian cystectomy is established as the standard surgical approach for the treatment of benign ovarian cysts. However, previous studies have shown that potential fertility can be directly impaired by laparoscopic ovarian cystectomy, diminished ovarian reserve (DOR), and even premature ovarian failure. Therefore, fertility-preserving interventions are required for benign gynecologic diseases. However, there are still little data on the time period required for recovery of ovarian reserve after the laparoscopic unilateral ovarian cystectomy, which is very important for the individualization of treatment protocols. This study aimed at investigating the time needed for the ovarian reserve to recover after laparoscopic unilateral ovarian non-endometriotic cystectomy. Materials and Methods: Sixty-seven patients with unilateral ovarian non-endometriotic cyst from Zhoupu and Punan Hospitals who underwent laparoscopic unilateral ovarian cystectomy were recruited as a postoperative observation group (POG). Also, 69 healthy age-matched women without ovarian cyst who did not undergo surgery were recruited as a referent group (RFG). Ovarian reserve with the serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), estradiol (E2) levels, ovarian arterial resistance index (OARI), and antral follicle counts (AFCs) were measured on the third to fifth days of the same menstrual cycle. A postoperative 6-month follow-up of cases was performed. Results: Compared with RFG, AFC of cyst side in the POG group showed no difference in the first, third, and sixth postoperative month (F = 0.03, F = 0.02, F = 0.55, respectively; p = 0.873, p = 0.878, p = 0.460, respectively). The OARI of cyst side in the POG group revealed no differences in the first, third, and sixth postoperative month (F = 0.73, F = 3.57, F = 1.75, respectively; p = 0.395, p = 0.061, p = 0.701, respectively). In the first month, the postoperative AMH levels significantly declined, reaching 1.88 ng/ml [interquartile range (IQR): 1.61-2.16 ng/ml] in POG and 2.57 ng/ml (IQR: 2.32-2.83 ng/ml) in RFG (F = 13.43, p = 0.000). For the data of AMH levels stratified by age, the same trend was observed between less than 25 and more than 26 years old. At this same time interval, the postoperative rate of decline was significantly lower compared to the preoperative one in POG (32.75%). The same trend was observed between the POG and RFG groups (26.67%). Conclusions: The optimal time for recovery of ovarian reserve after laparoscopic unilateral ovarian cystectomy is estimated to be 6 months.

Role of salt­inducible kinase 2 in the malignant behavior and glycolysis of colorectal cancer cells.

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Currently, surgery, chemotherapy and radiation therapy are the conventional approaches used to treat CRC. However, these therapy strategies cause several side effects. The present study aimed to develop an alternative and more effective treatment approach for patients with CRC. It has been reported that salt­inducible kinase 2 (SIK2) acts as an oncogene. Therefore, in the present study, the expression levels of SIK2 were determined in CRC cells using western blot analysis and reverse transcription­quantitative PCR. In addition, SIK2 was knocked down in CRC cells to evaluate its role in cell proliferation, migration, invasion and glycolysis using Cell Counting Kit­8, wound healing, Transwell assays and glycolysis cell­based assay kit, respectively. Additionally, the target genes of SIK2 were identified using bioinformatics analysis, while SIK2 overexpression experiments were carried out to determine whether SIK2 could regulate CRC cell malignant behavior and glycolysis. The results revealed that SIK2 was upregulated in CRC cells. Furthermore, SIK2 knockdown attenuated CRC cell proliferation, migration, invasion and glycolysis. Bioinformatics analysis predicted that SIK2 could interact with tripartite motif containing 28 (TRIM28), while TRIM28 overexpression could reverse the effects of SIK2 silencing on cell proliferation, migration, invasion and glycolysis. This finding indicated that the aforementioned effects of SIK2 were mediated by regulating TRIM28. In conclusion, the findings of the present study suggested that SIK2 may be involved in CRC carcinogenesis and glycolysis by regulating TRIM28 expression. These findings could provide a novel approach to targeted therapy and clinical diagnosis of CRC in the future.

The evaluation of sleep disturbances for Chinese frontline medical workers under the outbreak of COVID-19.

OBJECTIVE: To evaluate sleep disturbances of Chinese frontline medical workers (FMW) under the outbreak of coronavirus disease 2019 (COVID-19), and make a comparison with non-FMW. METHODS: The medical workers from multiple hospitals in Hubei Province, China, volunteered to participate in this cross-sectional study. An online questionnaire, including Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS) and Visual Analogue Scale (VAS), was used to evaluate sleep disturbances and mental status. Sleep disturbances were defined as PSQI>6 points or/and AIS>6 points. We compared the scores of PSQI, AIS, anxiety and depression VAS, as well as prevalence of sleep disturbances between FMW and non-FMW. RESULTS: A total of 1306 subjects (801 FMW and 505 non-FMW) were enrolled. Compared to non-FMW, FMW had significantly higher scores of PSQI (9.3 ± 3.8 vs 7.5 ± 3.7; P < 0.001; Cohen's d = 0.47), AIS (6.9 ± 4.3 vs 5.3 ± 3.8; P < 0.001; Cohen's d = 0.38), anxiety (4.9 ± 2.7 vs 4.3 ± 2.6; P < 0.001; Cohen's d = 0.22) and depression (4.1 ± 2.5 vs 3.6 ± 2.4; P = 0.001; Cohen's d = 0.21), as well as higher prevalence of sleep disturbances according to PSQI > 6 points (78.4% vs 61.0%; relative risk [RR] = 1.29; P < 0.001) and AIS > 6 points (51.7% vs 35.6%; RR = 1.45; P < 0.001). CONCLUSION: FMW have higher prevalence of sleep disturbances and worse sleep quality than non-FMW. Further interventions should be administrated for FMW, aiming to maintain their healthy condition and guarantee their professional performance in the battle against COVID-19.