Salvia miltiorrhiza suppresses cardiomyocyte ferroptosis after myocardial infarction by activating Nrf2 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferroptosis, a recently identified non-apoptotic form of cell death reliant on iron, is distinguished by an escalation in lipid reactive oxygen species (ROS) that are iron-dependent. This phenomenon has a strong correlation with irregularities in iron metabolism and lipid peroxidation. Salvia miltiorrhiza Bunge (DS), a medicinal herb frequently utilized in China, is highly esteemed for its therapeutic effectiveness in enhancing blood circulation and ameliorating blood stasis, particularly during the treatment of cardiovascular diseases (CVDs). Numerous pharmacological studies have identified that DS manifests antioxidative stress effects as well as inhibits lipid peroxidation. However, ambiguity persists regarding the potential of DS to impede ferroptosis in cardiomyocytes and subsequently improve myocardial damage post-myocardial infarction (MI). AIM OF THE STUDY: The present work focused on investigating whether DS could be used to prevent the ferroptosis of cardiomyocytes and improve post-MI myocardial damage. MATERIALS AND METHODS: In vivo experiments: Through ligation of the left anterior descending coronary artery, we constructed both a wild-type (WT) and NF-E2 p45-related factor 2 knockout (Nrf2-/-) mouse model of MI. Effects of DS and ferrostatin-1 (Fer-1) on post-MI cardiomyocyte ferroptosis were examined through detecting ferroptosis and myocardial damage-related indicators as well as Nrf2 signaling-associated protein levels. In vitro experiments: Erastin was used for stimulating H9C2 cardiomyocytes to construct an in vitro ferroptosis cardiomyocyte model. Effects of DS and Fer-1 on cardiomyocyte ferroptosis were determined based on ferroptosis-related indicators and Nrf2 signaling-associated protein levels. Additionally, inhibitor and activator of Nrf2 were used for confirming the impact of Nrf2 signaling on DS's effect on cardiomyocyte ferroptosis. RESULTS: In vivo: In comparison to the model group, DS suppressed ferroptosis in cardiomyocytes post-MI and ameliorated myocardial damage by inducing Nrf2 signaling-related proteins (Nrf2, xCT, GPX4), diminishing tissue ferrous iron and malondialdehyde (MDA) content. Additionally, it enhanced glutathione (GSH) levels and total superoxide dismutase (SOD) activity, effects that are aligned with those of Fer-1. Moreover, the effect of DS on alleviating cardiomyocyte ferroptosis after MI could be partly inhibited through Nrf2 knockdown. In vitro: Compared with the erastin group, DS inhibited cardiomyocyte ferroptosis by promoting the expression of Nrf2 signaling-related proteins, reducing ferrous iron, ROS, and MDA levels, but increasing GSH content and SOD activity, consistent with the effect of Fer-1. Additionally, Nrf2 inhibition increased erastin-mediated ferroptosis of cardiomyocytes through decreasing Nrf2 signaling-related protein expressions. Co-treatment with DS and Nrf2 activator failed to further enhance the anti-ferroptosis effect of DS. CONCLUSION: MI is accompanied by cardiomyocyte ferroptosis, whose underlying mechanism is probably associated with Nrf2 signaling inhibition. DS possibly suppresses ferroptosis of cardiomyocytes and improves myocardial damage after MI through activating Nrf2 signaling.

Trends in exposure to drugs and prohibited substances among sports: A nationwide analysis of 2008-2022 inquiry records.

To prevent athletes from unintentional doping, the anti-doping authorities in Taiwan have launched several sports-prohibited substances inquiry services since 2008. This study aimed to enhance the prevention of sports-prohibited substance misuse by analyzing data collected from major nationwide service systems, enabling the identification of trends in athletes' exposure to drugs and prohibited substances. The study collected over 30,000 data points from three major national anti-doping inquiry systems, spanning from 2008 to 2022. The information of the users consulted products, prohibited substances, and sports disciplines in the data were calculated and categorized. The usage of inquiry systems has shown an increasing trend from 2008 to 2022. Athletes comprised the majority of users (> 40%), significantly outnumbering other user groups (all below 20%). Among the inquiries, Western medicine accounted for the highest percentage (up to 79.6%), and it also contained the majority of the prohibited substances. Interestingly, traditional Chinese medicines had a higher chance (35.9%) of containing prohibited substances, as indicated by the mobile application. The prohibited substances mainly belonged to class S6 stimulants and S9 glucocorticoids. Among the daily medicinal products and nutritional supplements encountered by sports personnel, approximately 30% of them were found to contain prohibited substances. Future educational efforts should focus on raising awareness about traditional Chinese medicines and drugs for the common cold, ADHD, and pain relief, as well as their regulation, to prevent the misuse of prohibited substances.

Esculin induces endoplasmic reticulum stress and drives apoptosis and ferroptosis in colorectal cancer via PERK regulating eIF2α/CHOP and Nrf2/HO-1 cascades.

ETHNOPHARMACOLOGICAL RELEVANCE: Cortex fraxini (also known as Qinpi), the bark of Fraxinus rhynchophylla Hance and Fraxinus stylosa Lingelsh, constitutes a crucial component in several traditional Chinese formulas (e.g., Baitouweng Tang, Jinxiao Formula, etc.) and has demonstrated efficacy in alleviating intestinal carbuncle and managing diarrhea. Cortex fraxini has demonstrated commendable anticancer activity in the realm of Chinese ethnopharmacology; nevertheless, the underlying mechanisms against colorectal cancer (CRC) remain elusive. AIM OF THE STUDY: Esculin, an essential bioactive compound derived from cortex fraxini, has recently garnered attention for its ability to impede viability and induce apoptosis in cancer cells. This investigation aims to assess the therapeutic potential of esculin in treating CRC and elucidate the underlying mechanisms. MATERIALS AND METHODS: The impact of esculin on CRC cell viability was assessed using CCK-8 assay, Annexin V/PI staining, and Western blotting. Various cell death inhibitors, along with DCFH-DA, ELISA, biochemical analysis, and Western blotting, were employed to delineate the modes through which esculin induces HCT116 cells death. Inhibitors and siRNA knockdown were utilized to analyze the signaling pathways influenced by esculin. Additionally, an azomethane/dextran sulfate sodium (AOM/DSS)-induced in vivo CRC mouse model was employed to validate esculin's potential in inhibiting tumorigenesis and to elucidate its underlying mechanisms. RESULTS: Esculin significantly suppressed the viability of various CRC cell lines, particularly HCT116 cells. Investigation with diverse cell death inhibitors revealed that esculin-induced cell death was associated with both apoptosis and ferroptosis. Furthermore, esculin treatment triggered cellular lipid peroxidation, as evidenced by elevated levels of malondialdehyde (MDA) and decreased levels of glutathione (GSH), indicative of its propensity to induce ferroptosis in HCT116 cells. Enhanced protein levels of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and p-eIF2α suggested that esculin induced cellular endoplasmic reticulum (ER) stress, subsequently activating the Nrf2/ARE signaling pathway and initiating the transcriptional expression of heme oxygenase (HO)-1. Esculin-induced excessive expression of HO-1 could potentially lead to iron overload in HCT116 cells. Knockdown of Ho-1 significantly attenuated esculin-induced ferroptosis, underscoring HO-1 as a critical mediator of esculin-induced ferroptosis in HCT116 cells. Furthermore, utilizing an AOM/DSS-induced colorectal cancer mouse model, we validated that esculin potentially inhibits the onset and progression of colon cancer by inducing apoptosis and ferroptosis in vivo. CONCLUSIONS: These findings provide comprehensive insights into the dual induction of apoptosis and ferroptosis in HCT116 cells by esculin. The activation of the PERK signaling pathway, along with modulation of downstream eIF2α/CHOP and Nrf2/HO-1 cascades, underscores the mechanistic basis supporting the clinical application of esculin on CRC treatment.

An auxiliary strategy of partial least squares regression in pharmacokinetic/pharmacodynamic studies: A case of application of guhong injection in myocardial ischemia/reperfusion rats.

Guhong injection (GHI) has been applied in the therapy of cardio-cerebrovascular disease in clinic, but there is no report about the pharmacokinetic/pharmacodynamic (PK/PD) research on GHI treating myocardial ischemia/reperfusion (MI/R) injury in rats. In this study, eight compounds of GHI in plasma, including N-acetyl-L-glutamine (NAG), chlorogenic acid (CGA), hydroxysafflor yellow A (HSYA), p-coumaric acid ( pCA), rutin, hyperoside, kaempferol-3-O-rutinoside, and kaempferol-3-O-glucoside, were quantified by LC-MS/MS. We discovered that the values of t1/2ß, k12, V2, and CL2 were larger than those of t1/2α, k21, V1, and CL1 for all compounds. The levels of four biomarkers, creatine kinase-MB (CK-MB), cardiac troponin I (cTn I), ischemia-modified albumin (IMA), and alpha-hydroxybutyrate dehydrogenase (α-HBDH) in plasma were determined by ELISA. The elevated level of these biomarkers induced by MI/R was declined to different degrees via administrating GHI and verapamil hydrochloride (positive control). The weighted regression coefficients of NAG, HSYA, CGA, and pCA in PLSR equations generated from The Unscrambler X software (version 11) were mostly minus, suggesting these four ingredients were positively correlated to the diminution of the level of four biomarkers. Emax and ED50, two parameters in PK/PD equations that were obtained by adopting Drug and Statistics software (version 3.2.6), were almost enlarged with the rise of GHI dosage. Obviously, all analytes were dominantly distributed and eliminated in the peripheral compartment with features of rapid distribution and slow elimination. With the enhancement of GHI dosage, the ingredients only filled in the central compartment if the peripheral compartment was replete. Meanwhile, high-dose of GHI generated the optimum intrinsic activity, but the affinity of compounds with receptors was the worst, which may be caused by the saturation of receptors. Among the eight analytes, NAG, HSYA, CGA, and pCA exhibited superior cardioprotection, which probably served as the pharmacodynamic substance basis of GHI in treating MI/R injury.

Ultrasound imaging guided targeted sonodynamic therapy enhanced by magnetophoretically controlled magnetic microbubbles.

Sonodynamic therapy (SDT) utilizes ultrasonic excitation of a sensitizer to generate reactive oxygen species (ROS) to destroy tumor. Two dimensional (2D) black phosphorus (BP) is an emerging sonosensitizer that can promote ROS production to be used in SDT but it alone lacks active targeting effect and showed low therapy efficiency. In this study, a stable dispersion of integrated micro-nanoplatform consisting of BP nanosheets loaded and Fe3O4 nanoparticles (NPs) connected microbubbles was introduced for ultrasound imaging guided and magnetic field directed precision SDT of breast cancer. The targeted ultrasound imaging at 18 MHz and efficient SDT effects at 1 MHz were demonstrated both in-vitro and in-vivo on the breast cancer. The magnetic microbubbles targeted deliver BP nanosheets to the tumor site under magnetic navigation and increased the uptake of BP nanosheets by inducing cavitation effect for increased cell membrane permeability via ultrasound targeted microbubble destruction (UTMD). The mechanism of SDT by magnetic black phosphorus microbubbles was proposed to be originated from the ROS triggered mitochondria mediated apoptosis by up-regulating the pro-apoptotic proteins while down-regulating the anti-apoptotic proteins. In conclusion, the ultrasound theranostic was realized via the magnetic black phosphorus microbubbles, which could realize targeting and catalytic sonodynamic therapy.

Strictosamide alleviates acute lung injury via regulating T helper 17 cells, regulatory T cells, and gut microbiota.

BACKGROUND: Nauclea officinalis (Pierre ex Pit.) Merr. & Chun (Rubiaceae) is widely used to treat respiratory diseases in China. Strictosamide is its main active component and has significant anti-inflammatory activity. However, the effects and molecular mechanisms of strictosamide in the treatment of acute lung injury (ALI) remain largely unknown. PURPOSE: This study aimed to examine the regulatory effects of strictosamide on T helper 17 cells (Th17 cells)/Regulatory T cells (Treg cells) and gut microbiota in ALI-affected mice. MATERIALS AND METHODS: The ALI model was induced using lipopolysaccharide (LPS) intraperitoneal injection. Hematoxylin-eosin (H&E) staining, the number of inflammatory cells in broncho-alveolar lavage fluid (BALF), the Wet/Dry (W/D) ratio, and myeloperoxidase (MPO) activity were utilized as evaluation indices for the therapeutic efficacy of strictosamide on ALI. Flow cytometry (FCM), enzyme-linked immune sorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to determine the regulation of strictosamide on the Th17/Treg cells and the STAT3/STAT5 signaling pathway. The analysis of gut microbiota was conducted using 16S rDNA sequencing. The verification of the relationship between the gut microbiome and immune function was conducted using Spearman analysis. RESULTS: Strictosamide attenuated inflammation on ALI induced by LPS, which reduced the levels of Th17-related factors interleukin (IL)-6 and IL-17 and increased Treg-related factors IL-10 and transforming growth factor (TGF)-ß. In the spleens and whole blood, strictosamide reduced the proportion of Th17 cells and increased the proportion of Treg cells. Furthermore, strictosamide increased Forkhead/winged helix transcription factor 3 (Foxp3) and p-STAT5 protein expression while inhibiting Retinoid-related orphan nuclear receptors-γt (RORγt) and p-STAT3 expression. Moreover, strictosamide reshaped the diversity and structure of the gut microbiota, and influence the associations between immune parameters and gut microbiota in ALI mice. CONCLUSIONS: In summary, the results of the current investigation showed that strictosamide has a therapeutic impact on LPS-induced ALI. The mechanism of action of this effect may be associated with the modulation of Th17 and Treg cells differentiation via the SATA signaling pathway, as well as the impact of the gut microbiota.

[Systematic review and Meta-analysis of efficacy and safety of Bidouyan Oral Liquid in treatment of rhinosinusitis].

This study aimed to systematically review the efficacy and safety of Bidouyan Oral Liquid in the treatment of rhinosinu-sitis(RS). CNKI, Wanfang, SinoMed, VIP, Cochrane Library, PubMed, EMbase, Web of Science, and Ovid were searched for the randomized controlled trial(RCT) of Bidouyan Oral Liquid for the treatment of RS patients. Moreover, the reference lists and the grey literature were searched manually. Two researchers independently screened the literature and extracted data. The Cochrane collaboration's tool for assessing risk of bias(RoB 2.0) in randomized trial was used to assess the methodological quality of the included stu-dies. Meta-analysis was performed in RevMan 5.3 and Stata 12.0, and the grades of recommendation, assessment, development and evaluation(GRADE) was employed to evaluate the quality of evidence. A total of 54 RCTs(35 with drug combinations and 19 with single drugs) comprising 7 511 patients(3 973 in the observation group and 3 538 in the control group) were included. Meta-analysis showed that Bidouyan Oral Liquid + conventional treatment was superior to conventional treatment alone in increasing the total response rate(RR=1.19, 95%CI[1.15, 1.24], P<0.000 01) and decreasing the Lund-Kennedy scores(MD=-1.94, 95%CI[-2.61,-1.26], P<0.000 01), Lund-Mackay scores(MD=-2.14, 95%CI[-2.98,-1.31], P<0.000 01), and visual analogue scale(VAS) scores(MD_(total VAS scores)=-1.28, 95%CI[-1.56,-1.01], P<0.000 01; MD_(nasal congestion VAS scores)=-0.58, 95%CI[-0.89,-0.27], P=0.000 2; MD_(runny nose VAS scores)=-0.61, 95%CI[-0.93,-0.29], P=0.000 2; MD_(olfactory dysfunction VAS scores)=-0.43, 95%CI[-0.52,-0.34], P<0.000 01; MD_(head and facial pain VAS scores)=-0.41, 95%CI[-0.57,-0.26], P<0.000 01). Furthermore, the combined treatment outperformed conventional treatment alone in improving the mucociliary transport rate(MTR)(MD=1.64, 95%CI[1.08, 2.20], P<0.000 01) and lowering the levels of inflammatory cytokines{tumor necrosis factor-α(TNF-α)(SMD=-1.95, 95%CI[-2.57,-1.33], P<0.000 01), interleukin-6(IL-6)(SMD=-2.64, 95%CI[-4.08,-1.21], P=0.000 3)} in RS patients. In addition, the combined treatment did not increase the incidence of adverse reactions(RR=0.83, 95%CI[0.44, 1.57], P=0.57). Bidouyan Oral Liquid was superior to conventional treatment in increasing total response rate(RR=1.25, 95%CI[1.18, 1.32], P<0.000 01), decreasing the Lund-Kennedy(P<0.01) and Lund-Mackay scores(P<0.05), alleviating major symptoms(P_(total VAS scores)<0.01; P_(nasal congestion VAS scores)<0.01; P_(runny nose VAS scores)<0.01; P_(olfactory dysfunction VAS scores)<0.05; P_(head and facial pain VAS scores)<0.01), and decreasing adverse reactions(P=0.03). The results showed that either Bidouyan Oral Liquid or Bidouyan Oral Liquid + conventional treatment can increase the total response rate, decrease the Lund-Kennedy and Lund-Mackay scores, and mitigate major symptoms. In addition, Bidouyan Oral Liquid + conventional treatment improved MTR and reduced the expression of TNF-α and IL-6 without causing serious adverse events. However, due to the limited methodological quality of the included studies, large-sample and high-quality RCTs are needed to provide evidence support.

Enhancing precision in lung tumor ablation through innovations in CT-guided technique and angle control.

BACKGROUND: This retrospective study aimed to evaluate the precision and safety outcomes of image-guided lung percutaneous thermal ablation (LPTA) methods, focusing on radiofrequency ablation (RFA) and microwave ablation (MWA). The study utilized an innovative angle reference guide to facilitate these techniques in the treatment of lung tumors. METHODS: This study included individuals undergoing LPTA with the assistance of laser angle guide assembly (LAGA) at our hospital between April 2011 and March 2021. We analyzed patient demographics, tumor characteristics, procedure details, and complications. Logistic regressions were employed to assess risk factors associated with complications. RESULTS: A total of 202 patients underwent ablation for 375 lung tumors across 275 sessions involving 495 ablations. Most procedures used RFA, especially in the right upper lobe, and the majority of ablations were performed in the prone position (49.7%). Target lesions were at a median depth of 39.3 mm from the pleura surface, and remarkably, 91.9% required only a single puncture. Complications occurred in 31.0% of ablations, with pneumothorax being the most prevalent (18.3%), followed by pain (12.5%), sweating (6.5%), fever (5.0%), cough (4.8%), hemothorax (1.6%), hemoptysis (1.2%), pleural effusion (2.0%), skin burn (0.6%), and air emboli (0.2%). The median procedure time was 21 min. Notably, smoking/chronic obstructive pulmonary disease emerged as a significant risk factor for complications. CONCLUSION: The LAGA-assisted LPTA enhanced safety by improving accuracy and reducing risks. Overall, this investigation contributes to the ongoing efforts to refine and improve the clinical application of these thermal ablation techniques in the treatment of lung tumors.

Triacanthine enhances the sensitivity of colorectal cancer cells to 5-fluorouracil by regulating RRM2.

BACKGROUND: According to the literatures, triacanthine is isolated from the leaves of Gleditsia triacanthos L. and acts as an anti-hypertensive agent, also cardiotonic, antispasmodic and a respiratory analeptic. The 5-fluorouracil (5-FU) is widely used to treat the patients of colorectal cancer (CRC), but the resistance to 5-FU treatment restricts the therapeutic efficacy of CRC patients. PURPOSE: This study aims to explore a novel therapeutics regimen overcoming CRC resistance to 5-FU. METHODS: The cell proliferation of CRC cells was determined by SRB and colony formation assay. Transwell and wound-healing assay were applied to explore the potential metastatic abilities of CRC cells. qRT-PCR and Western blot were performed to evaluate the level of indicated mRNAs and proteins respectively. Xenograft assay was used to explore the anti-CRC effect of triacanthine. RESULTS: Triacanthine statistically restrained CRC proliferation both in vitro and in vivo. Triacanthine induced cell cycle G1/G0 phase arrest in CRC cells. Meanwhile, triacanthine also inhibited the migrative and invasive abilities of CRC cells. A Venn diagram was generated showing that O-6-Methylguanine-DNA Methyltransferase (MGMT) might be a molecular target of triacanthine in treating CRC. Furthermore, triacanthine plus 5-FU significantly suppressed the cell proliferation of CRC cells compared with single agent treatment alone, and highly synergistic anti-cancer effects were scored when 5-FU was combined with triacanthine in CRC cells. In addition, triacanthine sensitized the anti-cancer activity of 5-FU via regulating Ribonucleotide Reductase Regulatory Subunit M2 (RRM2). MGMT or RRM2 might be novel biomarkers for evaluating the therapeutical efficiency of 5-FU in CRC patients. CONCLUSION: We firstly demonstrated triacanthine suppressed cell proliferation and metastasis abilities and found the novel molecular targets of triacanthine in CRC cells. This is the first study to evaluate the anti-cancer efficiency of triacanthine plus 5-FU. Our study has revealed triacanthine as a pertinent sensitizer to 5-FU, and provided novel strategies for predicting outcomes and reversing resistance of 5-FU therapy.

Cognitive protection and brain entropy changes from omega-3 polyunsaturated fatty acids supplement in late-life depression: A 52-week randomized controlled trial.

BACKGROUND: Late-life depression (LLD) is associated with risk of dementia, yet intervention of LLD provides an opportunity to attenuate subsequent cognitive decline. Omega-3 polyunsaturated fatty acids (PUFAs) supplement is a potential intervention due to their beneficial effect in depressive symptoms and cognitive function. To explore the underlying neural mechanism, we used resting-state functional MRI (rs-fMRI) before and after omega-3 PUFAs supplement in older adults with LLD. METHODS: A 52-week double-blind randomized controlled trial was conducted. We used multi-scale sample entropy to analyze rs-fMRI data. Comprehensive cognitive tests and inflammatory markers were collected to correlate with brain entropy changes. RESULTS: A total of 20 patients completed the trial with 11 under omega-3 PUFAs and nine under placebo. While no significant global cognitive improvement was observed, a marginal enhancement in processing speed was noted in the omega-3 PUFAs group. Importantly, participants receiving omega-3 PUFAs exhibited decreased brain entropy in left posterior cingulate gyrus (PCG), multiple visual areas, the orbital part of the right middle frontal gyrus, and the left Rolandic operculum. The brain entropy changes of the PCG in the omega-3 PUFAs group correlated with improvement of language function and attenuation of interleukin-6 levels. LIMITATIONS: Sample size is small with only marginal clinical effect. CONCLUSION: These findings suggest that omega-3 PUFAs supplement may mitigate cognitive decline in LLD through anti-inflammatory mechanisms and modulation of brain entropy. Larger clinical trials are warranted to validate the potential therapeutic implications of omega-3 PUFAs for deterring cognitive decline in patients with late-life depression.

Polysaccharide from Panax japonicus C.A. Mey prevents non-alcoholic fatty liver disease development based on regulating liver metabolism and gut microbiota in mice.

In this study, a new polysaccharide (PSPJ) with specific molecular weight and monosaccharide compositions was isolated and purified from the water extract of Panacis Japonici Rhizoma (PJR). 16S rRNA analysis and untargeted metabolomic analysis were used to assess PSPJ's efficacy in averting non-alcoholic fatty liver disease (NAFLD). This study indicated that PSPJ significantly reduced liver fat accumulation, the increase in blood lipids and ALT caused by HFD, indicating that PSPJ can prevent NAFLD. We demonstrated through cell experiments that PSPJ does not directly affect liver cells. The gut microbiota disorder and alterations in short-chain fatty acids (SCFAs) induced by the high-fat diet (HFD) were ameliorated by PSPJ, as evidenced by the analysis of 16S rRNA. In particular, supplementing PSPJ reduced the abundance of Turicibacter, Dubosiella, and Staphylococcus, and increased the abundance of Bacteroides, Blautia, and Lactobacillus. Untargeted metabolomic analysis shows that PSPJ improves liver metabolic disorders by regulating arachidonic acid metabolism, carbohydrate digestion and absorption, fatty acid biosynthesis, fatty acid metabolism and retinol metabolism. The findings of our investigation indicate that PSPJ has the potential to modulate liver metabolism through alterations in the composition of intestinal bacteria, hence preventing NAFLD.

The Impact of Hippocampal-Sparing Whole-Brain Radiotherapy on Survival and Cognitive Function in Patients with Brain Metastases.

Objective: To explore the effects on cognitive function and survival time of whole-brain intensity-modulated radiotherapy using radiotherapy equipment to protect the hippocampus. Methods: Thirty-six patients with brain metastases treated at Qianjiang Central Hospital were enrolled in this study from January 2019 to September 2022. The patients were randomly divided into 2 groups: 15 patients received hippocampal-protection whole-brain radiotherapy, and 21 patients received conventional whole-brain radiotherapy. The Montreal Cognitive Assessment was used to evaluate the cognitive function of patients before and 24 hours, 2 months, 6 months, and 12 months after radiotherapy. Cognitive dysfunction and survival time were compared between the 2 groups. Results: The overall mean differences in the Montreal Cognitive Assessment scores between the hippocampal-protection group and the conventional whole-brain radiotherapy group were statistically significant at 6 months (P = .006) and 12 months (P = .04) after radiotherapy. The median overall survival was 16 months (95% CI, 11.54-20.46) for the hippocampal-protection group and 14 months (95% CI, 12.9-15.21) for the conventional whole-brain radiotherapy group (P = .578). The median progression-free survival was 12 months (95% CI, 9.74-14.26) for the hippocampal-protection group and 9 months (95% CI, 6.60-11.44) for the conventional whole-brain radiotherapy group (P = .494). Conclusion: Whole-brain radiotherapy for protecting the hippocampus can delay cognitive dysfunction in patients to some extent.

A systematic review for prevention of cisplatin-induced nephrotoxicity using different hydration protocols and meta-analysis for magnesium hydrate supplementation.

BACKGROUND: Nephrotoxicity remains the most serious side effect of cisplatin therapy. Cisplatin-induced nephrotoxicity (CIN) limits the use of this drug and affects up to 20% of patients. Several possible interventions such as magnesium supplementation may prevent CIN. This study aimed to review different types of hydration protocols and we conducted a meta-analysis of magnesium supplementation to understand its effect in protecting against CIN. METHODS: A search of the PubMed, Embase, and Cochrane databases was performed. Trials were eligible if they enrolled patients who received cisplatin and different hydration protocols to prevent CIN. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the efficacy of different protocols. RESULTS: We initially identified 1113 different studies and included 33 of them which met the selection criteria. A meta-analysis of 11 retrospective studies that examined magnesium supplementation during hydration showed that this treatment provided significant protection against CIN (OR = 0.22, 95% CI = 0.14 to 0.35). CONCLUSION: There has been uncertainty regarding the best method to prevent CIN. Our results highlight the potentially protective effect of magnesium supplementation during hydration. This study is registered in PROSPERO, CRD42020212682.

Protective Effects of Danmu Extract Syrup on Acute Lung Injury Induced by Lipopolysaccharide in Mice through Endothelial Barrier Repair.

OBJECTIVE: To investigate the effects of Danmu Extract Syrup (DMS) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and explore the mechanism. METHODS: Seventy-two male Balb/C mice were randomly divided into 6 groups according to a random number table (n=12), including control (normal saline), LPS (5 mg/kg), LPS+DMS 2.5 mL/kg, LPS+DMS 5 mL/kg, LPS+DMS 10 mL/kg, and LPS+Dexamethasone (DXM, 5 mg/kg) groups. After pretreatment with DMS and DXM, the ALI mice model was induced by LPS, and the bronchoalveolar lavage fluid (BALF) were collected to determine protein concentration, cell counts and inflammatory cytokines. The lung tissues of mice were stained with hematoxylin-eosin, and the wet/dry weight ratio (W/D) of lung tissue was calculated. The levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1 ß in BALF of mice were detected by enzyme linked immunosorbent assay. The expression levels of Claudin-5, vascular endothelial (VE)-cadherin, vascular endothelial growth factor (VEGF), phospho-protein kinase B (p-Akt) and Akt were detected by Western blot analysis. RESULTS: DMS pre-treatment significantly ameliorated lung histopathological changes. Compared with the LPS group, the W/D ratio and protein contents in BALF were obviously reduced after DMS pretreatment (P<0.05 or P<0.01). The number of cells in BALF and myeloperoxidase (MPO) activity decreased significantly after DMS pretreatment (P<0.05 or P<0.01). DMS pre-treatment decreased the levels of TNF-α, IL-6 and IL-1 ß (P<0.01). Meanwhile, DMS activated the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway and reversed the expressions of Claudin-5, VE-cadherin and VEGF (P<0.01). CONCLUSIONS: DMS attenuated LPS-induced ALI in mice through repairing endothelial barrier. It might be a potential therapeutic drug for LPS-induced lung injury.

Association between potential supplement-drug interactions and liver diseases in patients with cancer: A large prospective cohort study.

BACKGROUND & AIMS: The concurrent use of herbal and dietary supplements and conventional drugs can lead to interactions in patients with cancer, of which hepatotoxicity is one of the most concerning sequelae. This study examined the potential supplement-drug interactions involving the hepatic system, and their associations with documented liver diseases, among patients with cancer in a large population-based cohort in the UK Biobank. METHODS: Participants diagnosed with cancer and had completed supplement-use assessment after diagnosis were included. Potentially interacting supplement-drug combinations that involved CYP enzymes or increased the risk of hepatotoxicity were identified from four tertiary databases. Liver diseases were identified using ICD-codes K70-77. Log-binomial regression was used to investigate the associations between potentially-interacting supplement-drug combinations and liver diseases documented (1) at any time, and (2) confined to only after the time of supplement-use assessment, adjusting for age, sex and pre-existing comorbidities. RESULTS: This analysis included 30,239 participants (mean age = 60.0 years; 61.9% female). Over half (n = 17,698, 58.5%) reported the use of supplements after cancer diagnoses. Among supplements users, 36.9% (n = 6537/17,698) were on supplement-drug combinations with interacting potential involving the hepatic system. Patients taking supplements and drugs who had hepatic comorbidities were more likely to take potentially interacting pairs (adjusted risk ratio = 1.14, 95% CI = 1.06-1.23, p < 0.001). However, no significant association was observed between the use of these combinations and subsequent liver diseases (all p > 0.05). CONCLUSION: Approximately one-third of the participants who had cancer and were supplement users had a risk of potential supplement-drug interactions that contribute to adverse liver effect. Healthcare professionals should communicate with patients with cancer, especially those with pre-existing liver diseases, about supplement use and proactively assess the clinical significance of potential interactions.

Pulmonary embolism after diagnostic curettage in patient with adenomyosis and hysteromyoma: A case report and brief review of literature.

RATIONALE: Pulmonary embolism (PE) is a common cause of cardiovascular death whose major acquired risk factors include postoperative states, pregnancy, malignancy, and age. We report a case of PE that occurred after diagnostic curettage for abnormal uterine bleeding, with a medical history of adenomyosis and hysteromyoma. PATIENT CONCERNS AND DIAGNOSES: A 31-year-old Han Chinese female was referred to our hospital with menstrual disorders, increased menstrual flow, and severe anemia. After admission, the patient was treated with a blood transfusion, iron supplementation, and erythropoietin, and diagnostic curettage was performed the following day. On the first postoperative day, the patient developed pulmonary embolism with dyspnea and fever diagnosed by CT pulmonary angiography and significantly elevated D-dimer. INTERVENTIONS AND OUTCOMES: Molecular weight heparin was administered for PE for 2 weeks, dyspnea was relieved significantly after 2 days of treatment and the uterine bleeding did not increase; and gonadotropin-releasing hormone agonists were administered for adenomyosis after 1 week of anticoagulant therapy to reduce bleeding. We followed up for 6 months, and the patient had no recurrence of thrombosis and uterine bleeding had improved. CONCLUSION: We speculate that the occurrence of pulmonary embolism was closely related to adenomyosis, hysteromyoma, and curettage in this patient. Treating the presence of both menstrual bleeding and thromboembolism is challenging, and careful management is necessary to avoid therapeutic contradictions.

The hypothalamic steroidogenic pathway mediates susceptibility to inflammation-evoked depression in female mice.

BACKGROUND: Depression is two-to-three times more frequent among women. The hypothalamus, a sexually dimorphic area, has been implicated in the pathophysiology of depression. Neuroinflammation-induced hypothalamic dysfunction underlies behaviors associated with depression. The lipopolysaccharide (LPS)-induced mouse model of depression has been well-validated in numerous laboratories, including our own, and is widely used to investigate the relationship between neuroinflammation and depression. However, the sex-specific differences in metabolic alterations underlying depression-associated hypothalamic neuroinflammation remain unknown. METHODS: Here, we employed the LPS-induced mouse model of depression to investigate hypothalamic metabolic changes in both male and female mice using a metabolomics approach. Through bioinformatics analysis, we confirmed the molecular pathways and biological processes associated with the identified metabolites. Furthermore, we employed quantitative real-time PCR, enzyme-linked immunosorbent assay, western blotting, and pharmacological interventions to further elucidate the underlying mechanisms. RESULTS: A total of 124 and 61 differential metabolites (DMs) were detected in male and female mice with depressive-like behavior, respectively, compared to their respective sex-matched control groups. Moreover, a comparison between female and male model mice identified 37 DMs. We capitalized on biochemical clustering and functional enrichment analyses to define the major metabolic changes in these DMs. More than 55% of the DMs clustered into lipids and lipid-like molecules, and an imbalance in lipids metabolism was presented in the hypothalamus. Furthermore, steroidogenic pathway was confirmed as a potential sex-specific pathway in the hypothalamus of female mice with depression. Pregnenolone, an upstream component of the steroid hormone biosynthesis pathway, was downregulated in female mice with depressive-like phenotypes but not in males and had considerable relevance to depressive-like behaviors in females. Moreover, exogenous pregnenolone infusion reversed depressive-like behaviors in female mice with depression. The 5α-reductase type I (SRD5A1), a steroidogenic hub enzyme involved in pregnenolone metabolism, was increased in the hypothalamus of female mice with depression. Its inhibition increased hypothalamic pregnenolone levels and ameliorated depressive-like behaviors in female mice with depression. CONCLUSIONS: Our study findings demonstrate a marked sexual dimorphism at the metabolic level in depression, particularly in hypothalamic steroidogenic metabolism, identifying a potential sex-specific pathway in female mice with depressive-like behaviors.

Analysis of the heavy metal contents' effect on steroidal saponins and the anti-breast cancer activity of Paris polyphylla var. yunnanensis.

Background: P. polyphylla var. yunnanensis, as a near-threatened and ethnic medicine in China, used to be a key ingredient in traditional Chinese medicine in treatment of traumatic injuries, sore throat, snakebites, and convulsions for thousands of years. However, there were no reports on the inverse relationship between the contents of heavy metals and saponins and its anti-breast cancer pharmacological activity in P. polyphylla var. yunnanensis. Methods: The present study aimed to reveal the characteristics of heavy metal contents and saponins and its anti-breast cancer pharmacological activity and their interrelationships in P. polyphylla var. yunnanensis from different production areas. The contents of heavy metal and steroidal saponins in P. polyphylla var. yunnanensis were analyzed by inductively coupled plasma mass spectrometry (ICP-MS) and the high-performance liquid chromatography technique, respectively. The Pearson correlation was used to study the correlation between saponins and heavy metals. 4T1 mouse mammary tumor cells were selected and cultivated for antitumor studies in vitro. Cell Counting Kit-8 (CCK-8) assay, Hoechst staining, and flow cytometry analysis were used for the examination of the proliferation and apoptosis of 4T1 tumor cells. Mouse breast cancer 4T1 cells were subcutaneously injected into BALB/c mice to construct a tumor model to explore the in vivo inhibitory effect on breast cancer. TUNEL assay and immunohistochemistry were used for the examination of the effect of P. polyphylla var. yunnanensis from different origins on cancer cell proliferation and apoptosis induction in 4T1 tumor mice. Results: Heavy metal contents were highly correlated with the content of steroidal saponins. The overall content of 10 metals in the three producing origins was of the order C3 >C2 >C1. The total content of eight steroidal saponins in the extracts of P. polyphylla var. yunnanensis from three different origins was C1 >C2 >C3. The Pearson correlation study showed that in all of the heavy metals, the contents of Cd and Ba were positively correlated with the main steroidal saponins in P. polyphylla var. yunnanensis, while Al, Cr, Cu, Fe, Zn, As, Hg, and Pb showed a negative correlation. In vitro experiments showed that the extracts of P. polyphylla var. yunnanensis from three origins could inhibit the proliferation and induce cell apoptosis of 4T1 cells in a concentration- and time-dependent manner, especially in the C1 origin. In vivo experiments showed that the extract of P. polyphylla var. yunnanensis from the three origins could inhibit the growth of tumors and induce the apoptosis of tumor cells. In the three origins, C1 origin had the lowest total heavy metal level but the highest total steroidal saponin level. Therefore, it showed a better effect in reducing the expression of the human epidermal growth factor receptor 2 (HER2) and Kiel 67 (Ki67) and increasing the expression of p53 in tumor tissues compared to the other origins. In conclusion, in the three origins, C1 origin exhibits antitumor pharmacological effects in vivo and in vitro which are better than those in the other origins. Conclusion: In this study, we found that with the increase of the heavy metal content, the content of steroid saponins and anti-breast cancer activity decreased. The results showed that the high content of the total heavy metals may not be conducive to the accumulation of steroidal saponins in P. polyphylla var. yunnanensis and lead to the low anti-breast cancer activity. The results of this study suggest that the content of heavy metals should be controlled in the artificial cultivation process of P. polyphylla var. yunnanensis.

Induction of ferroptosis and apoptosis in endometrial cancer cells by dihydroisotanshinone I.

Danshen, also known as Salvia miltiorrhiza, is a medicinal herb used in traditional Chinese medicine. Its potential impact on endometrial cancer has not been thoroughly investigated. This study aimed to examine the effect of dihydroisotanshinone I (DT), a compound found in Danshen, on the viability of ARK1 and ARK2 endometrial cancer cells and its mechanisms. The results showed that 10 µM DT inhibited cell viability of ARK1 and ARK2 cells by inducing apoptosis and ferroptosis, which was achieved by blocking the expression of GPX4. In vivo experiments using a xenograft nude mouse model indicated that DT treatment significantly reduced tumor volume without causing any adverse effects. These findings suggest that DT may be a potential therapeutic agent for inhibiting endometrial cancer cell viability, but further research is needed to confirm these results.

Methionine-CBS axis promotes intracellular ROS levels by reprogramming serine metabolism.

As a non-essential amino acid, cysteine could be obtained through both exogenous uptake and endogenous de novo synthesis pathways. Research has demonstrated that restricting the uptake of cystine could result in a depletion of intracellular cysteine and glutathione, ultimately leading to an increase in intracellular reactive oxygen species (ROS) levels. However, the role of methionine in regulating intracellular ROS levels is currently unclear. Here, we want to explore the role of methionine in regulating intracellular ROS levels. We found that methionine restriction could lead to a decrease in intracellular ROS levels, while supplementation with SAM can restore these levels through flow cytometry. Mechanically, we found that the methionine-SAM axis relies on CBS when regulating intracellular ROS levels. Furthermore, we speculate and prove that the methionine-SAM-CBS axis alters the metabolism of serine, thereby reducing intracellular reductive power, therefore promoting intracellular ROS levels through changing metabolite levels and genetic methods. Finally, our study revealed that high expression of CBS in tumor cells could lead to increased intracellular ROS levels, ultimately resulting in faster proliferation rates. Together, our study confirmed that methionine plays a promoting role in the regulation of intracellular ROS levels.