Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1ß and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1ß and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

P-tau217 correlates with neurodegeneration in Alzheimer's disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy.

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration.

Cyclin-dependent kinase 7 (CDK7) inhibitors as a novel therapeutic strategy for different molecular types of breast cancer.

BACKGROUND: Cyclin-dependent kinase (CDK) 7 is aberrantly overexpressed in many types of cancer and is an attractive target for cancer therapy due to its dual role in transcription and cell cycle progression. Moreover, CDK7 can directly modulate the activities of estrogen receptor (ER), which is a major driver in breast cancer. Breast cancer cells have exhibited high sensitivity to CDK7 inhibition in pre-clinical studies. METHODS: In this review, we provide a comprehensive summary of the latest insights into CDK7 biology and recent advancements in CDK7 inhibitor development for breast cancer treatment. We also discuss the current application of CDK7 inhibitors in different molecular types of breast cancer to provide potential strategies for the treatment of breast cancer. RESULTS: Significant progress has been made in the development of selective CDK7 inhibitors, which show efficacy in both triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer (HR+). Moreover, combined with other agents, CDK7 inhibitors may provide synergistic effects for endocrine therapy and chemotherapy. Thus, high-quality studies for developing potent CDK7 inhibitors and investigating their applications in breast cancer therapy are rapidly emerging. CONCLUSION: CDK7 inhibitors have emerged as a promising therapeutic strategy and have demonstrated significant anti-cancer activity in different subtypes of breast cancer, especially those that have been resistant to current therapies.

Effects of intravenous glucocorticoids on postoperative delirium in adult patients undergoing major surgery: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: The effects of intravenous glucocorticoids on postoperative delirium (POD) in adult patients undergoing major surgery remain controversial. Therefore, we conducted this meta-analysis to assess whether intravenous glucocorticoids can decrease POD incidence in the entire adult population undergoing major surgery and its association with patients age, type of surgery, and type of glucocorticoid. METHODS: We searched the relevant literature published before November 3, 2023, through Cochrane Library, PubMed, Embase, and Web of Science. The primary outcome was POD incidence. The risk ratio for the primary outcome was calculated using the Mantel-Haenszel method. The secondary outcomes included 30-day mortality, length of hospital stay, ICU duration, mechanical ventilation duration, and occurrence of glucocorticoid-related adverse effects (e.g., infection and hyperglycemia). This meta-analysis was registered in PROSPERO: CRD42022345997. RESULTS: We included eight randomized controlled studies involving 8972 patients. For the entire adult population undergoing major surgery, intravenous glucocorticoids reduced the POD incidence (risk ratio = 0.704, 95% confidence interval, 0.519-0.955; P = 0.024). However, subgroups defined by type of surgery showed differential effects of glucocorticoids on POD. Intravenous glucocorticoids can not reduce POD incidence in adult patients undergoing cardiac surgery (risk ratio = 0.961, 95% confidence interval, 0.769-1.202; P = 0.728), with firm evidence from trial sequential analysis. However, in major non-cardiac surgery, perioperative intravenous glucocorticoid reduced the incidence of POD (risk ratio = 0.491, 95% confidence interval, 0.338-0.714; P < 0.001), which warrants further studies due to inconclusive evidence by trial sequence analysis. In addition, the use of glucocorticoids may reduce the mechanical ventilation time (weighted mean difference, -1.350; 95% confidence interval, -1.846 to -0.854; P < 0.001) and ICU duration (weighted mean difference = -7.866; 95% confidence interval, -15.620 to -0.112; P = 0.047). CONCLUSIONS: For the entire adult population undergoing major surgery, glucocorticoids reduced the POD incidence. However, the effects of glucocorticoids on POD appear to vary according to the type of surgery. In patients receiving major non-cardiac surgery, glucocorticoid may be an attractive drug in the prevention of POD, and further studies are needed to draw a definitive conclusion. In cardiac surgery, intravenous glucocorticoids have no such effect.

A Trojan Horse Delivery Vehicle Carrying siRNA Nanotherapeutics with Multiple Tumor Microenvironment Responsiveness Elicits Robust Antitumor Immune Responses In Situ via a "Self-Synergistic" Approach.

The potential of small interfering RNAs (siRNAs) in the treatment of malignant tumors has attracted increasing attention due to their inherent advantages. However, their therapeutic performance strongly depends on the efficiency of their cytoplasmic delivery in vivo by the delivery vehicle with good cellular permeability and histocompatibility. Herein, a polycationic carrier camouflaged with macrophage membrane (MPM) is constructed biomimetically, which is condensed from endogenous spermine monomers through diselenide bonds. The developed Trojan horse delivery vehicle has desirable compression efficacy for siRNA oligo against PD-L1 (siPDL1) as well as intracytoplasmic release properties derived from its sequential degradation triggered by redox microenvironment in tumor cells. Furthermore, the coloading of photosensitizer can mediate photodynamic therapy (PDT) accompanied by the generation of reactive oxygen species (ROS) upon light irradiation applied, which accelerated the degradation of the carrier as well as the release of cargoes while enhancing the PD-L1 blockage-mediated immunotherapy by inducing in-situ immunogenic cell death. Moreover, the synchronously delivered siPDL1 attenuated the ROS-induced increase in immunosuppressive PD-L1 expression, thereby effectively eliciting a robust antitumor immune response with a "self-synergistic" manner in the xenograft breast cancer mouse model.

Intraoperative Radiotherapy as a Tumour-Bed Boost Combined with Whole Breast Irradiation Versus Conventional Radiotherapy in Patients with Early-Stage Breast Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: There is no definitive answer regarding the efficacy of intraoperative radiotherapy (IORT) as a tumour bed boost for patients with early-stage breast cancer. The purpose of this meta-analysis was to summarise the available evidence and explore the efficacy and safety of IORT combined with whole breast irradiation (WBI) versus conventional radiotherapy in women with early-stage breast cancer who underwent breast-conserving surgery. METHODS: The PUBMED, MEDLINE, EMBASE, Web of Science, and Cochrane Library databases were searched from inception to December 31, 2022. We collected studies on the efficacy, cosmetic outcome, and safety of IORT boost combined with WBI compared with those of conventional radiotherapy in patients with early-stage breast cancer after breast-conserving surgery. Two authors independently performed the literature selection and data extraction. The quality of the randomised, controlled trials (RCTs) was assessed according to the PEDro scale. The quality of non-RCTs was assessed according to the Methodological Index for Non-Randomised Studies. Risk ratios (RRs) for the local recurrence rate (LRR), distant metastasis rate (DMR), disease-free survival (DFS), cosmetic outcome, and toxicity were pooled using fixed or random effects models. Meta-analysis of the included studies was performed by using RevMan 5.3 software. RESULTS: Nine studies, including one RCT and eight non-RCTs, with a total of 3219 patients were included. In terms of LRR, there was no significant benefit of IORT boost+WBI over conventional radiotherapy (with or without the tumour bed boost) (RR = 0.77, 95% confidence interval (CI): 0.54-1.09, P = 0.14), but a trend towards benefit could be identified. There was a significant reduction in DMR in the IORT boost+WBI group (RR = 0.63, 95% CI: 0.46-0.85, P = 0.003) and a significant improvement in DFS (RR = 0.40, 95% CI: 0.25-0.65, P = 0.0002). Exploratory subgroup analysis showed that the DMR and DFS of the electron boost group were significantly better than those of conventional radiotherapy group, and there was a tendency for LRR to improve in the electron boost group. However, the LRR, DMR, and DFS did not effectively improve in the x-ray boost group. In terms of appearance and toxicity, there were no significant differences in cosmetic outcome, fibrosis, and hyperpigmentation between the two groups (RR = 0.99, 95% CI: 0.91-1.07, P = 0.78; RR = 1.02, 95% CI: 0.41-2.56, P = 0.96; RR = 0.42, 95% CI: 0.10-1.72, P = 0.23), but the incidence of oedema was significantly reduced in the IORT boost+WBI group (RR = 0.27, 95% CI: 0.13-0.59, P = 0.0009). CONCLUSIONS: IORT boost+WBI is more effective than conventional radiotherapy after breast-conserving surgery in patients with early-stage breast cancer, and electron boost exhibits better efficacy than x-ray boost. In addition, the cosmetic and safety profiles of IORT boost+WBI are not inferior to those of conventional radiotherapy.

Headspace single drop microextraction based visual colorimetry for highly sensitive, selective and matrix interference-resistant determination of sulfur dioxide in food samples.

Excessive intake of SO2, a widely-used food additive, is able to cause respiratory, cardiovascular and neurological disease. For effectively monitoring SO2 level, we have developed a headspace single drop microextraction based visual colorimetry for highly sensitive and selective sensing of SO2 with TMB (3,3',5,5'-tetramethylbenzidine) as a classic chromogenic reagent. A combination of single drop and headspace microextraction integrated merits of high extraction efficiency, low consumption of reagents and excellent matrix interference-resistant ability. The colorimetric principle was based on oxidation of TMB, and SO2 could compete with TMB to preferentially react with ·OH, resulting in the fading of color blue that could be easily read out by naked eye. LOD was calculated to be 0.53 µM and 5 µM by UV-vis and naked eye, respectively. The method was successfully utilized to analysis of food samples, and the experimental device was miniaturized and easy to construct, thus showing a promising potential in field analysis.

A novel incision technique of a totally implanted venous access port in the upper arm for patients with breast cancer.

BACKGROUND: A totally implanted venous access port (TIVAP) in the upper arm is a safe and cost-effective vascular access device and is widely used in breast cancer patients. Traditional tunnelling technique increases the operation time and has an unsatisfied cosmetic effect, so we explored the feasibility, cosmetic effect and complications of an upper arm port with a novel incision in this retrospective study. METHODS: We reviewed 489 cases of totally implantable venous access port implantation in the upper arm with two types of incisions in our centre from 1 January 2018 to 30 January 2022. The patients were divided into two different incision groups including the puncture site incision group (n = 282) and the conventional tunnelling group (n = 207). The comparison of the results was collected between the two groups, and contributing factors were analyzed for major complications. RESULTS: A total of 489 patients were successfully implanted with arm ports using the puncture site incision technique (n = 282, 57.7%) and conventional tunnelling technique (n = 207, 42.3%). The average operation time of the two types of incisions was 36.5 ± 15 min in the puncture site incision group and 55 ± 18.1 min in the tunnel needle group (P < 0.05). In terms of complications, 33 catheter-related complications occurred (6.4%), including 9 cases of infection, 15 cases of catheter-related thrombosis and 7 cases of skin exposure. Fourteen patients in the puncture site incision group developed complications compared with 17 in the traditional incision group. There were no significant differences between the two groups in terms of overall complication events (5.0% and 8.2%, P = 0.145) while the same result was found in each complication event. Weight, total cholesterol and diabetes were found to be associated with device-related infections in the univariate Cox proportional hazard regression models. Diabetes was found to be associated with device-related infections in multivariate analysis while hypertension was associated with thrombosis. CONCLUSIONS: The puncture site incision method is a novel technique with a better cosmetic appearance and less operation time than the traditional tunnelling technique, providing a comparable overall rate of complications. It offers a preferable choice for clinicians when dealing with different situations of patients. It is worthy of being used and promoted for patients requiring the totally implanted venous access port in the upper arm.

Effects of Chinese provincial CDCs WeChat official account article features on user engagement during the COVID-19 pandemic.

Background: WeChat has become a potent medium for disseminating public health information, especially during the coronavirus disease 2019 (COVID-19) pandemic. WeChat is important for public health organizations when considering users' information needs and preferences to further explore factors that affect user engagement. Methods: We collected data from WeChat official accounts (WOAs) of the Chinese provincial Center for Disease Control and Prevention (CDC) to identify factors affecting and predicting the behavior of user engagement as measured by the level of reading and re-sharing during different phases of the COVID-19 pandemic between January 1, 2019, and December 31, 2020. We used multiple logistic regression analyses to identify features of articles with higher reading and re-sharing levels from 31 Chinese provincial CDCs. We developed a nomogram to predict the effect on user engagement. Results: We collected a total of 26 302 articles. Release position, title type, article content, article type, communication skills, marketing elements, article length, and video length were key determinants of user engagement. Although the feature patterns also varied between different pandemic stages, the article content, release position, and article type were still the most prominent features driving user engagement. Regarding article content, the COVID-19 pandemic report and guidance for public protection were more likely to obtain high-level reading (normalization: odds ratio (OR) = 12.340, 95% confidence interval (CI) = 9.357-16.274) and re-sharing (normalization: OR = 7.254, 95% CI = 5.554-9.473) than other contents throughout the pandemic. When we compared release position with secondary push, users who used main push were more likely to exhibit high-level reading and re-sharing during any period, especially during normalization (OR = 6.169, 95% CI = 5.554-6.851; OR = 4.230, 95% CI = 3.833-4.669). For article type, a combination of text, links and pictures was associated with a higher rate of reading (normalization: OR = 4.262, 95% CI = 3.509-5.176) and re-sharing level (normalization: OR = 4.480, 95% CI = 3.635-5.522) compared to text only. Simultaneously, the prediction model showed good discriminatory power and calibration. Conclusions: Discrepancies exist in article features between different pandemic stages. Public health agencies should make full use of official WOAs and consider the information needs and preferences of users in order to better carry out health education and health communication with the public when public health events occur.

The Role of MbEGS1 and MbEGS2 in Methyleugenol Biosynthesis by Melaleuca bracteata.

Many aromatic plant volatile compounds contain methyleugenol, which is an attractant for insect pollination and has antibacterial, antioxidant, and other properties. The essential oil of Melaleuca bracteata leaves contains 90.46% methyleugenol, which is an ideal material for studying the biosynthetic pathway of methyleugenol. Eugenol synthase (EGS) is one of the key enzymes involved in the synthesis of methyleugenol. We recently reported two eugenol synthase genes (MbEGS1 and MbEGS2) present in M. bracteata, where MbEGS1 and MbEGS2 were mainly expressed in flowers, followed by leaves, and had the lowest expression levels in stems. In this study, the functions of MbEGS1 and MbEGS2 in the biosynthesis of methyleugenol were investigated using transient gene expression technology and virus-induced gene silencing (VIGS) technology in M. bracteata. Here, in the MbEGSs genes overexpression group, the transcription levels of the MbEGS1 gene and MbEGS2 gene were increased 13.46 times and 12.47 times, respectively, while the methyleugenol levels increased 18.68% and 16.48%. We further verified the function of the MbEGSs genes by using VIGS, as the transcript levels of the MbEGS1 and MbEGS2 genes were downregulated by 79.48% and 90.35%, respectively, and the methyleugenol content in M. bracteata decreased by 28.04% and 19.45%, respectively. The results indicated that the MbEGS1 and MbEGS2 genes were involved in the biosynthesis of methyleugenol, and the transcript levels of the MbEGS1 and MbEGS2 genes correlated with the methyleugenol content in M. bracteata.

Tailoring biomimetic dual-redox-responsive nanoplexes for enhanced RNAi-synergized photodynamic cancer immunotherapy.

Despite the strong potential of RNA interference (RNAi) therapies, critical issues, such as poor permeability across biological membranes and efficacy of their delivery into the cytoplasm, remain to be addressed before their successful clinical application. The current study aimed to address these issues by constructing a biomimetic nanoplex with dual redox responsiveness, which is derived from a cationic polymer formed by the condensation of endogenous spermine monomers via diselenide bonds. The developed nanoplexes decomposed in response to the redox microenvironment in cancer cells, thereby avoiding accumulation toxicity and poor transfection efficiency owing to incomplete siRNA release. When co-delivered with siPDL1 and a photosensitizer, the reactive oxygen species generated by irradiated nanoplexes accelerated the cytoplasmic release of siPDL1, which was expected to alleviate the PDT-induced increase in immunosuppressive PD-L1 expression. In a murine model of 4T1 xenografted breast cancer, the fabricated macrophage membrane (MPM)-camouflaged nanoplexes with payloads boosted antitumor immune responses in situ through a "self-synergistic" immunogenic cell death induced by photodynamic therapy (PDT). Overall, the study reported a new strategy for harnessing photodynamic immunotherapy for treating immunologically cold tumors. STATEMENT OF SIGNIFICANCE: This study provides a biomimetic nanoplex with dual redox responsiveness, which is derived from a novel cationic polymer formed by the condensation of endogenous spermine monomers through diselenide bonds. The developed nanoplex disassembles according to the redox microenvironment in cancer cells, thereby avoiding accumulation toxicity and poor transfection efficiency due to incomplete siRNA release. When co-delivery of siPDL1 and photosensitizer in vivo, the ROS generated by irradiated nanoplexes accelerated the cytoplasmic release of siPDL1, and which is expected to alleviate PDT-induced increase in immunosuppressive PD-L1 expression, thereby boosting antitumor immune responses in situ through a "self-synergistic" immunogenic cell death induced by PDT. Our findings reveal a new strategy of harnessing photodynamic immunotherapy therapy toward immunologically cold tumors.

Effect of opioid-free anesthesia on postoperative nausea and vomiting after gynecological surgery: a systematic review and meta-analysis.

Background: Postoperative nausea and vomiting (PONV) is a common complication, that can reduce patient satisfaction and may lead to serious consequences, such as wound dehiscence. Many strategies have been proposed to prevent PONV; however, it remains common, especially in high-risk surgeries such as gynecological surgery. In recent years, opioid-free anesthesia has been widely studied because it minimizes adverse reactions of opioids, such as nausea, vomiting, and itching; however, conclusions have been inconsistent. Therefore, we conducted this meta-analysis to investigate the effects of opioid-free anesthesia on PONV in patients undergoing gynecological surgery. Methods: A systematic search of the PubMed, Web of Science, Cochrane Library, and Embase databases, from inception to 28 August 2023, was performed. Keywords and other free terms were used with Boolean operators (OR and, AND) to combine searches. This review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Six studies involving 514 patients who underwent gynecological surgery were included. The forest plot revealed that the incidence of PONV (risk ratio = 0.52; p < 0.00001) and consumption of postoperative antiemetics use (risk ratio = 0.64; p = 0.03) were significantly lower in the opioid-free anesthesia group. In addition, opioid-free anesthesia improved the quality of recovery (mean difference = 4.69; p < 0.0001). However, there were no significant differences in postoperative pain scores (mean difference = 0.05; p = 0.85), analgesic use (risk ratio = 1.09; p = 0.65), and the time of extubation (mean difference = -0.89; p = 0.09) between the opioid-free anesthesia and control groups. Conclusion: OFA reduces PONV and the use of antiemetic drugs. In addition, it improves the quality of postoperative recovery. However, OFA can not reduce the postoperative pain scores, analgesic use and the time of extubation. Due to the strength of the evidence, we cannot support OFA as an ideal anesthesia method in gynecological surgery, and the implementation of anesthesia strategies should be case-by-case. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=462044], identifier [CRD42023462044].

Preservation of Litchi Fruit with Nanosilver Composite Particles (Ag-NP) and Resistance against Peronophythora litchi.

Litchi (Litchi chinensis Sonn.) is susceptible to infection by Peronophythora litchi post storage, which rapidly decreases the sensory and nutritional quality of the fruit. In this study, the effects of nanosilver (Ag-NP) solution treatment on the shelf life of litchi fruit and the inhibition of P. litchi were examined, and the underlying mechanisms were discussed. For investigations, we used one variety of litchi ('Feizixiao'), dipping it in different concentrations of Ag-NP solution after harvesting. Meanwhile, we treated P. litchi with different concentrations of Ag-NP solution. According to the data analysis, litchi treated with 400 µg/mL Ag-NPs and stored at 4 °C had the highest health rate and the lowest browning index among all the samples. In the same trend, treatment with 400 µg/mL Ag-NPs produced the best results for anthocyanin content, total soluble solids content, and titratable acidity content. Additionally, according to the results of the inhibition test, 800 µg/mL Ag-NP solution had a 94.97% inhibition rate against P. litchi. Within 2-10 h following exposure to 400 µg/mL Ag-NP solution, the contents of superoxide dismutase, peroxidase, and catalase in P. litchi gradually increased and peaked, followed by a gradual decline. At this time, the integrity of the cell membrane of P. litchi could be broken by Ag-NP solution, and the sporangia showed deformed germ tubes and abnormal shapes. Taken together, these results suggested that Ag-NP treatment inhibited respiration and P. litchi activity, which might attenuate litchi pericarp browning and prolong the shelf life of litchi. Accordingly, Ag-NPs could be used as an effective antistaling agent in litchi fruit and as an ecofriendly fungicide for the post-harvest control of litchi downy blight. This study provides new insights into the application of Ag-NP as an antistaling agent for fruit storage and as an ecofriendly fungicide.

Anti-quorum sensing evaluation of methyleugenol, the principal bioactive component, from the Melaleuca bracteata leaf oil.

Quorum sensing (QS) is a cell-to-cell communication in bacteria that couples gene expression through the accumulation of signaling molecules, which finally induce the production of several virulence factors and modulate bacterial behaviors. Plants have evolved an array of quorum sensing inhibitors (QSIs) to inhibit the pathogens, of which aromatic compounds are widely recognized. The essential oil of Melaleuca bracteata was found to exhibit anti-quorum sensing activity, and its principal bioactive component, methyleugenol (ME), had been isolated in our previous study. Here, ME interfered effectively with the QS-regulated processes of toxin secretion in Chomobacterium violaceum ATCC31532, resulting in strong inhibition of QS genes, cviR, cviI, vioA-E, hmsHNR, lasA-B, pilE1-3, and hcnABC, leading to impaired virulence, including violacein production, biofilm biomass, and swarming motility. The accumulation of the signal molecule (N-hexanoyl-DL-homoserine lactone, C6-HSL) in C. violaceum declined upon treatment with ME, suggesting an inhibition effect on the C6-HSL production, and the ME was also capable of degrading the C6-HSL in vitro assay. Molecular docking technique and the consumption change of exogenous C6-HSL in C. violaceum CV026 revealed the anti-QS mechanism of ME consisted of inhibition of C6-HSL production, potentially via interaction with CviR and/or CviI protein. Collectively, the isolated ME, the principal active components of M. bracteata EO, exhibited a wide range of inhibition processes targeting C. violaceum QS system, which supports the potential anti-pathogenic use of M. bracteata EO and ME for treatment of pathogen contamination caused by bacterial pathogens.

Clinical features and antibiotic treatment of early-onset neonatal listeriosis.

OBJECTIVE: To analyze the clinical features, efficacy of antibiotic treatment, and outcome of neonatal listeriosis. METHODS: This was a retrospective study that included all neonates diagnosed with listeriosis between January 2010 and December 2021. RESULTS: Nine male patients and five female patients were analyzed, including 11 preterm and 3 term infants. The mean gestational age was 34 ± 2.6 weeks (29 + 2-40 + 2 weeks), and the mean birth weight was 2392 ± 603 g (1370-3580 g). The maternal clinical manifestations included fever (13/14 [92.9%]), meconium-stained amniotic fluid (12/14 [85.7%]), and intrauterine fetal distress (11/14 [78.6%]). The neonates presented with fever (14/14 [100%]), generalized maculopapular rash (7/14 [50%]), and convulsions (8/14 [57.1%]). Laboratory tests showed leukocytosis (11/14 [78.6%]), monocytosis (9/14 [64.3%]), elevated C-reactive protein levels (13/14 [92.9%]), and thrombocytopenia (6/14 [42.9%]). Eight patients had central nervous system involvement, and Listeria monocytogenes was isolated from the blood in all cases. Empiric antibiotic therapy consisted of a combination of third-generation cephalosporins and penicillin or vancomycin. Four patients died, and 10 patients were cured. CONCLUSIONS: Preterm infants were more susceptible to listeria infection than term infants, with most having multiple organ injuries. Combined antibiotic application improved the effectiveness of treatment.

Genome-Wide Identification of MAPKK and MAPKKK Gene Family Members and Transcriptional Profiling Analysis during Bud Dormancy in Pear (Pyrus x bretschneideri).

The mitogen-activated protein kinase (MAPK) cascade consisting of three types of reversibly major signal transduction module (MAPKKK, MAPKK, and MAPK) is distributed in eukaryotes. MAPK cascades participate in various aspects of plant development, including hormone responses, cell division and plant dormancy. Pear is one of the most economically important species worldwide, and its yield is directly affected by dormancy. In this study, genome-wide identification of MAPKK and MAPKKK gene family members in Pyrus x bretschneideri and transcriptional expression analysis of MAPK cascades during pear dormancy were performed. We identified 8 MAPKKs (PbrMKKs) and 100 MAPKKKs (PbrMAPKKKs) in Pyrus using recent genomic information. PbrMAPKKs were classified into four subgroups based on phylogenetic analysis, whereas PbrMAPKKKs were grouped into 3 subfamilies (MEKK, Raf, and ZIK). Most PbrMAPKKKs and PbrMAPKKs in the same subfamily had similar gene structures and conserved motifs. The genes were found on all 17 chromosomes. The comprehensive transcriptome analysis and quantitative real-time polymerase chain reaction (qRT-PCR) results showed that numerous MAPK cascade genes participated in pear bud dormancy. The interaction network and co-expression analyses indicated the crucial roles of the MAPK member-mediated network in pear bud dormancy. Overall, this study advances our understanding of the intricate transcriptional control of MAPKKK-MAPKK-MAPK genes and provides useful information on the functions of dormancy in perennial fruit trees.

Injectable Natural Polymer Hydrogels for Treatment of Knee Osteoarthritis.

Osteoarthritis (OA) is a serious chronic and degenerative disease that increasingly occurs in the aged population. Its current clinical treatments are limited to symptom relief and cannot regenerate cartilage. Although a better understanding of OA pathophysiology has been facilitating the development of novel therapeutic regimen, delivery of therapeutics to target sites with minimal invasiveness, high retention, and minimal side effects remains a challenge. Biocompatible hydrogels have been recognized to be highly promising for controlled delivery and release of therapeutics and biologics for tissue repair. In this review, the current approaches and the challenges in OA treatment, and unique properties of injectable natural polymer hydrogels as delivery system to overcome the challenges are presented. The common methods for fabrication of injectable polysaccharide-based hydrogels and the effects of their composition and properties on the OA treatment are detailed. The strategies of the use of hydrogels for loading and release cargos are also covered. Finally, recent efforts on the development of injectable polysaccharide-based hydrogels for OA treatment are highlighted, and their current limitations are discussed.

Value of Neutrophil to Lymphocyte Ratio, Platelet to Lymphocyte Ratio, and Red Blood Cell Distribution Width in Evaluating the Prognosis of Children with Severe Pneumonia.

OBJECTIVE: To investigate the value of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and red blood cell distribution width (RDW) in evaluating the prognosis of children with severe pneumonia (SP). METHODS: A retrospective analysis of the data of 91 children with SP admitted to our hospital from March 2018 to March 2021. According to the survival status after 28 days of treatment, all children were divided into the survival group (n = 59) and the death group (n = 32). The clinical data and laboratory indicators of the patients were recorded. Multivariate logistic regression was used to analyze the risk factors of prognosis, and the ROC curve was used to analyze the predictive value of each index. RESULTS: The Acute Physiology and Chronic Health Evaluation II (APACHE II) score and CURB-65 score of the death group were higher than those of the survival group (P < 0.05). The RDW, NLR, PLR, and high-sensitivity C-reactive protein, procalcitonin blood lactic acid (Lac) of the death group, were higher than those of the survival group, and LYM was lower than the survival group (P < 0.05). Multivariate regression analysis showed that APACHE II score, RDW, NLR, PLR, and Lac were all independent risk factors for poor prognosis in children with SP (P < 0.05). The AUC of NLR, PLR, and RDW for evaluating the prognosis of children with SP were 0.798, 0.781, and 0.777, respectively. The sensitivity was 56.25%, 90.63%, and 56.25%, respectively, and the specificity was 89.83%, 55.93%, and 91.53%, respectively. The AUC of NLR, PLR, and RDW combined to evaluate the prognosis of children with SP was 0.943. When the best cut-off value was 0.8528, the sensitivity was 93.75%, and the specificity was 91.53%. CONCLUSION: NLR, PLR, and RDW have certain predictive value for the prognosis of children with SP; the combination of the three indicators has a higher value in evaluating the prognosis of children with SP, which can better guide the prognostic treatment.

Influencing factors and strategies of enhancing nanoparticles into tumors in vivo.

The administration of nanoparticles (NPs) first faces the challenges of evading renal filtration and clearance of reticuloendothelial system (RES). After that, NPs infiltrate through the expanded endothelial space and penetrated the dense stroma of tumor microenvironment to tumor cells. As long as possible to prolong the time of NPs remaining in tumor tissue, NPs release active agent and induce pharmacological action. This review provides a comprehensive summary of the physical and chemical properties of NPs and the influence of various biological factors in tumor microenvironment, and discusses how to improve the final efficacy through adjusting the characteristics and structure of NPs. Perspectives and future directions are also provided.

Multi-omics landscape of circadian rhythm pathway alterations in Glioma.

Circadian rhythm pathway was demonstrated pathological functions in glioma on single-gene level. We aim to depict the multi-omics landscape of circadian rhythm pathway alteration in glioma using bioinformatic analyses. Multi-omics data were obtained from "cBioPortal" database. Comparisons were done regarding clinical parameters, differential-expressed genes and functional annotations. A pathway index was generated using the expression data from TCGA and GTEx to quantify the general alteration level of the pathway with clinical association of circadian rhythm pathway index explored. A total of 30 genes were mapped on the circadian rhythm pathway. Genomic profile ofcircadian rhythm pathway genes exhibited distinct characteristics on multiple levels between lower grade glioma (LGG) and glioblastoma multiforme (GBM) patients. LGG patients presented significantly higher frequencies of multi-omics mutations, as well as significant clinical relevance, on single-gene level. Differential-expressed genes between LGG and GBM patients revealed different functions between subtypes that related to the alteration of circadian rhythm pathway. LGG have significantly higher pathway index than normal brain tissue, while GBM significantly lower than normal tissue (P < 0.01), indicating distinctly altered circadian pathway in LGG. Circadian rhythm pathway index correlated with the prognosis of LGG, but not GBM, patients, with higher score indicating better survival outcome (LGG: HR = 0.39, 95% CI: 0.26 - 0.59, P < 0.001). In conclusion, LGG have more multi-omics alterations of circadian rhythm pathway than GBM. Quantification of circadian rhythm pathway using pathway index demonstrated hyperactivated pathway status in LGG and correlated with the prognosis of LGG patients.