Assessing the Impact of Morphine on Adverse Outcomes in ACS Patients Treated with P2Y12 Inhibitors: Insights from Multiple Real-World Evidence.

Purpose: Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators. Patients and Methods: Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis. Results: Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted-P =3.55*10-209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI. Conclusion: The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.

The Frequency of Neuropsychiatric Sequelae After Traumatic Brain Injury in the Global South: A systematic review and meta-analysis.

This study aimed to assess the prevalence of neuropsychiatric sequelae following traumatic brain injury (TBI) among the Western Asian, South Asian and African regions of the global south. All studies on psychiatric disturbances or cognitive impairment following TBI conducted (until August 2021) in the 83 countries that constitute the aforementioned regions were reviewed; 6 databases were selected for the literature search. After evaluating the articles using the Joanna Briggs Institute guidelines, the random effects model was used to estimate the prevalence of depression, anxiety, post-traumatic stress disorder (PTSD), TBI-related sleep disturbance (TBI-SD), obsessive-compulsive disorder (OCD) and cognitive impairment. Of 56 non-duplicated studies identified in the initial search, 27 were eligible for systematic review and 23 for meta-analysis. The pooled prevalence of depression in 1,882 samples was 35.35%, that of anxiety in 1,211 samples was 28.64%, that of PTSD in 426 samples was 19.94%, that of OCD in 313 samples was 19.48%, that of TBI-SD in 562 samples was 26.67% and that of cognitive impairment in 941 samples was 49.10%. To date, this is the first critical review to examine the spectrum of post-TBI neuropsychiatric sequelae in the specified regions. Although existing studies lack homogeneous data due to variability in the diagnostic tools and outcome measures utilised, the reported prevalence rates are significant and comparable to statistics from the global north.

ROS-induced imbalance of the miR-34a-5p/SIRT1/p53 axis triggers chronic chondrocyte injury and inflammation.

Osteoarthritis is a chronic degenerative disease based on the degeneration and loss of articular cartilage. Inflammation and aging play an important role in the destruction of the extracellular matrix, in which microRNA (miRNA) is a key point, such as miRNA-34a-5p. Upregulation of miRNA-34a-5p was previously reported in a rat OA model, and its inhibition significantly suppressed interleukin (IL)-1ß-induced apoptosis in rat chondrocytes. However, Oxidative stress caused by reactive oxygen species (ROS) can exacerbate the progression of miRNA regulated OA by mediating inflammatory processes. Thus, oxidative stress effects induced via tert-butyl hydroperoxide (tBHP) in human chondrocytes were assessed in the current research by evaluating mitochondrial ROS production, mitochondrial cyclooxygenase (COX) activity, and cell apoptosis. We also analyzed the activities of antioxidant enzymes including glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD). Additionally, inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, and IL-24, which contribute to OA development, were detected by enzyme-linked immunosorbent assay (ELISA). The results of this study indicated that miR-34a-5p/silent information regulator 1 (SIRT1)/p53 axis was involved in the ROS-induced injury of human chondrocytes. Moreover, dual-luciferase assay revealed that SIRT1 expression was directly regulated by miR-34a-5p, indicating the presence of a positive feedback loop in the miR-34a-5p/SIRT1/p53 axis that plays an important role in cell survival. However, ROS disrupted the miR-34a-5p/SIRT1/p53 axis, leading to the development of OA, and articular injection of SIRT1 agonist, SRT1720, in a rat model of OA effectively ameliorated OA progression in a dose-dependent manner. Our study confirms that miRNA-34a-5p could participate in oxidative stress responses caused by ROS and further regulate the inflammatory process via the SIRT1/p53 signaling axis, ultimately affecting the onset of OA, thus providing a new treatment strategy for clinical treatment of OA.

Distraction and related risk factors among professional and non-professional drivers.

Background: Distraction is one of the main driver's behavioral factors that reduces the performance of the drivers and might increase the accident risk. Distraction while driving holds significant importance, especially among professional drivers, and failure to address this matter may result in adverse implications for traffic safety. The present study was conducted to investigate distraction and related risk factors between two groups of private vehicle drivers and taxi drivers. Methods: This analytical cross-sectional study was carried out in Tabriz, Iran in 2022. The total sample size in this study was 701 taxi drivers, professional drivers, and private vehicle drivers. The independent samples t-test was used to determine the statistically significant difference between groups and its sub-scales between the two studied groups. Moreover, the multivariable linear regression analysis was used to determine the predictors that affect distraction score. The test's level of significance was considered at 0.05. Results: The mean distraction score among taxi drivers surpasses that of private vehicle drivers (2.82 vs. 2.32, p-value<0.05). The drivers with negative scores, over the past year, among private vehicle drivers and taxi drivers were 2.5 % and 5.2 %, respectively (p-value<0.05). A group of taxi drivers exhibits a higher level of distraction while driving and the mean distraction score for private vehicle drivers is lower than that of taxi drivers (ß = -0.11, CI 95 %: 0.17, -0.05). Also, a history of damage or injury accidents has a significant impact on distraction while driving (ß = 0.12, CI 95 %; 0.06-0.17). Conclusions: The results indicate that distraction while driving is high amongst taxi drivers rather than private vehicle drivers. To have effective driver safety promotion interventions, it is recommended to consider driver distraction based on professional and non-professional drivers.

Spinal cord ischemia following laryngotracheal reconstruction surgery: a case report.

We present a 20-year-old patient with subglottic and tracheal stenosis was taken for a tracheal resection and end-to-end anastomosis. The patient's neck was positioned in hyperflexion using chin stitches to minimize tension at the anastomosis. On post-operative period, the patient developed paresthesias in upper and lower extremities associated with motor weakness. Magnetic resonance imaging was performed showing lesions compromising ventral spinal cord at the level of C4-C5 and C6-C7. Chin stitches were removed and neck flexion was reduced. The patient remained in the intensive care unit with vasopressors, physical therapy and intravenous fluid-therapy to maintain mean arterial pressure above 90 mmHg. After 3 weeks, the patient was discharged with no neurologic deficit. There are few cases reported of acute ischemic spinal injury following tracheal reconstruction. If this complication arises, neck posture should be corrected, maintenance of MAP above 90 mmHg and implementation of early physical therapy is key to improve neurologic outcomes.

Diving Into the Health Problems of Competitive Divers: A Systematic Review of Injuries and Illnesses in Pre-elite and Elite Diving Athletes.

CONTEXT: The Olympic sport of diving involves the competitive disciplines of 3 m springboard and 10 m platform. Although it is generally accepted that lumbar spine injuries are common in diving athletes, the existing literature of health problems in diving athletes remains scarce. OBJECTIVE: To identify the incidence, prevalence, and type of health problems that occur in competitive diving athletes. DATA SOURCES: Medline, EMBASE, SportsDiscus, PsycINFO, and Google Scholar. STUDY SELECTION: Studies written in English investigating elite or pre-elite competitive diving (springboard, platform) injuries and/or illnesses were eligible. Two independent reviewers screened for inclusion by title, abstract, and full text in accordance with the eligibility criteria. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: Data extraction was completed by 1 author using a structured form. A second author then independently reviewed and verified the extracted data, any discrepancies were resolved through consensus. RESULTS: The search identified 2554 potential articles, with 28 studies meeting eligibility criteria. The surveillance setting of most studies was restricted to competition-based events, with the reported injury incidence proportion ranging from 2.1% to 22.2%. The reported injury incidence rate ranged from 1.9 to 15.5 per 1000 athlete-exposures. Injuries to the shoulder, lower back/lumbar spine, trunk, and wrist/hand were reported most frequently. The prevalence of low back pain was reported as high as 89% (lifetime), 43.1% (period), and 37.3% (point). The illness incidence proportion ranged from 0.0% to 22.2%, with respiratory and gastrointestinal illness reported most frequently. CONCLUSION: Up to 1 in 5 diving athletes sustain an injury and/or illness during periods of competition. A reporting bias was observed, with most cohort studies limiting surveillance to short competition-based periods only. This limits the current understanding of the health problems experienced by diving athletes to competition periods only and requires expansion to whole-of-year surveillance.

Return to work in persons with persistent postconcussion symptoms: a survey study examining the perspectives of employees and managers.

OBJECTIVE: To examine challenges in return to work (RTW) for persons with persistent postconcussion symptoms (PPCS) experienced by the affected employees and their managers. METHODS: A survey of employees (S-E) and two surveys of managers (S-M1, S-M2) executed 4 months apart to capture the time perspective. Inclusion: Adults aged 18-66 with PPCS > 4 weeks, employed at the time of mTBI who returned to work within the previous year. Managers involved in their RTW process. OUTCOME MEASURES: Work status, working hours, work functioning (Work Role Functioning Questionnaire, WRFQ), work productivity. RESULTS: Ninety-two employees and 66 managers were recruited. Three-fourths of the employees had returned to work but only one-third worked under similar conditions. Weekly working hours decreased from 36,3 hours (SD = 10,5) before mTBI to 17,6 hours (SD = 9,7). Employees had difficulties with tasks 43% of time (WRFQ). They needed more breaks, struggled with multitasking and work speed. About 65.9% experienced affected work productivity. Managers reported lack of knowledge and difficulties assessing the number of working hours and suitable tasks. CONCLUSIONS: Most employees returned to work but only a minority worked under similar conditions as before mTBI. Employees and managers struggled to estimate workload. The affected employees and their workplaces need a long-term RTW support.

[Cardiac biomarkers prior to noncardiac surgery]. / Kardiale Biomarker vor nicht-kardiochirurgischen Eingriffen.

BACKGROUND: Cardiac biomarkers, such as high-sensitivity cardiac troponin (hs-cTn) and brain natriuretic peptide (BNP) or N­terminal prohormone of brain natriuretic peptide (NT-proBNP) are measured perioperatively to improve the prognosis and risk prediction. The European Society of Cardiology (ESC), European Society of Anesthesiology and Intensive Care (ESAIC) and the German Society of Anesthesiology and Intensive Care Medicine (DGAI) have recently published guidelines on the use of cardiac biomarkers prior to surgery. OBJECTIVE/RESEARCH QUESTION: This article provides an overview of the available evidence on perioperative troponin and BNP/NT-proBNP measurements. Current guideline recommendations are presented and discussed. MATERIAL AND METHODS: MEDLINE, Cochrane and google.scholar were searched for relevant keywords. Titles and abstracts of identified papers were checked for relevance and published results were summarized. Guideline recommendations from the ESC, ESAIC and DGAI are presented, compared and evaluated based on the available literature. In addition, the significance of new perioperative cardiac biomarkers is discussed based on the existing evidence. RESULTS: The definitions, diagnosis and management of cardiovascular events in the perioperative context differ from those in the nonsurgical setting. The evidence for the measurement of hs-cTn and BNP/NT-proBNP is evaluated differently in the guidelines and the resulting recommendations are partly contradictory. In particular, recommendations for changes in perioperative management based on biomarker measurements diverge. The ESC guidelines propose an algorithm that uses preoperative biomarkers as the basis for additional cardiac investigations. In particular, invasive coronary angiography is recommended for patients with stable chronic coronary syndrome who have no preoperative cardiac symptoms but elevated biomarkers. In contrast, the ESAIC guidelines emphasize that the available evidence is not sufficient to use perioperative biomarker measurements as a basis for a change in perioperative management. DISCUSSION: Treating physicians should coordinate interdisciplinary (surgery, anesthesiology, cardiology) recommendations for clinical practice based on the aforementioned guidelines. If cardiac biomarkers are routinely determined in high-risk patients, this should be done in accordance with the ESC algorithm.

Acyclovir treatment of varicella-zoster virus meningeal infections and acute kidney injury: a multicentre case series study.

BACKGROUND: Systematic treatment with intravenous acyclovir is usually given when varicella zoster virus (VZV) DNA is isolated in cerebrospinal fluid (CSF), indicating central nervous system (CNS) involvement. Our study aimed to describe therapeutic management and acute kidney injury (AKI) occurrence during acyclovir treatment of VZV infection with CNS involvement. METHODS: Multicentre, retrospective study including all patients from 2010 to 2022 with VZV DNA in CSF. Patient management and outcomes were compared according to clinical presentation and indications for intravenous acyclovir: i) definite (encephalitis, myelitis or stroke, peripheral nervous system (PNS) with ≥ 2 roots, herpes zoster ≥ 3 dermatomes, immunosuppression), ii) questionable (1 or 2 dermatomes) or iii) no indication (other situations). RESULTS: 154 patients were included (median age 66 (interquartile range 43-77), 87 (56%) males); 60 (39%) had encephalitis, myelitis or stroke, 35 (23%) had PNS involvement, 37 (24%) had isolated meningitis, 14 (9%) had isolated cutaneous presentation, and 8 (5%) had other presentations. Overall, 128 (83%) received intravenous acyclovir for more than 72 h. AKI occurred in 57 (37%) patients. Finally, 42 (27%) and 25 (16%) patients had respectively no or a questionable indication for intravenous acyclovir, while 29 (69%) and 23 (92%) of them received it for more than 72 h, with AKI in 13 (35%) and 13 (52%) patients, respectively. In-hospital mortality was 12% (n = 18), and no deaths were reported in isolated meningitis. CONCLUSIONS: Intravenous acyclovir is widely prescribed when VZV DNA is isolated in CSF, regardless of the clinical presentation, with a high rate of AKI. Further studies are needed to better define the value of intravenous acyclovir in isolated VZV meningitis.

Endoscopic Tissue Expander Implantation in Post-Burn Reconstruction: A Review of the Literature.

BACKGROUND: Tissue expansion generates new tissue that can be used in post-burn reconstruction. Expanders are placed through small incisions, requiring difficult and sometimes blind dissection to prepare an adequate pocket. Recently, the use of endoscopy to assist in expander placement has been described, which may improve intraoperative visualization and allow for a smaller incision. In this review, we summarize the existing literature of endoscopic tissue expander (TE) placement in post-burn reconstruction and highlight areas for future research. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were utilized to conduct this review. The following databases were queried for the initial search of relevant articles: PubMed, Embase, Scopus, Cochrane, and Web of Science. The data was assessed qualitatively due to the heterogeneity in reporting between the studies. RESULTS: Our literature query yielded 1,023 studies. Sixteen manuscripts underwent full-text review, and seven met inclusion criteria. All studies demonstrated that the endoscopic approach led to successful tissue expansion. Four articles performed a comparative analysis between the open and endoscopic approach, all of which found a significant reduction in complications like seroma, hematoma formation, and device exposure with endoscopic TE implantation. Two studies demonstrated that the use of endoscopy significantly reduced operative time and length of stay. CONCLUSION: Endoscopy is a safe and effective tool in tissue expansion for post-burn reconstruction. Further prospective research should include evaluating the cost-benefit of this approach and long-term outcomes for patients who have undergone endoscopic-assisted tissue expander placement.

Long-term Outcomes of Multiligament Knee Injuries in American Football Players.

BACKGROUND: Long-term outcomes for isolated anterior cruciate ligament (ACL) reconstructions in competitive American football athletes are well reported in the literature, but little data currently exist regarding multiligament knee injury (MLKI) reconstruction outcomes. PURPOSE: To examine patient-reported and return-to-sport outcomes of competitive American football athletes who underwent primary, single-staged, multiligament knee reconstruction. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We identified patients from our institution's prospectively collected data repository between 2001 and 2020 who underwent single-staged surgical reconstruction of an MLKI sustained during competitive participation in American football. We assessed patient-reported outcomes at a minimum of 2 years after surgery using the International Knee Documentation Committee (IKDC) Subjective Knee Form and questions regarding surgical satisfaction and return to sport. Successful return to sport was defined as a return to preinjury level of competition. We summarized all outcome data and compared outcomes between 2-ligament and >2-ligament groups and between ACL-only MLKI injury and bicruciate MLKI injury groups using independent t test for IKDC scores and chi-square test for return to sport. Additionally, we evaluated predictors of postoperative IKDC scores using linear regression and predictors of return to sport using logistic regression. RESULTS: Outcome data were successfully collected for 53 of 73 total eligible patients (73%; mean follow-up time, 7.7 ± 4.0 years; all male; mean age at surgery, 18.1 ± 2.7 years). The mean postoperative IKDC score was 84 ± 16. The most common level of preinjury competition was high school (n = 36; 68%), followed by college (n = 10; 19%). Seven patients did not return to sport competition at any level due to limitations from their knee surgery, and 82% of patients that attempted to return to preinjury level of sport were able to do so. A total of 50 patients (94%) were satisfied or very satisfied with their surgical outcome. The 2-ligament (n = 39) and >2-ligament (n = 14) groups did not significantly differ in IKDC scores (P = .96) or proportions with successful return to sport (P = .77). Similarly, the ACL-MLKI injury (n = 39) and bicruciate MLKI injury (n = 14) groups did not significantly differ in IKDC scores (P = .89) or proportions with successful return to sport (P = .77). Age and body mass index were not significantly associated with IKDC scores or successful return to sport at follow-up (all P > .05). CONCLUSION: This study may represent the largest cohort of competitive American football athletes evaluated for longitudinal outcomes after multiligament knee reconstruction. Despite the severity of these injuries, we found good knee-related function and that the large majority of athletes who attempted to return to sport were successful. The majority of athletes (94%) were satisfied with their operative treatment.

ANXA1sp modulates the protective effect of Sirt3-induced mitophagy against sepsis-induced myocardial injury in mice.

AIM: Sepsis-induced myocardial injury (SIMI) may be associated with insufficient mitophagy in cardiomyocytes, but the exact mechanism involved remains unknown. Sirtuin 3 (Sirt3) is mainly found in the mitochondrial matrix and is involved in repairing mitochondrial function through means such as the activation of autophagy. Previously, we demonstrated that the annexin-A1 small peptide (ANXA1sp) can promote Sirt3 expression in mitochondria. In this study, we hypothesized that the activation of Sirt3 by ANXA1sp induces mitophagy, thereby providing a protective effect against SIMI in mice. METHODS: A mouse model of SIMI was established via cecal ligation and puncture. Intraperitoneal injections of ANXA1sp, 3TYP, and 3MA were administered prior to modeling. After successful modeling, IL-6, TNF-α, CK-MB, and CTn-I levels were measured; cardiac function was assessed using echocardiography; myocardial mitochondrial membrane potential, ROS, and ATP production were determined; myocardial mitochondrial ultrastructure was observed using transmission electron microscopy; and the expression levels of Sirt3 and autophagy-related proteins were detected using western blotting. RESULTS: ANXA1sp significantly reduced serum IL-6, TNF-α, CK-MB, and CTn-I levels; decreased myocardial ROS production; increased mitochondrial membrane potential and ATP synthesis; and improved myocardial mitochondrial ultrastructure in septic mice. Furthermore, ANXA1sp promoted Sirt3 expression and activated the AMPK-mTOR pathway to induce myocardial mitophagy. These protective effects of ANXA1sp were reversed upon treatment with the Sirt3 blocker, 3-TYP. CONCLUSION: ANXA1sp can reverse SIMI, and the underlying mechanism may be related to the activation of the AMPK-mTOR pathway following upregulation of Sirt3 by ANXA1sp, which, in turn, induces autophagy.

Prevalence and Correlates of Poor Safety Awareness and Accidental Injury in AASD, ADHD, ASD + ADHD, and Neurotypical Youth Samples.

The purpose of the present study is to compare risk and predictors of poor safety awareness and accidental injuries in ASD, ADHD, and neurotypical samples. Neurodivergent groups (ADHD-I n = 309; ADHD-C n = 747; ASD-only n = 328; ASD + ADHD n = 1,108) were 2-17 years old. The neurotypical group (n = 186) was 6-12 years of age. Maternal ratings on the Pediatric Behavior Scale examined safety awareness, accidental injury, and psychological problems. Children with ASD + ADHD had significantly poorer safety awareness and accidental injury ratings than all other groups. Predictors of poor safety awareness in the total ASD and/or ADHD sample were: impulsivity, younger age, lower IQ, and hyperactivity. Predictors of accidental injuries were: incoordination, hyperactivity, and conduct problems. Clinicians working with children who have ASD and ADHD are encouraged to screen for poor safety awareness, discuss child safety measures, and provide evidence-based intervention to improve safety awareness and mitigate the risk of injury.

Management of Meniscus Pathology with Concomitant Anterior Cruciate Ligament Injury.

PURPOSE OF REVIEW: The purpose of this review is to summarize current clinical knowledge on the prevalence and types of meniscus pathology seen with concomitant anterior cruciate ligament (ACL) injury, as well as surgical techniques, clinical outcomes, and rehabilitation following operative management of these pathologies. RECENT FINDINGS: Meniscus pathology with concomitant ACL injury is relatively common, with reports of meniscus pathology identified in 21-64% of operative ACL injuries. These concomitant injuries have been associated with increased age and body mass index. Lateral meniscus pathology is more common in acute ACL injury, while medial meniscus pathology is more typical in chronic ACL deficiency. Meniscus tear patterns associated with concomitant ACL injury include meniscus root tears, lateral meniscus oblique radial tears of the posterior horn (14%), and ramp lesions of the medial meniscus (8-24%). These meniscal pathologies with concomitant ACL injury are associated with increased rotational laxity and meniscal extrusion. There is a paucity of comparative studies to determine the optimal meniscus repair technique, as well as rehabilitation protocol, depending on specific tear pattern, location, and ACL reconstruction technique. There has been a substantial increase in recent publications demonstrating the importance of meniscus repair at the time of ACL repair or reconstruction to restore knee biomechanics and reduce the risk of progressive osteoarthritic degeneration. Through these studies, there has been a growing understanding of the meniscus tear patterns commonly identified or nearly missed during ACL reconstruction. Surgical management of meniscal pathology with concomitant ACL injury implements the same principles as utilized in the setting of isolated meniscus repair alone: anatomic reduction, biologic preparation and augmentation, and circumferential compression. Advances in repair techniques have demonstrated promising clinical outcomes, and the ability to restore and preserve the meniscus in pathologies previously deemed irreparable. Further research to determine the optimal surgical technique for specific tear patterns, as well as rehabilitation protocols for meniscus pathology with concomitant ACL injury, is warranted.

The Combination of Zhuli Decoction and N-butylphthalide Inhibits Cell Apoptosis Induced by CO Poisoning through the PI3K/AKT/GSK-3ß Signaling Pathway.

Carbon monoxide poisoning (COP) represents a significant global health burden, characterized by its morbidity and high mortality rates. The pathogenesis of COP-induced brain injury is complex, and effective treatment modalities are currently lacking. In this study, we employed network pharmacology to identify therapeutic targets and associated signaling pathways of Zhuli Decoction (ZLD) for COP. Subsequently, we conducted both in vitro and in vivo experiments to validate the therapeutic efficacy of ZLD in combination with N-butylphthalide (NBP) for acute COP-induced injury. Our network pharmacology analysis revealed that the primary components of ZLD exerted therapeutic effects through the modulation of multiple targets and pathways. The in vitro and in vivo experiments demonstrated that the combination of NBP and ZLD effectively inhibited apoptosis and up-regulated the activities of P-PI3K (Tyr458), P-AKT (Ser473), P-GSK-3ß (Ser9), and Bcl-2, thus leading to the protection of neuronal cells and improvement in cognitive function in rats following COP, which was better than the effects observed with NBP or ZLD alone. The rescue experiment further showed that LY294002, a PI3K inhibitor, significantly attenuated the therapeutic efficacy of NBP + ZLD. The neuroprotection effects of NBP and ZLD against COP-induced brain injury are closely linked to the activation of the PI3K/AKT/GSK-3ß signaling pathway.

Gum arabic coating alleviates chilling injury of cold-stored peach by regulating reactive oxygen species, phenolic, and sugar metabolism.

In this study, gum arabic (GA) coating was employed to mitigate chilling injury in peach fruit, and it was observed that 10% GA coating exhibited the most favorable effect. GA coating significantly inhibited the decline of AsA content and enhanced antioxidant enzyme activity in peach fruit, thereby enhancing reactive oxygen species (ROS) scavenging rate while reducing its accumulation. Simultaneously, GA coating inhibited the activity of oxidative degradation enzymes for phenolics and enhanced synthase activity, thus maintaining higher levels of total phenolics and flavonoids in fruits. Additionally, compared to the control fruit, GA-coated fruits demonstrated higher concentrations of sucrose and sorbitol, accompanied more robust activity of sucrose synthase and sucrose phosphate synthase, as well as reduced activity of acid invertase and neutral invertase. Our study demonstrates that GA coating can effectively enhance the cold resistance of peach fruit by regulating ROS, phenolics, and sugar metabolism, maintaining high levels of phenolics and sucrose while enhancing antioxidant activity.

Microfluidic human physiomimetic liver model as a screening platform for drug induced liver injury.

The pre-clinical animal models often fail to predict intrinsic and idiosyncratic drug induced liver injury (DILI), thus contributing to drug failures in clinical trials, black box warnings and withdrawal of marketed drugs. This suggests a critical need for human-relevant in vitro models to predict diverse DILI phenotypes. In this study, a porcine liver extracellular matrix (ECM) based biomaterial ink with high printing fidelity, biocompatibility and tunable rheological and mechanical properties is formulated for supporting both parenchymal and non-parenchymal cells. Further, we applied 3D printing and microfluidic technology to bioengineer a human physiomimetic liver acinus model (HPLAM), recapitulating the radial hepatic cord-like structure with functional sinusoidal microvasculature network, biochemical and biophysical properties of native liver acinus. Intriguingly, the human derived hepatic cells incorporated HPLAM cultured under physiologically relevant microenvironment, acts as metabolic biofactories manifesting enhanced hepatic functionality, secretome levels and biomarkers expression over several weeks. We also report that the matured HPLAM reproduces dose- and time-dependent hepatotoxic response of human clinical relevance to drugs typically recognized for inducing diverse DILI phenotypes as compared to conventional static culture. Overall, the developed HPLAM emulates in vivo like functions and may provide a useful platform for DILI risk assessment to better determine safety and human risk.

In vitro modeling of skeletal muscle ischemia-reperfusion injury based on sphere differentiation culture from human pluripotent stem cells.

Skeletal muscle ischemia-reperfusion (IR) injury poses significant challenges due to its local and systemic complications. Traditional studies relying on two-dimensional (2D) cell culture or animal models often fall short of faithfully replicating the human in vivo environment, thereby impeding the translational process from animal research to clinical applications. Three-dimensional (3D) constructs, such as skeletal muscle spheroids with enhanced cell-cell interactions from human pluripotent stem cells (hPSCs) offer a promising alternative by partially mimicking human physiological cellular environment in vivo processes. This study aims to establish an innovative in vitro model, human skeletal muscle spheroids based on sphere differentiation from hPSCs, to investigate human skeletal muscle developmental processes and IR mechanisms within a controlled laboratory setting. By eticulously recapitulating embryonic myogenesis through paraxial mesodermal differentiation of neuro-mesodermal progenitors, we successfully established 3D skeletal muscle spheroids that mirror the dynamic colonization observed during human skeletal muscle development. Co-culturing human skeletal muscle spheroids with spinal cord spheroids facilitated the formation of neuromuscular junctions, providing functional relevance to skeletal muscle spheroids. Furthermore, through oxygen-glucose deprivation/re-oxygenation treatment, 3D skeletal muscle spheroids provide insights into the molecular events and pathogenesis of IR injury. The findings presented in this study significantly contribute to our understanding of skeletal muscle development and offer a robust platform for in vitro studies on skeletal muscle IR injury, holding potential applications in drug testing, therapeutic development, and personalized medicine within the realm of skeletal muscle-related pathologies.

Kaempferol mitigates sepsis-induced acute lung injury by modulating the SphK1/ S1P/ SIPR1/ MLC2 signaling pathway to restore the integrity of the pulmonary endothelial cell barrier.

Sepsis-induced acute lung injury (SALI) is the common complication of sepsis, resulting in high incidence and mortality rates. The primary pathogenesis of SALI is the interplay between acute inflammation and endothelial barrier damage. Studies have shown that kaempferol (KPF) has anti-sepsis properties. Sphingosine kinase 1 (Sphk1)/sphingosine-1-phosphate (S1P) signaling pathway's significance in acute lung damage and S1P Receptor 1 (S1PR1) agonists potential in myosin light chain 2 (MLC2) phosphorylation are documented. Whether KPF can regulate the SphK1/S1P/SIPR1/MLC2 signaling pathway to protect the lung endothelial barrier remains unclear. This study investigates the KPF's therapeutic effects and molecular mechanisms in repairing endothelial cell barrier damage in both LPS-induced sepsis mice and human umbilical vein endothelial cells (HUVECs). KPF significantly reduced lung tissue damage and showed anti-inflammatory effects by decreasing IL-6 and TNF-α synthesis in the sepsis mice model. Further, KPF administration can reduce the high permeability of the LPS-induced endothelial cell barrier and alleviate lung endothelial cell barrier injury. Mechanistic studies showed that KPF pretreatment can suppress MLC2 hyperphosphorylation and decrease SphK1, S1P, and S1PR1 levels. The SphK1/S1P/S1PR1/MLC2 signaling pathway controls the downstream proteins linked to endothelial barrier damage, and the Western blot (WB) showed that KPF raised the protein levels. These proteins include zonula occludens (ZO)-1, vascular endothelial (VE)-cadherin and Occludin. The present work revealed that in mice exhibiting sepsis triggered by LPS, KPF strengthened the endothelial barrier and reduced the inflammatory response. The SphK1/S1P/S1PR1/MLC2 pathway's modulation is the mechanism underlying this impact.

Ginkgolic acids induce liver injury in mice through cell cycle arrest and immune stress under specific condition.

Ginkgo biloba L. is a valuable plant, which can be used for medicine, food and ornamental purposes. Despite the above benefits, the components of ginkgolic acids (GA) in ginkgo are considered to cause allergies, embryotoxicity, liver damage and some other adverse reactions. However, the mechanism of GA induced liver injury is still unclear. In this study, we developed an acute liver injury model induced by GA in mice, and investigated the mechanism of GA induced liver injury from the perspectives of oxidative stress, steatosis, apoptosis, and immune response. Intraperitoneal injection of GA (400 mg/kg) can cause liver damage. The levels of serum transaminase, oxidation and triglycerides were increased, liver fibrosis, hepatocyte apoptosis, G2/M phase arrest of the hepatic cell cycle and monocyte infiltration in the liver were detected in GA-treated mice. Flow cytometry analysis of cells separated from the spleen showed that the proportion of Th1 and Th17 cells were increased, and the proportion of Th2 cells were decreased in GA-treated mice. The rise in Th1/Th2 ratio and Th17 cell ratio usually cause inflammatory problems. At the same time, cleaved Caspase-8 and Caspase-3 were detected in hepatocytes, indicating that GA may induce apoptosis through FADD pathway. Although GA is capable of causing the above problems, the inflammation and damage in liver tissue are not severe and there are certain individual differences. Our study reveals the potential hepatotoxicity of GA in ginkgo and its mechanism of action, providing a new perspective for the intervention and prevention of ginkgo toxicity.