Current Knowledge and Perspectives of Phage Therapy for Combating Refractory Wound Infections.

Wound infection is one of the most important factors affecting wound healing, so its effective control is critical to promote the process of wound healing. However, with the increasing prevalence of multi-drug-resistant (MDR) bacterial strains, the prevention and treatment of wound infections are now more challenging, imposing heavy medical and financial burdens on patients. Furthermore, the diminishing effectiveness of conventional antimicrobials and the declining research on new antibiotics necessitate the urgent exploration of alternative treatments for wound infections. Recently, phage therapy has been revitalized as a promising strategy to address the challenges posed by bacterial infections in the era of antibiotic resistance. The use of phage therapy in treating infectious diseases has demonstrated positive results. This review provides an overview of the mechanisms, characteristics, and delivery methods of phage therapy for combating pathogenic bacteria. Then, we focus on the clinical application of various phage therapies in managing refractory wound infections, such as diabetic foot infections, as well as traumatic, surgical, and burn wound infections. Additionally, an analysis of the potential obstacles and challenges of phage therapy in clinical practice is presented, along with corresponding strategies for addressing these issues. This review serves to enhance our understanding of phage therapy and provides innovative avenues for addressing refractory infections in wound healing.

Interdigital-type antifungal socks for prevention and treatment of tinea pedis.

BACKGROUND: Interdigital tinea pedis is the most common type of foot infection, which is often treated by topical or systemic antifungals. Due to the increase in antifungal resistance, antifungal socks are becoming potential alternatives for the daily management of tinea pedis. METHODS: In this study, antifungal fibres were adopted to produce interdigital hygiene socks to split the third and fourth toe seams of the feet. In vitro antifungal activity was first examined to verify the effectiveness of the socks. Preventive efficacy against tinea pedis was then evaluated among healthy participants, followed by therapeutic effect detection in patients diagnosed with tinea pedis by analysing the improvement in total symptom scores (TTS). RESULTS: The interdigital-type hygiene socks exhibited apparent antifungal activities in vitro. An in vivo study demonstrated significant preventive effects against tinea pedis for interdigital socks compared to plain socks (P = 0.011) and a lower TTS than noninterdigital (P = 0.04) or plain socks (P < 0.0001). Moreover, interdigital socks showed a total effectiveness rate of 72.9% in patients with tinea pedis, with most of the symptoms alleviated. CONCLUSION: Interdigital-type hygiene socks not only exhibited in vitro antifungal activities but also showed significant prophylactic and therapeutic effects against interdigital tinea pedis in vivo.

[Role of NLRP3 inflammasomes in musculoskeletal disorders].

Inflammasomes are innate immune sensors and receptors that play key pathological roles in the development and progression of numerous diseases. Recent studies have shown that NLRP3 inflammasomes are critical in the pathology of diseases with a high impact on public health, such as musculoskeletal disorders. Musculoskeletal disorders, mainly caused or aggravated by work and the surrounding environment, are locomotor system disorders such as muscles, joints, bones, as well as diseases associated with neurological and circulatory system injuries. Activation of NLRP3 inflammasomes can induce inflammation and pyroptosis, leading to further bodily harm. Therefore, investigating the mechanism and function of NLRP3 inflammasomes, holds great significance and importance for the prevention and treatment of musculoskeletal disorders. This review provides a summary of the activation pathway and mechanism of NLRP3 inflammasomes, and analyzes the role in musculoskeletal disorders such as sarcopenia, osteoporosis and arthritis, with the aim to facilitate the treatment of musculoskeletal disorders.

Combination of H1 and H2 Histamine Receptor Antagonists: Current Knowledge and Perspectives of a Classic Treatment Strategy.

Histamine receptor antagonists, which can bind to specific histamine receptors on target cells, exhibit substantial therapeutic efficacy in managing a variety of histamine-mediated disorders. Notably, histamine H1 and H2 receptor antagonists have been extensively investigated and universally acknowledged as recommended treatment agents for numerous allergic diseases and acid-related disorders, respectively. Historically, the combination of H1 and H2 receptor antagonists has been considered a classic treatment strategy, demonstrating relatively superior efficacy compared with single-drug therapies in the treatment of diverse histamine-mediated diseases. The latest emerging studies have additionally suggested the underlying roles of histamine and H1R and H2R in the development of anxiety disorders, arthritic diseases, and postexercise hypotension. Nevertheless, there is still a lack of systematic reviews on the clinical efficacy of combination therapy, greatly limiting our understanding of its clinical application. Here, we present a comprehensive overview of the current knowledge and perspectives regarding the combination of H1 and H2 histamine receptor antagonists in various histamine-mediated disorders. Furthermore, we critically analyze the adverse effects and limitations associated with combination therapy while suggesting potential solutions. Our review can offer a systematic summary and promising insights into the in-depth and effective application of the combination of H1 and H2 receptor antagonists.

Lactate induces C2C12 myoblasts differentiation by mediating ROS/p38 MAPK signalling pathway.

Lactate serves not merely as an energy substrate for skeletal muscle but also regulates myogenic differentiation, leading to an elevation of reactive oxygen species (ROS) levels. The present study was focused on exploring the effects of lactate and ROS/p38 MAPK in promoting C2C12 myoblasts differentiation. Our results demonstrated that lactate increased C2C12 myoblasts differentiation at a range of physiological concentrations, accompanied by enhanced ROS contents. We used n-acetylcysteine (NAC, a ROS scavenger) pretreatment and found that it delayed lactate-induced C2C12 myoblast differentiation by upregulating Myf5 expression on days 5 and 7 and lowering MyoD and MyoG expression. The finding implies that lactate accompanies ROS-dependent manner to promote C2C12 myoblast differentiation. Additionally, lactate significantly increased p38 MAPK phosphorylation to promote C2C12 cell differentiation, but pretreatment with SB203580 (p38 MAPK inhibitor) reduced lactate-induced C2C12 myoblasts differentiation. whereas lactate pretreatment with NAC inhibited p38 MAPK phosphorylation in C2C12 cells, demonstrating that lactate mediated ROS and regulated the p38 MAPK signalling pathway to promote C2C12 cell differentiation. In conclusion, our results suggest that the promotion of C2C12 myoblasts differentiation by lactate is dependent on ROS and the p38 MAPK signalling pathway. These observations reveal a beneficial role for lactate in increasing myogenesis through ROS-sensitive mechanisms as well as providing new ideas regarding the positive impact of ROS in improving the function of skeletal muscle.

Lactate ameliorates palmitate-induced impairment of differentiative capacity in C2C12 cells through the activation of voltage-gated calcium channels.

Palmitic acid (PA), a saturated fatty acid enriched in high-fat diet, has been implicated in the development of skeletal muscle regeneration dysfunction. This study aimed to examine the effects and mechanisms of lactate (Lac) treatment on PA-induced impairment of C2C12 cell differentiation capacity. Furthermore, the involvement of voltage-gated calcium channels in this context was examined. In this study, Lac could improve the PA-induced impairment of differentiative capacity in C2C12 cells by affecting Myf5, MyoD and MyoG. In addition, Lac increases the inward flow of Ca2+, and promotes the depolarization of the cell membrane potential, thereby activating voltage-gated calcium channels during C2C12 cell differentiation. The enchancement of Lac on myoblast differentiative capacity was abolished after the addition of efonidipine (voltage-gated calcium channel inhibitors). Therefore, voltage-gated calcium channels play an important role in improving PA-induced skeletal muscle regeneration disorders by exercising blood Lac. Our study showed that Lac could rescue the PA-induced impairment of differentiative capacity in C2C12 cells by affecting Myf5, MyoD and MyoG through the activation of voltage-gated calcium channels.

Gooderoside A from Anoectochilus elatus attenuates acute and chronic pains by inhibiting NO/cGMP and IRAK4/IRAK1/TAK1 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Anoectochilus elatus Lindl. was traditionally used for pain treatment and Gooderoside A (GA) was regarded as its principal constituent. AIM OF THE STUDY: To investigate whether GA can be responsible for the antinociceptive activity of A. elatus and explore its underlying mechanism. MATERIALS AND METHODS: Acetic acid-induced abdominal writhing and tail flick tests were employed to evaluate the antinociceptive activity of ethanolic extract of A. elatus (EEA) and GA. Formalin test was used to ascertain the antinociceptive pattern of GA. Entobarbital sodium induced sleep test was adopted to exclude its hypnotic effect, while open-field test was performed to rule out its motor impairment effect. Chronic constriction injury (CCI)-induced neuropathic pain in rats was developed to evaluate its efficacy on neuropathic pain, and BV-2 cells were used to explore the underlying mechanism. RESULTS: EEA and GA, significantly inhibited chemical and thermal nociception. GA suppressed nociception in formalin test in both phase I and II, whereas methylene blue and L-NAME partially reversed its efficacy. GA located inner and slightly blocked sodium channel current, and did not show any hypnotic effect or motor impairment effect. Crucially, GA markedly attenuated chronic neuropathic pain in rats, inhibited the phosphorylation of IRAK4, IRAK1 and TAK1, and suppressed MAPKs pathway in BV-2 cells. CONCLUSION: GA relieved acute and chronic pains in vivo. The mechanism of action involves the blocking of NO/cGMP and IRAK4/IRAK1/TAK1 pathways. These results suggested GA may be a promising candidate for antinociceptive drug development.

Expression and electrophysiological characteristics of VGSC during mouse myoblasts differentiation.

Voltage-gated sodium channels (VGSC) are essential for triggering and relaying action potentials (AP), which perform critical functions in a variety of physiological processes, such as controlling muscle contractions and facilitating the release of neurotransmitters. In this study, we used a mouse C2C12 cell differentiation model to study the molecular expression and channel dynamics of VGSC and to investigate the exact role of VGSC in the development of muscle regeneration. Immunofluorescence, Real-time quantitative polymerase chain reaction, Western blot, and whole-cell patch clamp were employed for this purpose in mouse myoblasts. The findings revealed an increase in intracellular sodium concentration, NaV1.4 gene expression, and protein expression with the progress of differentiation (days 0, 1, 3, 5 and 7). Furthermore, VGSC dynamics exhibit the following characteristics: ① The increase of sodium current (INa); ② The decrease in the activation threshold and the voltage trigger maximum of INa; ③ A positive shift in the steady-state inactivation curve; ④ The recovery of INa during repolarization is delayed, the activity-dependent decay rate of INa was accelerated, and the proportionate amount of the fraction of activated channels was reduced. Based on these results, it is postulated that the activation threshold of AP could be decreased, and the refractory period could be extended with the extension of differentiation duration, which may contribute to muscle contraction. Taken together, VGSC provides a theoretical and empirical basis for exploring potential targets for neuromuscular diseases and other therapeutic muscle regeneration dysfunctions.

Tri-Layer Core-Shell Fibers from Coaxial Electrospinning for a Modified Release of Metronidazole.

Polymers are the backbone of drug delivery. Electrospinning has greatly enriched the strategies that have been explored for developing novel drug delivery systems using polymers during the past two decades. In this study, four different kinds of polymers, i.e., the water-soluble polymer poly (vinyl alcohol) (PVA), the insoluble polymer poly(ε-caprolactone) (PCL), the insoluble polymer Eudragit RL100 (ERL100) and the pH-sensitive polymer Eudragit S100 (ES100) were successfully converted into types of tri-layer tri-polymer core-shell fibers through bi-fluid coaxial electrospinning. During the coaxial process, the model drug metronidazole (MTD) was loaded into the shell working fluid, which was an emulsion. The micro-formation mechanism of the tri-layer core-shell fibers from the coaxial emulsion electrospinning was proposed. Scanning electron microscope and transmission electron microscope evaluations verified the linear morphology of the resultant fibers and their obvious tri-layer multiple-chamber structures. X-ray diffraction and Fourier transform infrared spectroscopy measurements demonstrated that the drug MTD presented in the fibers in an amorphous state and was compatible with the three polymeric matrices. In vitro dissolution tests verified that the three kinds of polymer could act in a synergistic manner for a prolonged sustained-release profile of MTD in the gut. The drug controlled-release mechanisms were suggested in detail. The protocols reported here pioneer a new route for creating a tri-layer core-shell structure from both aqueous and organic solvents, and a new strategy for developing advanced drug delivery systems with sophisticated drug controlled-release profiles.

Serum anti-phospholipase A2 receptor antibody in pathological diagnosis of type 2 diabetes mellitus patients with proteinuria.

Patients with diabetes mellitus complicated with proteinuria can be diabetic nephropathy (DN), diabetic complicated with non-diabetic kidney disease (NDKD), or DN with NDKD. Among these membranous nephropathy accounted for a large proportion of DN with NDRD. At present, serum anti-phospholipase A2 receptor (PLA2R) antibody is widely used in the diagnosis and evaluation of therapy in idiopathic membranous nephropathy, our study aimed to investigate the diagnostic significance of anti-PLA2R antibody in type 2 diabetes mellitus (T2DM) patients with proteinuria, providing a method for patients with contraindications of kidney biopsy. Eighty-seven T2DM patients with proteinuria who went on kidney biopsy were divided into the DN group, idiopathic membranous nephropathy (IMN) group, and others group according to their pathological results. In our study, 52.87% and 28.74% of patients were found to have IMN and diabetic nephropathy respectively. The levels of anti-PLA2R antibody, total cholesterol, triglyceride, and estimated glomerular filtration rate (eGFR) were higher in the IMN group, while the prevalence of diabetic retinopathy (DR), systolic blood pressure (SBP) and HbA1c were higher in the DN group. For T2DM patients with proteinuria, anti-PLA2R antibody (AUC = 0.904, 95%CI 0.838-0.970) has a high diagnostic value for IMN. The duration of diabetes (OR = 0.798, P = 0.030), eGFR level (OR = 1.030, P = 0.024), and positive anti-PLA2R antibody (OR = 72.727, P < 0.001) favor the diagnosis of IMN, while DR (OR = 50.234, P < 0.001), SBP (OR = 1.041, P = 0.030), and negative anti-PLA2R antibody (OR = 0.008, P = 0.001) is beneficial to the diagnosis of DN. Our study found that NDKD is not uncommon in patients with T2DM and proteinuria, and IMN was the main pathological type. Positive anti-PLA2R antibody has a strong accuracy in the diagnosis of IMN in patients with T2DM and proteinuria.

New insight into the role of fibroblasts in the epithelial immune microenvironment in the single-cell era.

The skin is exposed to environmental challenges and contains heterogeneous cell populations such as epithelial cells, stromal cells, and skin-resident immune cells. As the most abundant type of stromal cells, fibroblasts have been historically considered silent observers in the immune responses of the cutaneous epithelial immune microenvironment (EIME), with little research conducted on their heterogeneity and immune-related functions. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have overcome the limitations of bulk RNA sequencing and help recognize the functional and spatial heterogeneity of fibroblasts, as well as their crosstalk with other types of cells in the cutaneous EIME. Recently, emerging single-cell sequencing data have demonstrated that fibroblasts notably participate in the immune responses of the EIME and impact the initiation and progression of inflammatory skin diseases. Here, we summarize the latest advances in the role of fibroblasts in the cutaneous EIME of inflammatory skin diseases and discuss the distinct functions and molecular mechanisms of activated fibroblasts in fibrotic skin diseases and non-fibrotic inflammatory skin diseases. This review help unveil the multiple roles of fibroblasts in the cutaneous EIME and offer new promising therapeutic strategies for the management of inflammatory skin diseases by targeting fibroblasts or the fibroblast-centered EIME.

Integrating Chinese Herbs and Western Medicine for New Wound Dressings through Handheld Electrospinning.

In this nanotechnology era, nanostructures play a crucial role in the investigation of novel functional nanomaterials. Complex nanostructures and their corresponding fabrication techniques provide powerful tools for the development of high-performance functional materials. In this study, advanced micro-nanomanufacturing technologies and composite micro-nanostructures were applied to the development of a new type of pharmaceutical formulation, aiming to achieve rapid hemostasis, pain relief, and antimicrobial properties. Briefly, an approach combining a electrohydrodynamic atomization (EHDA) technique and reversed-phase solvent was employed to fabricate a novel beaded nanofiber structure (BNS), consisting of micrometer-sized particles distributed on a nanoscale fiber matrix. Firstly, Zein-loaded Yunnan Baiyao (YB) particles were prepared using the solution electrospraying process. Subsequently, these particles were suspended in a co-solvent solution containing ciprofloxacin (CIP) and hydrophilic polymer polyvinylpyrrolidone (PVP) and electrospun into hybrid structural microfibers using a handheld electrospinning device, forming the EHDA product E3. The fiber-beaded composite morphology of E3 was confirmed through scanning electron microscopy (SEM) images. Fourier-transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) analysis revealed the amorphous state of CIP in the BNS membrane due to the good compatibility between CIP and PVP. The rapid dissolution experiment revealed that E3 exhibits fast disintegration properties and promotes the dissolution of CIP. Moreover, in vitro drug release study demonstrated the complete release of CIP within 1 min. Antibacterial assays showed a significant reduction in the number of adhered bacteria on the BNS, indicating excellent antibacterial performance. Compared with the traditional YB powders consisting of Chinese herbs, the BNS showed a series of advantages for potential wound dressing. These advantages include an improved antibacterial effect, a sustained release of active ingredients from YB, and a convenient wound covering application, which were resulted from the integration of Chinese herbs and Western medicine. This study provides valuable insights for the development of novel multiscale functional micro-/nano-composite materials and pioneers the developments of new types of medicines from the combination of herbal medicines and Western medicines.

Brain-targeted nanoreactors prevent the development of organophosphate-induced delayed neurological damage.

BACKGROUND: Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed. METHODS: We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood-brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed. RESULTS: The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality. CONCLUSION: The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders.

Association of serum 25-hydroxyvitamin D3, fibroblast growth factor-23, and C1q/tumor necrosis factor-related protein-3 with coronary artery calcification in nondialysis chronic kidney disease patients.

OBJECTIVE: To assess serum 25-hydroxyvitamin D3 (25(OH)D3), fibroblast growth factor 23 (FGF23), and C1q/tumor necrosis factor-related protein-3 (CTRP3) levels in nondialysis chronic kidney disease (CKD) patients and their relationship with coronary artery calcification (CAC). METHODS: One hundred and twenty-eight patients diagnosed with CKD were selected and all underwent cardiac computed tomography. CAC was assessed using the Agatston score, and coronary artery calcification score (CACs) >10 was identified as CAC. The differences in serum 25(OH)D3, FGF23, and CTRP3 levels between the CAC and non-CAC groups were analyzed. Their correlation with CACs was assessed by Spearman's analysis, and logistic regression analysis was used to find risk factors for CAC. RESULTS: Compared to the non-CAC group, the CAC group was older (64.21 ± 9.68 years), with a higher percentage of hypertension (93.10%) and diabetes (63.80%) and higher levels of serum CTRP3 [1079.20 (644.4-1567.2) ng/mL]. However, there was no significant difference in serum 25(OH)D3 and FGF23 between these two groups. The high level CTRP3 group had a higher prevalence of CAC (61.5%). Logistic regression results showed that age, diabetes, decreased 25(OH)D3 (odds ratio (OR) = 0.95, p = .030) and high levels of CTRP3 (OR = 3.19, p = .022) were risk factors for CAC in nondialysis CKD patients. CONCLUSIONS: Serum CTRP3 levels progressively increased with the progression of kidney disease, while 25(OH)D3 levels progressively decreased. Decreased 25(OH)D3 and high levels of CTRP3 are associated with CAC in patients with nondialysis CKD.

Biphasic drug release from electrospun structures.

INTRODUCTION: Biphasic release, as a special drug-modified release profile that combines immediate and sustained release, allows fast therapeutic action and retains blood drug concentration for long periods. Electrospun nanofibers, particularly those with complex nanostructures produced by multi-fluid electrospinning processes, are potential novel biphasic drug delivery systems (DDSs). AREAS COVERED: This review summarizes the most recent developments in electrospinning and related structures. In this review, the role of electrospun nanostructures in biphasic drug release was comprehensively explored. These electrospun nanostructures include monolithic nanofibers obtained through single-fluid blending electrospinning, core-shell and Janus nanostructures prepared via bifluid electrospinning, three-compartment nanostructures obtained via trifluid electrospinning, nanofibrous assemblies obtained through the layer-by-layer deposition of nanofibers, and the combined structure of electrospun nanofiber mats with casting films. The strategies and mechanisms through which complex structures facilitate biphasic release were analyzed. EXPERT OPINION: Electrospun structures can provide many strategies for the development of biphasic drug release DDSs. However, many issues such as the scale-up productions of complex nanostructures, the in vivo verification of the biphasic release effects, keeping pace with the developments of multi-fluid electrospinning, drawing support from the state-of-the-art pharmaceutical excipients, and the combination with traditional pharmaceutical methods need to be addressed for real applications.

Assessment soil cadmium and copper toxicity on barley growth and the influencing soil properties in subtropical agricultural soils.

Evaluation joint cadmium (Cd) and copper (Cu) phytotoxicity in wide range of subtropical agricultural soils is highly vital for phytoremediation of soils contaminated with Cd and Cu. In this study, barley root elongation assays were performed in 30 representative soils in response to single and combined Cd and Cu inhibition. The single Cd caused nearly 50% inhibition of barley root elongation, and Cu induced more than 50% inhibition in most soils. Mixed Cd + Cu caused significant inhibition on barley growth with average relative root elongation values of 20.0% and 30.4% in soil with a pH < 7 and pH > 7, respectively. An antagonistic interaction was evaluated in combined Cd + Cu toxicity, which was strong in soils containing low soluble Cu and Cd contents. Soil pH was the controlling factor in predicting single and mixed Cd and Cu phytotoxicity, which could explain 44% and 46% variation of single Cd and Cu toxicity, respectively. Soil organic carbon and effective cation exchange capacity were another important factor positively influencing metal toxicity, which further improved empirical prediction models accuracy, with determined coefficient (r2) values of 0.44-0.84. These results provide a theoretical basis for soils Cd and Cu pollution control.

HIF1-α upregulation induces proinflammatory factors to boost host killing capacity after Aspergillus fumigatus exposure.

Aims: HIF1-α is an important transcription factor in the regulation of the immune response. The protective function of HIF1-α in the host epithelial immune response to Aspergillus fumigatus requires further clarification. Methods: In this study we demonstrated the effect of upregulation of HIF1-α expression in A549 cells and mouse airway cells exposed to A. fumigatus in vivo. Results: The killing capacity was enhanced by boosting proinflammatory factors both in vitro and in vivo. Moreover, airway inflammation was reduced in the HIF1-α-upregulated mice. Conclusion: We identified a protective role for HIF1-α in anti-A. fumigatus immunity. Modulation of HIF1-α might be a target for the development of aspergillosis therapy.

Inhibition of stress and spontaneous respiration: Efficacy and safety of monitored anesthesia care by target-controlled infusion remifentanil in combination with dexmedetomidine in fibreoptic bronchoscopy for patients with severe tracheal stenosis.

Objective: This study aimed to determine the effective concentration of target-controlled infusion (TCI) of remifentanil used to inhibit stress during the treatment of severe tracheal stenosis with fibreoptic bronchoscopy and to evaluate the monitored anesthesia care (MAC) by remifentanil. Materials and methods: 60 patients with severe tracheal stenosis who underwent fibreoptic bronchoscopy was performed. Dexmedetomidine was initially administered at a bolus dose (0.8 mcg/kg), followed by a 0.5 mcg/(kg⋅h) continuous infusion. Remifentanil was administered by TCI. The effective concentration (EC) of remifentanil was titrated by the improved sequential method, and 30 patients were included. The EC95 of remifentanil was set as the plasma target concentration to evaluate the safety of the MAC, and another 30 patients were included. Results: The half effective effect-chamber concentration of remifentanil (EC50) was 2.243 ng/ml, and the EC95 was 2.710 ng/ml. Among the 30 patients who received an EC95 of remifentanil as the target concentration, one patient was remedied by injecting propofol, the score of Ramsay sedation was three. The incidence of subclinical hypoxemia (SPO2 of 90-95%) was 30%, the incidence of moderate hypoxemia (SPO2 of 75-89%, ≤60 s) was 20 and 86.7% of patients with oxygen saturation was less than 95% returned to normal by awakening. The satisfaction score of the operator was nine, the satisfaction score of the anesthesiologist was eight, the satisfaction score of the patients was 10, the rate of patient willingness to re-accept the procedure was 93.3% and the circulation was stable during the operation. Conclusion: MAC using TCI of remifentanil with continuous pumping dexmedetomidine can effectively inhibit the stress response to fibreoptic bronchoscopy in patients with severe tracheal stenosis while maintaining spontaneous breathing. Under the anesthesia management of an experienced anesthesiologist, it provides a reference to tracheoscopic anesthesia of autonomous breathing. Clinical trial registration: [http://www.chictr.org.cn/], identifier [ChiCTR 2100043380].

Association of ERCC1 rs11615 Polymorphism with the Risk of Cervical Cancer Especially in Chinese Populations: A Meta-Analysis.

Abnormalities of the ERCC1 gene can affect DNA repair pathways, thereby having a vital effect on genomic stability. A growing amount of case-control studies have focused on making an investigation of the association between ERCC1 rs11615 polymorphism and cervical cancer susceptibility. However, the controversial results have raised concerns. To draw a more accurate conclusion, six studies were elaborately selected from the electronic databases for this meta-analysis, with 753 cervical cancer cases and 851 healthy controls. We applied pooled ORs combined with 95% CIs to test the potential associations. Significant associations were revealed in Chinese populations (T vs C: OR = 1.557 and 95%CI = 1.234-1.966; TT vs CC: OR = 3.175 and 95%CI = 1.754-5.748; TT/CT vs CC: OR = 1.512 and 95%CI = 1.126-2,031; and TT vs CT/CC: OR = 2.836 and 95%CI = 1.592-5.051). Even when the studies deviating from HWE were excluded, an increased cervical cancer susceptibility was observed in Chinese. These results disclose that there is an obvious correlation between the risk of cervical cancer and ERCC1 rs11615 polymorphism, especially in Chinese populations, and the T variant is the risky one. Also, our findings need further studies to validate.

Dual-Modal Nanoscavenger for Detoxification of Organophosphorus Compounds.

Organophosphorus compounds (OPs) pose great military and civilian hazards. However, therapeutic and prophylactic antidotes against OP poisoning remain challenging. In this study, we first developed a novel nanoscavenger (rOPH/ZIF-8@E-Lipo) against methyl paraoxon (MP) poisoning using enzyme immobilization and erythrocyte-liposome hybrid membrane camouflage techniques. Then, we evaluated the physicochemical characterization, stability, and biocompatibility of the nanoscavengers. Afterward, we examined acetylcholinesterase (AChE) activity, cell viability, and intracellular reactive oxygen species (ROS) to indicate the protective effects of the nanoscavengers in vitro. Following the pharmacokinetic and biodistribution studies, we further evaluated the therapeutic and prophylactic detoxification efficacy of the nanoscavengers against MP in various poisoning settings. Finally, we explored the penetration capacity of the nanoscavengers across the blood-brain barrier (BBB). The present study validated the successful construction of a novel nanoscavenger with excellent stability and biocompatibility. In vitro, the resulting nanoscavenger exhibited a significant protection against MP-induced AChE inactivation, oxidative stress, and cytotoxicity. In vivo, apart from the positive therapeutic effects, the nanoscavengers also exerted significant prophylactic detoxification efficacy against single lethal MP exposure, repeated lethal MP challenges, and sublethal MP poisoning. These excellent detoxification effects of the nanoscavengers against OPs may originate from a dual-mode mechanism of inner recombinant organophosphorus hydrolase (rOPH) and outer erythrocyte membrane-anchored AChE. Finally, in vitro and in vivo studies jointly demonstrated that monosialoganglioside (GM1)-modified rOPH/ZIF-8@E-Lipo could penetrate the BBB with high efficiency. In conclusion, a stable and safe dual-modal nanoscavenger was developed with BBB penetration capability, providing a promising strategy for the treatment and prevention of OP poisoning.