Design, synthesis, biological evaluation of novel piperidine-based derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a crucial member of DNA repair enzymes responsible for repairing DNA single-strand breaks. Developing PARP inhibitors based on synthetic lethality strategies is an effective approach for treating breast cancer and other diseases. In this study, a series of novel piperidine-based benzamide derivatives were designed and synthesized using structure-based drug design principles. The anticancer activities of these compounds were evaluated against five human cancer cell lines (MDA-MB-436, CAPAN-1, SW-620, HepG2, SKOV3, and PC3) and the preliminary structure-activity relationships were delineated. Among the compounds, 6a and 15d demonstrated potent antiproliferative effects against MDA-MB-436 cells with IC50 values of 8.56 ± 1.07 µM and 6.99 ± 2.62 µM, respectively. Furthermore, both compounds exhibited excellent inhibitory activity against PARP-1, with IC50 values of 8.33 nM and 12.02 nM, respectively. Mechanistic investigations revealed that 6a and 15d effectively inhibited colony formation and cell migration of HCT116 cells. Moreover, they induced apoptosis by upregulating the expression of Bax and cleaved Caspase-3, while downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. Based on its impressive pharmacodynamic data in vitro, we conducted a study to evaluate the efficacy of 15d in a xenograft tumor model in mice when used in combination with cytotoxic agents. Collectively, these findings suggest that 15d could be promising drug candidates worthy of further investigation.

The gasdermin family: emerging therapeutic targets in diseases.

The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player in pyroptosis. This recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization, pyroptosis, and the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants and infections. GSDMs have been implicated in a range of diseases including, but not limited to, sepsis, viral infections, and cancer, either through involvement in pyroptosis or independently of this process. The regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various diseases. Current strategies for inhibiting GSDMD primarily involve binding to GSDMD, blocking GSDMD cleavage or inhibiting GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In this review, we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis, elucidate the activation mechanisms of GSDMs, explore their associations with a range of diseases, and discuss recent advancements and potential strategies for developing GSDMD inhibitors.

GPX4, ferroptosis, and diseases.

GPX4 (Glutathione peroxidase 4) serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing a significant role in maintaining the redox homeostasis within the body. Ferroptosis, a form of iron-dependent non-apoptotic cell death, has gained considerable attention in recent years due to its involvement in multiple pathological processes. GPX4 is closely associated with ferroptosis and functions as the primary inhibitor of this process. Together, GPX4 and ferroptosis contribute to the pathophysiology of several diseases, including sepsis, nervous system diseases, ischemia reperfusion injury, cardiovascular diseases, and cancer. This review comprehensively explores the regulatory roles and impacts of GPX4 and ferroptosis in the development and progression of these diseases, with the aim of providing insights for identifying potential therapeutic strategies in the future.

Supraglottic airway devices: a powerful strategy in airway management.

The escalating airway management demands of cancer patients have prompted us to continually curate airway devices, with supraglottic airway devices (SADs) playing a significant role in this regard. SADs serve as instrumental tools for maintaining an open upper airway. Since the inception of the earliest SADs in the early 1980s, an array of advanced and enhanced second-generation devices have been employed in clinical settings. These upgraded SADs integrate specific features designed to enhance positive-pressure ventilation and mitigate the risk of aspiration. Nowadays, they are extensively used in general anesthesia procedures and play a critical role in difficult airway management, pre-hospital care, and emergency medicine. In certain situations, SADs may be deemed a superior alternative to endotracheal tube (ETT) and can be employed in a broader spectrum of surgical and non-surgical cases. This review provides an overview of the current evidence, a summary of classifications, relevant application scenarios, and areas for improvement in the development or clinical application of future SADs.

UFL1 promotes antiviral immune response by maintaining STING stability independent of UFMylation.

The precise regulation of STING homeostasis is essential for its antiviral function. Post-translational modification, especially ubiquitination, is important for the regulation of STING homeostasis. Previous studies have focused on how STING is degraded, but little is known about its maintenance. Here, we show that UFM1 specific ligase UFL1 promotes innate immune response by maintaining STING expression independent of UFMylation. Mechanistically, UFL1 inhibits TRIM29 to interact with STING, thereby reducing its ubiquitination at K338/K347/K370 and subsequent proteasomal degradation. DNA virus infection reduces the UFL1 expression, which may promote STING degradation and facilitate viral expansion. Our study identifies UFL1 as a crucial regulator for the maintenance of STING stability and antiviral function, and provides novel insights into the mechanistic explanation for the immunological escape of DNA virus.

Clinical value of video-assisted single-lumen endotracheal intubation and application of artificial intelligence in it.

Visualization techniques and artificial intelligence (AI) are currently used for intubation device. By providing airway visualization during tracheal intubation, the technologies provide safe and accurate access to the trachea. The ability of AI to automatically identify airways from images of intubation device makes it attractive for use in intubation devices. The purpose of this review is to introduce the state of application of visualization techniques and AI in certain intubation devices. We reviewed the evidence of clinical implications of the use of video-assisted intubation device in the intubation time, first attempt success rate, and intubation of the difficult airway. Especially, VivaSight single-lumen tube with an incorporated optics allows direct viewing of the airway. VivaSight single-lumen tube has more advantages in tracheal intubation. AI has been applied to fiberoptic bronchoscopy (FOB) and video laryngoscope with automatic airway image recognition, and has achieved certain accomplishment. Further, we discussed the possibility of applying AI to the VivaSight single-lumen tube and proposed future directions of research and application.

Prediction of endotracheal tube size in pediatric patients: Development and validation of machine learning models.

Objective: We aimed to construct and validate machine learning models for endotracheal tube (ETT) size prediction in pediatric patients. Methods: Data of 990 pediatric patients underwent endotracheal intubation were retrospectively collected between November 2019 and October 2021, and separated into cuffed and uncuffed endotracheal tube subgroups. Six machine learning algorithms, including support vector regression (SVR), logistic regression (LR), random forest (RF), gradient boosting tree (GBR), decision tree (DTR) and extreme gradient boosting tree (XGBR), were selected to construct and validate models using ten-fold cross validation in training set. The optimal models were selected, and the performance were compared with traditional predictive formulas and clinicians. Furthermore, additional data of 71 pediatric patients were collected to perform external validation. Results: The optimal 7 uncuffed and 5 cuffed variables were screened out by feature selecting. The RF models had the best performance with minimizing prediction error for both uncuffed ETT size (MAE = 0.275 mm and RMSE = 0.349 mm) and cuffed ETT size (MAE = 0.243 mm and RMSE = 0.310 mm). The RF models were also superior in predicting power than formulas in both uncuffed and cuffed ETT size prediction. In addition, the RF models performed slightly better than senior clinicians, while they significantly outperformed junior clinicians. Based on SVR models, we proposed 3 novel linear formulas for uncuffed and cuffed ETT size respectively. Conclusion: We have developed machine learning models with excellent performance in predicting optimal ETT size in both cuffed and uncuffed endotracheal intubation in pediatric patients, which provides powerful decision support for clinicians to select proper ETT size. Novel formulas proposed based on machine learning models also have relatively better predictive performance. These models and formulas can serve as important clinical references for clinicians, especially for performers with rare experience or in remote areas.

Development of endotracheal intubation devices for patients with tumors.

The incidence and mortality of malignant tumors are rapidly increasing in the world. Patients with malignant tumors often need surgery for treatment. Endotracheal intubation is a necessary technique for surgical patients undergoing general anesthesia. It is also an important procedure for critically ill patients in the emergency room or ICU. Most patients with head and neck tumors and some specific patients have difficult airways, so the operator may need to use a variety of intubation devices. The commonly used devices for endotracheal intubation include endotracheal tube, direct laryngoscope, video laryngoscope, introducer, optical stylet, fiberoptic bronchoscope. With the advancement in science and technology, the endotracheal intubation devices have been improved, and new devices have been developed. These devices are safer and more feasible in clinical practice. In this review, we summarized the features and applications of some of the currently used devices. Each device has its own uniqueness and meets different needs. The devices and their respective properties are strongly suggested to be mastered by the anesthesiologists as well as related staffs, so as to select the appropriate device for intubation.

Application of "twelve-step" approach based on SEEKflex for difficult awake tracheal intubation in patients with cervical spinal tumor.

Difficult airway always occurs in patients with cervical spinal tumor. Awake tracheal intubation (ATI) is usually a primary safe approach for clinical doctors in these intractable difficult airways. It is of great significance to establish specific strategies to reduce related acute airway accidents. A novel "twelve-step" approach of awake tracheal intubation based on an improved introducer (Safe Easy Endotracheal Kit-flexible, "SEEKflex") was developed and practiced in model successfully. Patients with cervical spinal tumor in a single tertiary hospital were chosen to secure airway with this approach. Primary outcomes were safety and feasibility, defined as completion of ATI without serious adverse events, Secondary outcome was the first intubation attempt rate, total intubation time, satisfaction of patients in the whole process and relevant complications. We performed awake tracheal intubation with this approach to solve the difficult airway in five patients with cervical spinal tumor. The courses went successfully in all patients without any relevant complications. This novel "twelve-step" approach based on SEEKflex for ATI can be considered as one of optional safe choices for difficult airway in patients with cervical spinal tumor.

Reintubation during COVID-19 pandemic: a simple self-made guiding device facilitates reintubation and minimizes transmission.

Consensus guidelines to protect airway managers during COVID-19 were developed to encourage safe, accurate and swift performance in intubation and extubation, but reintubation was not considered. With the massive surge of patients requiring mechanical ventilation in this COVID-19 pandemic, great incidence of difficult airways may necessitate reintubation. Equipments could be used now in extubation and reintubation are either too expensive and time-consuming in decontamination, or have not gained wide acceptance. Here, we adapted an extubation device from an intubating stylet, which is provided as accessory of endotracheal tube. Such stylet could provide safe access for expediting reintubation both during and after the COVID-19 pandemic, which is inexpensive, single-use, readily available, straightforward to handle, and well-tolerated, thereby benefiting both the patients and healthcare providers.

Clinical characteristics and prediction analysis of the recovered COVID-19 patients with re-detectable positive RNA test.

BACKGROUND: Previous studies have unveiled the occurrence of re-detectable positive (RP) RNA test result after hospital discharge among recovered COVID-19 patients, but the clinical characteristics of RP patients (RP patients) and the potential features affecting RP RNA test outcome remain unclear. METHODS: A total of 742 COVID-19 patients discharged between March 1st, 2020 and March 20th, 2020 were enrolled. All patients were followed-up for SARS-CoV-2 RNA test and RP patents were identified. The clinical characteristics between RP patients and NRP patients were compared, and the potential features affecting re-detectable RNA test outcome were further evaluated. RESULTS: Up to April 9th, 2020, 60 recovered patients (8.09%) had been re-detected to be SARS-CoV-2 RNA positive. Among those 60 RP patients, the median RP time was 12 days from the last negative result of SARS-CoV-2 RNA test or 10 days from hospital discharge. RP patients were prone to be older, having mild/moderate conditions, unilateral lung involvement and fatigue, chills, stuffy or runny nose, with high lymphocyte count. Multivariate logistic analysis and COX regression analysis demonstrated that age, lymphocyte count, urea nitrogen, stuffy or runny nose as well as lung involvement were independently associated with RP RNA test (P<0.05). CONCLUSIONS: Older patients accompanied with stuffy or runny nose, low urea nitrogen as well as unilateral lung involvement were more likely to develop RP RNA test result after hospital discharge. Therefore, we strongly suggest using broncho-alveolar lavage fluid for RNA detection, extending quarantine time, and conducting continual follow-up medical examination for those discharged patients.

Clinical characteristics associated with long-term viral shedding in patients with coronavirus disease 2019.

BACKGROUND: To delineate the clinical characteristics associated with long-term viral shedding (>21 days) in patients with coronavirus disease 2019 (COVID-19). METHODS: In this retrospective study, factors associated with long-term (>21 days) severe acute respiratory coronavirus 2 (SARS-CoV-2) RNA shedding were evaluated in a conhort of 609 patients from two hospitals in Wuhan. RESULTS: The median duration of SARS-CoV-2 viral shedding was 19 days (interquartile range, 10-28 days) among all patients. There were 42% of patients having prolonged viral shedding time (>21 days), in which the longest viral shedding time was 58 days. When comparing patients with early (≤21 days) and late viral RNA clearance (>21 days), prolonged viral shedding was associated with age <65 (P=0.015), female sex (P=0.028), cough (P=0.025), fatigue (P=0.035), sore throat (P=0.013), aspartate aminotransferase (P=0.038), procalcitonin (P=0.010), albumin (P=0.003), D-dimer (P=0.011), lung involvement (P=0.014), reticular shadow (P<0.001) and lung consolidation (P=0.004). Age range (<65 years) (odds ratio [OR], 1.46 [95% CI, 1.05-2.03]) and female sex (odds ratio [OR], 1.40 [95% CI, 1.00-1.94]) were independent risk factors. CONCLUSIONS: Long-term viral shedding (>21 days) is not a rare phenomenon among COVID-19 infectious patients. Age range (<65) and female sex are independent risk factors for long-term viral shedding. Early antiviral treatment should be considered for COVID-19 patients with such risk factors. Further study should be conducted to know the infectivity of patients with long-term viral shedding in order to develop reasonable control measures.

Preventing Candida albicans from subverting host plasminogen for invasive infection treatment.

Candida albicans is a common fungal pathogen in humans that colonizes the skin and mucosal surfaces of the majority healthy individuals. How C. albicans disseminates into the bloodstream and causes life-threatening systemic infections in immunocompromised patients remains unclear. Plasminogen system activation can degrade a variety of structural proteins in vivo and is involved in several homeostatic processes. Here, for the first time, we characterized that C. albicans could capture and "subvert" host plasminogen to invade host epithelial cell surface barriers through cell-wall localized Eno1 protein. We found that the "subverted" plasminogen system plays an important role in development of invasive infection caused by C. albicans in mice. Base on this finding, we discovered a mouse monoclonal antibody (mAb) 12D9 targeting C. albicans Eno1, with high affinity to the 254FYKDGKYDL262 motif in α-helices 6, ß-sheet 6 (H6S6) loop and direct blocking activity for C. albicans capture host plasminogen. mAb 12D9 could prevent C. albicans from invading human epithelial and endothelial cells, and displayed antifungal activity and synergistic effect with anidulafungin or fluconazole in proof-of-concept in vivo studies, suggesting that blocking the function of cell surface Eno1 was effective for controlling invasive infection caused by Candida spp. In summary, our study provides the evidence of C. albicans invading host by "subverting" plasminogen system, suggesting a potential novel treatment strategy for invasive fungal infections.

Dectin-1 Facilitates IL-18 Production for the Generation of Protective Antibodies Against Candida albicans.

Invasive candidiasis (IC) is one of the leading causes of death among immunocompromised patients. Because of limited effective therapy treatment options, prevention of IC through vaccine is an appealing strategy. However, how to induce the generation of direct candidacidal antibodies in host remains unclear. Gpi7 mutant C. albicans is an avirulent strain that exposes cell wall ß-(1,3)-glucans. Here, we found that vaccination with the gpi7 mutant strain could protect mice against invasive candidiasis caused by C. albicans and non-albicans Candida spp. The protective effects induced by gpi7 mutant relied on long-lived plasma cells (LLPCs) secreting protective antibodies against C. albicans. Clinically, we verified a similar profile of IgG antibodies in the serum samples from patients recovering from IC to those from gpi7 mutant-vaccinated mice. Mechanistically, we found cell wall ß-(1,3)-glucan of gpi7 mutant facilitated Dectin-1 receptor dependent nuclear translocation of non-canonical NF-κB subunit RelB in macrophages and subsequent IL-18 secretion, which primed protective antibodies generation in vivo. Together, our study demonstrate that Dectin-1 engagement could trigger RelB activation to prime IL-18 expression and established a new paradigm for consideration of the link between Dectin-1 mediated innate immune response and adaptive humoral immunity, suggesting a previously unknown active vaccination strategy against Candida spp. infection.

Characteristics of asymptomatic COVID-19 infection and progression: A multicenter, retrospective study.

Novel coronavirus disease 2019 (COVID-19), caused by novel coronavirus SARS-CoV-2, has spread globally since the end of 2019. Asymptomatic carriers are of great concern as they can undermine the interventions to stop the pandemic. However, there is limited information about the characteristics and outcomes of the asymptomatic patients. Therefore, we conducted this retrospective study and retrieved data of 79 asymptomatic COVID-19 patients at admission from three designated hospitals in Wuhan, China. The asymptomatic patients could happen at any age, ranged from 9 to 96 years. These patients also had lower levels of alanine aminotransferase and C-reactive protein. Patchy shadowing was the most common manifestation in computed tomography scan. Some asymptomatic carriers developed mild or moderate symptoms during hospitalization. Age and comorbidities, especially hypertension, may be predictive factors for symptom development in the initially asymptomatic carriers at admission. Early detection and treatment for these presymptomatic patients before symptom onset can shorten the communicable period for the coronavirus and reduce the occurrence of severe cases.

Turning weakness into strength: Albumin nanoparticle-redirected amphotericin B biodistribution for reducing nephrotoxicity and enhancing antifungal activity.

As the gold standard treatment for invasive fungal infection, amphotericin B (AmB) is limited by its severe nephrotoxicity. It has been shown that AmB complex with albumin in vivo forms a sub-10 nm nanocomplex within kidney excretion size range and eventually induces the nephrotoxicity. This study presents an approach to take advantage of the "weakness" of such unique interaction between AmB and albumin to form AmB nanocomplex beyond the size range of kidney excretion. Herein, a novel strategy was developed by directly assembling molecular BSA into larger-sized nanostructures with the reconstructed intermolecular disulfide bond and hydrophobic interaction. The rich binding sites of AmB within BSA nanostructures enabled the efficient AmB loading and forming nanoparticle (AmB-NP) which exceeds the size range of kidney excretion (~ 60 nm). We found nanoassembly with BSA redirected biodistribution of AmB with a 2.8-fold reduction of drug accumulation in the kidney and significantly improved its renal impairment in mice. Furthermore, we found that nanoassembly with BSA significantly increased the biodistribution of AmB in brain and endowed it 100-folds increase in pharmacological effect against meningoencephalitis caused by common fungal pathogen Cryptococcus neoformans. Together, this study not merely overcomes the nephrotoxicity of AmB using its "weakness" by a nanoassembly method, and provides a new strategy for reducing toxicity of drugs with high albumin binding rate in vivo.

A nano-immunotraining strategy to enhance the tumor targeting of neutrophils via in vivo pathogen-mimicking stimulation.

Due to unsatisfactory tumor-targeting efficiency, hitch-hiking nanomedicines with tumor "smelling" immune cells have rapidly evolved to achieve a more precision delivery. However, the current research tends to default to the smelling capacity of neutrophils and largely overlooks the capacity of those immune cells that are heavily dependent on the pathogen exposure history of individuals. By avoiding risky strategies, such as altering the housing environment of mice for the improved activity of immune cells, we propose a new concept of nano-immunotraining strategy to quickly activate neutrophil tumor tropism and thereby give an enhanced tumor-targeting capacity. Such a strategy involves a facile construction of a vaccine-like nano-CpG adjuvant, followed by pre-immunizing on mice periodically to mimic the pathogen exposure. The results demonstrated that a significantly enhanced tumor-targeting accumulation of neutrophils harvested from nano-immunotrained mice could be achieved, either by intraperitoneal or intravenous injection. This easily accessed, reproducible, and biosafe nano-immunotraining strategy holds a great promise for more precision delivery of nanomedicines.

The critical role of Dectin-1 in host controlling systemic Candida krusei infection.

There are increasing invasive fungal infections associated with non-albicans, which causes mortal infections in immune deficiency population. Candida krusei is a major non-albicans that exhibits intrinsic resistance to fluconazole and makes clinical treatment difficult. Previous studies revealed that C-type lectin receptors (CLRs) Dectin-1 plays critical roles in host defense against C. albicans infections. C. krusei and C. albicans are phylogenetically different although in the same genus. Whether Dectin-1 contributes to host immune response against C. krusei infection is still unknown. In the present study, we explored the potential roles of the Dectin-1 in host defense against C. krusei. We found that Dectin-1 ligand ß-(1,3)-glucan markedly exposed on the cell surface of C. krusei, while ß-(1,3)-glucan of C. albicans is masked. Dectin-1 is required for host myeloid cells recognition, killing of C. krusei, and development of subsequent Th1 and Th17 cell-mediated adaptive immune response. Furthermore, Dectin-1-deficient mice (Dectin-1-/- ) are more susceptible to C. krusei infection. Together, we confirmed the important roles of Dectin-1 in host defense against C. krusei infection, demonstrating a previously unknown mechanism for C. krusei infection. Our study, therefore, provides a further understanding of host immune response against C. krusei.

Enhancement in Tonically Active Glutamatergic Inputs to the Rostral Ventrolateral Medulla Contributes to Neuropathic Pain-Induced High Blood Pressure.

Neuropathic pain increases the risk of cardiovascular diseases including hypertension with the characteristic of sympathetic overactivity. The enhanced tonically active glutamatergic input to the rostral ventrolateral medulla (RVLM) contributes to sympathetic overactivity and blood pressure (BP) in cardiovascular diseases. We hypothesize that neuropathic pain enhances tonically active glutamatergic inputs to the RVLM, which contributes to high level of BP and sympathetic outflow. Animal model with the trigeminal neuropathic pain was induced by the infraorbital nerve-chronic constriction injury (ION-CCI). A significant increase in BP and renal sympathetic nerve activity (RSNA) was found in rats with ION-CCI (BP, n = 5, RSNA, n = 7, p < 0.05). The concentration of glutamate in the RVLM was significantly increased in the ION-CCI group (n = 4, p < 0.05). Blockade of glutamate receptors by injection of kynurenic acid into the RVLM significantly decreased BP and RSNA in the ION-CCI group (n = 5, p < 0.05). In two major sources (the paraventricular nucleus and periaqueductal gray) for glutamatergic inputs to the RVLM, the ION-CCI group (n = 5, p < 0.05) showed an increase in glutamate content and expression of glutaminase 2, vesicular glutamate transporter 2 proteins, and c-fos. Our results suggest that enhancement in tonically active glutamatergic inputs to the RVLM contributes to neuropathic pain-induced high blood pressure.

Aging-related Atg5 defect impairs neutrophil extracellular traps formation.

Formation of neutrophil extracellular traps (NETs) is an important function of the innate immune system against infections. It has been proven that aging dysregulates immunity and impairs neutrophil function. However, the influence of aging on the ability to produce NETs has yet to be fully addressed. In this study, we tested the hypothesis that a lower level of autophagy in neutrophils from aged mice was responsible for the decrease in NET formation. We demonstrated that a broad range of Toll-like receptor 2 (TLR2) ligands could efficiently induce reactive oxygen species (ROS) -dependent NET release in young mice, but not in aged ones. We further explored that the difference between young and aged mice in TLR2 ligand-induced NETosis is the result of an Atg5 defect and subsequent impaired autophagy. Furthermore, we found that lower autophagy capacity led to not only reduced NET formation, but also increased apoptosis. Our results suggest an important role of Atg5 and autophagy in maintaining the function of NETs formation in response to infection and in regulating neutrophil death. Targeting autophagy-promoted NETs may present a therapeutic strategy to improve infection defence in an aged population.