Arrhythmia onsets triggered by acute myocardial ischemia are not mediated by lysophosphoglycerides accumulation in ventricular myocardium.

Lysophosphoglycerides (LPLs) have been reported to accumulate in myocardium and serve as a cause of arrhythmias in acute myocardial ischemia. However, in this study we found that LPLs level in the ventricular myocardium was decreased by the onset of acute myocardial ischemia in vivo in rats. Decreasing of LPLs level in left ventricular myocardium, but not right, was observed within 26 min of left myocardial ischemia, regardless of whether arrhythmias were triggered. Lower LPLs level in the ventricular myocardium was also observed in aconitine-simulated ventricular fibrillation (P < 0.0001) and ouabain-simulated III° atrioventricular block (P < 0.0001). Shot-lasting electric shock, e.g., ≤ 40 s, decreased LPLs level, while long-lasting, e.g., 5 min, increased it (fold change = 2.27, P = 0.0008). LPLs accumulation was observed in long-lasting myocardial ischemia, e.g., 4 h (fold change = 1.20, P = 0.0012), when caspase3 activity was elevated (P = 0.0012), indicating increased cell death, but not coincided with higher frequent arrhythmias. In postmortem human ventricular myocardium, differences of LPLs level in left ventricular myocardium was not observed among coronary artery disease- and other heart diseases-caused sudden death and non-heart disease caused death. LPLs level manifested a remarkable increasing from postmortem 12 h on in rats, thus abolishing the potential for serving as biomarkers of sudden cardiac death. Token together, in this study we found that LPLs in ventricular myocardium were initially decreased by the onset of ischemia, LPLs accumulation do not confer arrhythmogenesis during acute myocardial ischemia. It is necessary to reassess the roles of LPLs in myocardial infarction.

Ion-Cross-Linked Hybrid Photochromic Hydrogels with Enhanced Mechanical Properties and Shape Memory Behaviour.

Shape-shifting polymers usually require not only reversible stimuli-responsive ability, but also strong mechanical properties. A novel shape-shifting photochromic hydrogel system was designed and fabricated by embedding hydrophobic spiropyran (SP) into double polymeric network (DN) through micellar copolymerisation. Here, sodium alginate (Alg) and poly acrylate-co-methyl acrylate-co-spiropyran (P(SA-co-MA-co-SPMA)) were employed as the first network and the second network, respectively, to realise high mechanical strength. After being soaked in the CaCl2 solution, the carboxyl groups in the system underwent metal complexation with Ca2+ to enhance the hydrogel. Moreover, after the hydrogel was exposed to UV-light, the closed isomer of spiropyran in the hydrogel network could be converted into an open zwitterionic isomer merocyanine (MC), which was considered to interact with Ca2+ ions. Interestingly, Ca2+ and UV-light responsive programmable shape of the copolymer hydrogel could recover to its original form via immersion in pure water. Given its excellent metal ion and UV light stimuli-responsive and mechanical properties, the hydrogel has potential applications in the field of soft actuators.

NIR-Mediated Deformation from a CNT-Based Bilayer Hydrogel.

Shape-shifting polymers are widely used in various fields such as intelligent switches, soft robots and sensors, which require both multiple stimulus-response functions and qualified mechanical strength. In this study, a novel near-infrared-light (NIR)-responsible shape-shifting hydrogel system was designed and fabricated through embedding vinylsilane-modified carbon nanotubes (CNTs) into particle double-network (P-DN) hydrogels by micellar copolymerisation. The dispersed brittle Poly(sodium 2-acrylamido-2-methylpropane-1-sulfonate) (PNaAMPS) network of the microgels can serve as sacrificial bonds to toughen the hydrogels, and the CNTs endow it with NIR photothermal conversion ability. The results show that the CNTs embedded in the P-DN hydrogels present excellent mechanical strength, i.e., a fracture strength of 312 kPa and a fracture strain of 357%. Moreover, an asymmetric bilayer hydrogel, where the active layer contains CNTs, can achieve 0°-110° bending deformation within 10 min under NIR irradiation and can realise complex deformation movement. This study provides a theoretical and experimental basis for the design and manufacture of photoresponsive soft actuators.

Learning label smoothing for text classification.

Training with soft labels instead of hard labels can effectively improve the robustness and generalization of deep learning models. Label smoothing often provides uniformly distributed soft labels during the training process, whereas it does not take the semantic difference of labels into account. This article introduces discrimination-aware label smoothing, an adaptive label smoothing approach that learns appropriate distributions of labels for iterative optimization objectives. In this approach, positive and negative samples are employed to provide experience from both sides, and the performances of regularization and model calibration are improved through an iterative learning method. Experiments on five text classification datasets demonstrate the effectiveness of the proposed method.

Defensive glands in Stylotermitidae (Blattodea, Isoptera).

The large abundance of termites is partially achieved by their defensive abilities. Stylotermitidae represented by a single extant genus, Stylotermes, is a member of a termite group Neoisoptera that encompasses 83% of termite species and 94% of termite genera and is characterized by the presence of the frontal gland. Within Neoisoptera, Stylotermitidae represents a species-poor sister lineage of all other groups. We studied the structure of the frontal, labral and labial glands in soldiers and workers of Stylotermes faveolus, and the composition of the frontal gland secretion in S. faveolus and Stylotermes halumicus. We show that the frontal gland is a small active secretory organ in soldiers and workers. It produces a cocktail of monoterpenes in soldiers, and some of these monoterpenes and unidentified proteins in workers. The labral and labial glands are developed similarly to other termite species and contribute to defensive activities (labral in both castes, labial in soldiers) or to the production of digestive enzymes (labial in workers). Our results support the importance of the frontal gland in the evolution of Neoisoptera. Toxic, irritating and detectable monoterpenes play defensive and pheromonal functions and are likely critical novelties contributing to the ecological success of these termites.

First Report of Colletotrichum fioriniae Causing Anthracnose on Persimmon in China.

Persimmons (Diospyros kaki Thunb.) have a longstanding history of cultivation in China. Both aesthetically pleasing and edible, they often symbolize a sweet and fulfilling life. During the summer of 2022, a severe outbreak of anthracnose was observed on the lower leaves of persimmon trees in the National Field Genebank for Persimmon (NFGP), located in Yangling, Shaanxi, China (34°17'42.80″ N, 108°04'08.21″ E). The estimated incidence rate of this disease within the NFGP was approximately 30%. The typical symptoms of the disease included the presence of irregular lesions on leaves, and oval sunken lesions on infected fruit. Under high humidity conditions, pink sticky substances appeared in the affected areas. The presence of numerous lesions led to softening and detachment of persimmon fruit. To identify the causal pathogen, 5 × 5mm samples of the diseased leaves were collected from the interface between the infected and healthy leaves. The leaves were disinfected with 70% alcohol for 20 s, followed by rinsing with sterile water. Subsequently, the leaves were immersed in 1% NaClO for 2 to 3 minutes, rinsed with sterile water three times, dried using sterile absorbent paper, and the leaf samples were then transferred onto potato dextrose agar (PDA) medium, and cultured in 25°C incubators. Once the colony reached a certain size, small pieces of hyphae were extracted from edge and transferred for purification and repeated three times. After being cultured on PDA for 7 days, the colony showed a white spongy surface with a pink-orange center. The conidia displayed a fusiform shape and were transparent, measuring 4.58 to 6.53 µm × 9.27 to 13.11 µm (n=50). The isolates share morphological similarities with Colletotrichum fioriniae. The representative isolate HY-7 was selected for molecular identification. The internal transcribed spacers (ITS) region, chitin synthase (CHS-1), actin (ACT), beta-tubulin 2 (TUB2), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene were amplified using ITS1/4 (White et al. 1990), CHS-79F/CHS-345R (Carbone & Kohn, 1999), ACT512F/ACT (Carbone & Kohn, 1999), T1/BT2B (Glass & Donaldson 1995, O'Donnell et al., 1997), and GDF/GDR (Templeton et al. 1992), respectively. The generated sequences were deposited at GenBank under accession numbers OR878056 (ITS), OR766019 (CHS-1), OR766021(TUB2), OR766018 (ACT) and OR766020 (GAPDH). BLAST analysis revealed the sequences were 100% identical to C. fioriniae (MH865005 for ITS, JQ948953 for CHS-1, JQ949613 for ACT, JQ949943 for TUB2 and JQ948622 for GAPDH). The morphological characteristics and molecular analyses of the isolate matched the description of C. fioriniae. To fulfill Koch's postulates, the twigs and leaves of 'Fupingjianshi' in four different directions were inoculated without wounding in the field, and 10 healthy fruits were selected for wound inoculation. The concentration of conidia used for inoculation was about 1 × 106 conidia/ml, and sterilized water was used as control. The experiment was replicated three times under the same conditions. One week after inoculation, characteristic symptoms resembling those observed on the leaves of primary diseased persimmon trees appeared on the leaves and fruits. No symptoms were observed on the leaves, twigs and fruits in the control treatment. The pathogen from the artificially infected leaves and fruits were reisolated and identified as C. fiorinae based on morphological and molecular characteristics. Persimmon anthracnose is a common disease in regions where the fruit is grown, to the best of our knowledge, this is the first documented occurrence of C. fioriniae-induced anthracnose on persimmons in China, which should be paid more attentions. This report will help identify disease symptoms in the field and provides a basis for determining the occurrence, distribution, and control of C. fioriniae on persimmon leaves and fruits.

Databases and computational methods for the identification of piRNA-related molecules: A survey.

Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNAs (ncRNAs) that plays important roles in many biological processes and major cancer diagnosis and treatment, thus becoming a hot research topic. This study aims to provide an in-depth review of computational piRNA-related research, including databases and computational models. Herein, we perform literature analysis and use comparative evaluation methods to summarize and analyze three aspects of computational piRNA-related research: (i) computational models for piRNA-related molecular identification tasks, (ii) computational models for piRNA-disease association prediction tasks, and (iii) computational resources and evaluation metrics for these tasks. This study shows that computational piRNA-related research has significantly progressed, exhibiting promising performance in recent years, whereas they also suffer from the emerging challenges of inconsistent naming systems and the lack of data. Different from other reviews on piRNA-related identification tasks that focus on the organization of datasets and computational methods, we pay more attention to the analysis of computational models, algorithms, and performances that aim to provide valuable references for computational piRNA-related identification tasks. This study will benefit the theoretical development and practical application of piRNAs by better understanding computational models and resources to investigate the biological functions and clinical implications of piRNA.

Effects of climate and environment on migratory old people with allergic diseases in China: Protocol for a Sanya cohort study.

Background: Several studies have reported that the mountain climate can alleviate asthma, however, the effect of tropical climate on migratory elderly, especially in people with respiratory or allergic diseases is unknown. Objectives: This cohort study aims to explore impact of climate and environmental changes on allergic diseases in migratory old people. Methods: In this prospective cohort study, we recruited 750 older migratory people, the majority of whom were homeowners to minimize the risk of loss to follow up. The study's inclusion criteria were elderly individuals had moved from northern China to Sanya and suffered from either asthma or allergic diseases. Prior to participation, these individuals provided informed consent and underwent baseline assessment. Subsequently, they will be followed for three years. A face-to-face interview was conducted to gather information regarding their living environment and habits. Trained investigators administered the questionnaires and performed physical examinations including height, weight, and blood pressure, while a professional respiratory doctor conducted pulmonary function tests. Blood samples were promptly tested routine blood test, liver function, kidney function, glucose, triglyceride, allergens, and inflammatory factors. Climate and environmental data were obtained from Sanya Meteorological Bureau and Ecological Environment Bureau, respectively. We primarily compared the differences of participants with asthma or allergic diseases between northern China and Sanya in southern China by Chi-square test, t-test or Wilcoxon rank-sum test. Findings: A total of 750 participants were recruited in this cohort from fourteen communities. All participants were surveyed questionnaires about health and family environment, underwent physical examinations, and collected biological samples for laboratory examinations. Novelty: This is the first study to evaluate the effects of tropical climate and environment on elderly migrants from cold regions. This study has important implication for the health tourism and aging health, especially for the elderly migrants who suffered the respiratory and allergic diseases. Furthermore, this cohort study establishes a solid foundation for investigating the influence of environmental changes on elderly migrants with allergic diseases.

Sanya climatic-treatment cohort profile: objectives, design, and baseline characteristics.

Background: The prevalence of allergic diseases has increased globally, climate and environment also have important effects on respiratory or allergic diseases. However, population-based studies investigating the impact of tropical climates and environments on migratory-bird old people (MBOP) are lacking. Methods/Design: For this prospective cohort study, we recruited 756 participants from the community in Sanya City, Hainan Province, China. In addition to the completed baseline survey, a follow-up survey will be conducted during the periods of October-December and March-April for the next 3 years of MBEPs from northern China who spend the winter in Sanya. We will continue to record the height, weight, and blood pressure of all participants, as well as lung function for those with asthma and chronic obstructive pulmonary disease (COPD). Venous blood at baseline and urine samples will be collected during follow-up. Results: A total of 756 volunteers were recruited. Their average age is 66.1 years; 32.1% of them have high-school educations, while 37.3% have graduated from college or done undergraduate studies. The top five diseases in this cohort are allergic rhinitis (57.9%); eczema, urticaria, or dermatitis (35.6%); bronchitis and bronchiectasis (35.6%); asthma (14.7%); and emphysema (11.7%). Compared with their symptoms while at their summer places of residence, rates of remission reported by participants while living in Sanya were 80.4% for allergic rhinitis, 82.3% for bronchitis and emphysema, 85.2% for asthma, 96.0% for COPD (P < 0.001). Conclusions: The baseline survey has been completed. The preliminary findings support that a tropical climate may relieve the symptoms of allergic diseases in migratory-bird old people.

[Clinical Study of Blinatumomab in the Treatment of Adult Relapsed/Refractory Ph-Negative Acute B-Lymphoblastic Leukemia].

OBJECTIVE: To investigate the efficacy and safety of CD19/CD3 bisecific monoclonalantibody (Blinatumomab) in the treatment of adult patients with relapsed / refractory Ph-negative acute B-lymphoblastic leukemia (R/R-B-ALL). METHODS: Ten adult R/R B-ALL patients were all treated with Blinatumomab. Each treatment cycle was administered for 28 days and stopped for 14 days. The dose was 9 µg/day for the first 7 days of cycle 1, and 28 µg/day for days 8-28 if there were no adverse reactions. From the second cycle onwards, the daily dose was 28 µg. The remission, survival time (EFS and OS) and adverse reactions were observed after treatment. RESULTS: Nine patients with curative effect could be evaluated. Four patients achieved CR after one course, and one patient achieved CR after two courses, the overall remission rate was 55.6%(5/9). The median EFS was 4 months (1-12 months), and the median OS was 6 months (2-44 months). Nine of the 10 patients had fever of different degrees. Serum levels of cytokines such as IL-6, IL-10, IL-17 and IFN-γ increased. Two patients resumed medication after 1 week of treatment interruption due to neurotoxicity and CRS, respectively. One patient was discontinued due to grade 3 CRS and died of tropical candidiaemia. CONCLUSION: Blinatumomab has a good response rate in the treatment of relapsed/refractory B-ALL patients, but the duration of remission is shorter. Drug-related adverse reactions are mainly CRS and neurotoxicity. Inflammatory factors IL-6, IL-10, IL-17 and IFN-γ can be used as indicators to monitor CRS. The bisspecificity MAbs provide an opportunity for subsequent allogeneic hematopoietic stem cell transplantation in R/R-B-ALL patients.

An overview of the past decade of bufalin in the treatment of refractory and drug-resistant cancers: current status, challenges, and future perspectives.

Profound progress has been made in cancer treatment in the past three decades. However, drug resistance remains prevalent and a critical challenge. Drug resistance can be attributed to oncogenes mutations, activated defensive mechanisms, ATP-bind cassette transporters overexpression, cancer stem cells, etc. Chinese traditional medicine toad venom has been used for centuries for different diseases, including resistant cancers. Bufalin is one of the bufadienolides in toad venom that has been extensively studied for its potential in refractory and drug-resistant cancer treatments in vitro and in vivo. In this work, we would like to critically review the progress made in the past decade (2013-2022) of bufalin in overcoming drug resistance in cancers. Generally, bufalin shows high potential in killing certain refractory and resistant cancer cells via multiple mechanisms. More importantly, bufalin can work as a chemo-sensitizer that enhances the sensitivity of certain conventional and targeted therapies at low concentrations. In addition, the development of bufalin derivatives was also briefly summarized and discussed. We also analyzed the obstacles and challenges and provided possible solutions for future perspectives. We hope that the collective information may help evoke more effort for more in-depth studies and evaluation of bufalin in both lab and possible clinical trials.

[High-Throughput Sequencing Technology for Detection of Gene Mutations in Myeloid Malignancies and Its Clinical Prognostic Significance].

OBJECTIVE: To detect the gene mutations in patients with myeloid malignancies by high-throughput sequencing and explore the correlation between gene mutations and prognosis. METHODS: A retrospective analysis was performed on 56 patients with myeloid malignancies who were hospitalized in the department of hematology, Peking University International Hospital from January 2020 to May 2021. The genetic mutations of the patients were detected by next-generation sequencing technology, and the correlation between the genetic mutations and prognosis of myeloid malignancies was analyzed. RESULTS: In 56 patients, the number of mutated genes detected in a single patient is 0-9, with a median of 3. Sequencing results showed that the most common mutated genes were RUNX1(21.4%), TET2(17.9%), DNMT3A(17.9%), TP53(14.3%) and ASXL1(14.3%), among which the most common mutations occurred in the signaling pathway-related genes (23.3%) and the transcription factor genes (18.3%). 84% of the patients carried multiple mutated genes (≥2), and correlation analysis showed there were obvious co-occurring mutations between WT1 and FLT3, NPM1 and FLT3-ITD, and MYC and FLT3. TP53 mutation was more common in MDS patients.The overall survival time of patients with NRAS mutation was significantly shortened (P =0.049). The prognosis of patients with TP53 mutation was poor compared with those without TP53 mutation, but the difference wasn't statistically significant (P =0.08). CONCLUSION: The application of next-generation sequencing technology is of great significance in myeloid malignancies, which is helpful to better understand the pathogenesis of the disease, to judge the prognosis and to find possible therapeutic targets.

Autoimmune Hemolytic Anemia After Cord Blood Transplantation: A Retrospective Single-Center Experience.

Objective: To describe the incidence, possible risk factors, and treatment options of autoimmune hemolytic anemia (AIHA) occurring after cord blood transplantation (CBT). Methods: We retrospectively analyzed the patients who underwent CBT at Peking University First Hospital between January 2004 and July 2022. Results: We totally identified thirty-six patients who received CBT. Median age was 27.5 years (range, 1.6-52). With a median 6 (range 0.6-10.0) years survivor follow-up, six patients developed AIHA (2 Evans syndrome included) at a median of 168 (range, 122-264) days post-CBT for 8% cumulative incidence density 3 years. Its mortality was 50% and mainly associated with concomitant infections (CMV reactivation rate nearly 100%). The possible risk factors for developing AIHA are CMV reactivation, GvHD and HLA mismatch. Conclusion: AIHA is a clinically significant common complication in recipients post-CBT. Corticosteroids combined with intravenous immunoglobulin (IvIg) is recommended for the treatment of warm antibody AIHA after CBT.

A molecular dynamics study on adsorption mechanisms of polar, cationic, and anionic polymers on montmorillonite.

Adsorption of polymers on clay in aqueous solutions has wide applications in environmental, medical, and energy-related areas, but the interactions between polymers and clay under varied conditions are still not fully understood. In this study, we investigated the adsorption mechanisms of four polymers belonging to different categories, namely anionic poly(acrylic acid) (poly-AA), cationic poly(diallyldimethylammonium chloride) (poly-DADMAC), nonionic polyacrylamide (poly-AM), and the copolymer of AA and DADMAC (poly-AADADMAC). By using molecular dynamics simulations, we compared the desorption kinetics of these polymers at different temperatures and found that poly-AA and poly-AM have the weakest and strongest adsorption abilities, respectively. Polymer adsorptions are slightly more stable at higher pressures, and high salinity favors the adsorption of charged polymers. Further analysis suggests that the adsorption of anionic poly-AA is less stable than that of cationic poly-DADMAC because the latter is attracted to the negatively charged surface by direct coulombic forces, and poly-AM is stabilized by van der Waals forces and hydrogen bonds. This study provides insights on how to enhance the adsorption affinity of polymers on a clay surface and may help the design or improvement of polymer/clay nanocomposite materials.

Kinetic Hydrate Inhibition of Natural Gels in Complex Sediment Environments.

Natural gels are emerging as a hotspot of global research for their greenness, environmental-friendliness, and good hydrate inhibition performance. However, previous studies mostly performed experiments for simple pure water systems and the inhibition mechanism in the sediment environment remains unclear. Given this, the inhibition performance of xanthan gum and pectin on hydrate nucleation and growth in sediment environments was evaluated via hydrate formation inhibition tests, and the inhibition internal mechanisms were revealed via a comprehensive analysis integrating various methods. Furthermore, the influences of natural gels on sediment dispersion stability and low-temperature fluid rheology were investigated. Research showed that the sediments of gas hydrate reservoirs in the South China Sea are mainly composed of micro-nano quartz and clay minerals. Xanthan gum and pectin can effectively inhibit the hydrate formation via the joint effects of the binding, disturbing, and interlayer mass transfer suppression processes. Sediments promote hydrate nucleation and yet inhibit hydrate growth. The interaction of sediments with active groups of natural gels weakens the abilities of gels to inhibit hydrate nucleation and reduce hydrate formation. Nonetheless, sediments help gels to slow down hydrate formation. Our comprehensive analysis pointed out that pectin with a concentration of 0.5 wt% can effectively inhibit the hydrate nucleation and growth while improving the dispersion stability and low-temperature rheology of sediment-containing fluids.

Investigation on Filtration Control of Zwitterionic Polymer AADN in High Temperature High Pressure Water-Based Drilling Fluids.

With the exploration and development of high-temperature and high-salt deep oil and gas, more rigorous requirements are warranted for the performance of water-based drilling fluids (WBDFs). In this study, acrylamide, 2-acrylamide-2-methylpropanesulfonic acid, diallyl dimethyl ammonium chloride, and N-vinylpyrrolidone were synthesized by free radical copolymerization in an aqueous solution to form a temperature and salt-resistant zwitterionic polymer gel filtration loss reducer (AADN). The zwitterionic polymer had excellent adsorption and hydration groups, which could effectively combine with bentonite through hydrogen bonds and electrostatic attraction, strengthening the hydration film thickness on the surface of bentonite, and promoting the stable dispersion of drilling fluid. In addition, the reverse polyelectrolyte effect of zwitterionic polymers strengthened the drilling fluid's ability to resist high-temperature and high-salt. The AADN-based drilling fluid showed excellent rheological and filtration control properties (FLAPI < 8 mL, FLHTHP < 29.6 mL) even after aging at high-temperature (200 °C) and high-salt (20 wt% NaCl) conditions. This study provides a new strategy for simultaneously improving the high-temperature and high-salt tolerance of WBDFs, presenting the potential for application in drilling in high-temperature and high-salt deep formations.

New Zwitterionic Polymer as a Highly Effective Salt- and Calcium-Resistant Fluid Loss Reducer in Water-Based Drilling Fluids.

To control the filtration loss of drilling fluids in salt-gypsum formations, a novel type of zwitterionic polymer gel (DNDAP) was synthesized by free radical polymerization, which was used as a salt- and calcium-resistant fluid loss reducer for water-based drilling fluids (WBDF). DNDAP was prepared with N, N-dimethylacrylamide (DMAA), N-vinylpyrrolidone (NVP), Diallyl dimethyl ammonium chloride (DMDAAC), 2-acrylamide-2-methylpropaneonic acid (AMPS), and isopentenol polyether (TPEG) as raw materials. Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H-NMR) were used to characterize the composition and structure of the DNDAP copolymer. The thermal stability of DNDAP was evaluated by the use of thermogravimetric analysis (TGA). WBDF with DNDAP was analyzed for zeta potential and particle size and the corresponding filter cake underwent energy dispersive spectrum (EDS) analysis and scanning electron microscope (SEM) analysis. The results showed that the thermal decomposition of DNDAP mainly occurred above 303 °C. DNDAP exhibits excellent rheological and filtration properties in water-based drilling fluids, even under high-temperature aging (up to 200 °C) and high salinity (20 wt% NaCl or 5 wt% CaCl2) environments. The strong adsorption effect of DNDAP makes the particle size of bentonite reasonably distributed to form a dense mud cake that reduces filtration losses.

A novel gut-restricted RIPK1 inhibitor, SZ-15, ameliorates DSS-induced ulcerative colitis.

As a key mediator of cell death and inflammation, receptor-interacting protein kinase 1 (RIPK1) responds to a broad set of inflammatory and pro-death stimuli in human diseases. Inhibitors targeting RIPK1 are being investigated for the treatment of a wide range of human diseases, including ulcerative colitis. In the present study, we designed, synthesized, and investigated the anti-necroptosis and RIPK1-inhibition effects of SZ-15-a symmetrical high-molecular-weight (>500 Da) compound. SZ-15 effectively inhibited necroptosis in U937 and HT-29 cells at concentrations of 1 nM and 10 nM, respectively, and SZ-15 at a concentration of 10 nM almost completely blocked RIPK1, RIPK3, and mixed-lineage kinase domain-like (MLKL) protein phosphorylation induced by necrosis inducers. SZ-15 suppressed the pro-necroptosis function of RIPK1 by downregulating the mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. The activities of SZ-15 were effectively restricted to the gut: The percent recovery of the parent form of SZ-15 in mouse feces was 85.75%. Nevertheless, SZ-15 was effectively absorbed and detected in colon tissues after 1 h at a concentration of 3335 ± 868 ng/g, indicating that membrane permeability was maintained. SZ-15 alleviated dextran sulfate sodium (DSS)-induced ulcerative colitis in vivo by decreasing TNF-α, IL-1ß, IL-22, and IL-6 mRNA expression in colonic tissues. Our preclinical study describes a novel gut-restricted RIPK1 inhibitor that shows great potential for use in the clinical treatment of ulcerative colitis.

C-C chemokine receptor 5 and acute graft-versus-host disease.

BACKGROUND: The C-C chemokine receptor 5 (CCR5) is mainly expressed in a variety of immune cells. It interacts with multiple chemokine ligands that mediate the trafficking and recruitment of effector cells toward sites of inflammation. CCR5 not only plays a critical role in cell growth, activation, differentiation, adhesion, and migration but also participates in the development of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. METHODS: This is a literature review article. The research design method is an evidence-based rapid review. The present discourse aim is first to scrutinize and assess the available literature on CCR5 and acute GVHD. Standard literature and database searches were implemented, gathered relevant material, and extracted information was then assessed. RESULTS: CCR5 is a marker of GVHD effector cells, and CCR5 expression is elevated when acute GVHD occurs. CCR5 blockade with maraviroc in clinical trials results in a low incidence of acute GVHD. The immune mechanism includes that CCR5 blockade inhibits donor T cell migration and recruitment toward target organs, reduces the absolute numbers of donor T cells, is capable of slightly suppressing dendritic cell maturation, and reduces the percentage of Th1 and Th17 subsets. CCR5 blockade also inhibits internalization and activation of chemokines, inhibits proliferation and chemotaxis of T cells, and decreases the production of TNF-α and IFN-γ. In addition, there may be a form of crosstalk between CCR5 and CCR2. Inconsistently, infusion of CCR5-/- Tregs into lethally irradiated mice significantly increased the infiltration of CD4+ and CD8+ T cells into the liver, resulting in earlier and more severe GVHD. CONCLUSION: This review indicates that CCR5 plays an important role in pathogenesis and development of acute GVHD. Elucidating its role in different immune cells will aid the development of targeted therapeutic treatments.

Two Novel Phenylpropanoid Trimers From Ligusticum chuanxiong Hort With Inhibitory Activities on Alpha-Hemolysin Secreted by Staphylococcus aureus.

The emergence of antibiotic resistance in Staphylococcus aureus has necessitated the development of innovative anti-infective agents acting on novel targets. Alpha-hemolysin (Hla), a key virulence factor of S. aureus, is known to cause various cell damage and death. In this study, with bioassay-guided fractionation, a pair of unusual epimeric lignan trimers, ligustchuanes A and B (1 and 2), were isolated from the rhizomes of Ligusticum chuanxiong Hort, together with two known phthalides being identified by UPLC-QTOF-MS. To the best of our knowledge, trimers with rare C8-C9″-type neolignan and ferulic acid fragments have not been identified in any natural product. Both of them were isolated as racemic mixtures, and their absolute configurations were determined by comparing experimental and calculated ECD spectra after enantioseparation. Ligustchuane B exhibited an outstanding inhibitory effect on α-hemolysin expression in both MRSA USA300 LAC and MSSA Newman strains at concentrations of 3 and 6 µM, respectively. Notably, a mouse model of infection further demonstrated that ligustchuane B could attenuate MRSA virulence in vivo.