Application of thifluzamide to stem rot in peppers: Infection and control mechanisms of sclerotium rolfsii.

In recent years, the fungal disease 'pepper stem rot', contracted from the soil-borne pathogen sclerotium rolfsii, has been increasing year by year, causing significant losses to the pepper (Capsicum annuum L.) industry. To investigate the infection mechanism of stem rot, the fungus S. rolfsii was used to infect the roots of pepper plants, and was found to affect root morphology and reduce root activity, which subsequently inhibited root growth and development. With fungal infestation, its secretions (oxalic acid, PG and PMG enzyme) were able to break normal tissues in the stem base and induced the burst of the active oxygen, which leads to injury aggravation. Morphological observations of the site of damage at the base of the stem using SEM revealed that the vascular bundles and stomata were completely blocked by hyphae, resulting in a blockade of material exchange in the plant. It was subsequently found that most of the stomata in the leaves were closed, which caused the leaves to lose their ability to photosynthesize, then turned yellow, wilt, shed, and the plant died. Commercialized fungicide thifluzamide with excellent in vitro (EC50 = 0.1 µg/mL) and in vivo curative (EC50 = 29.2 µg/mL) antifungal activity was selected to control the stem rot disease in peppers. The results demonstrated that it was able to suppress the secretion of associated pathogenic factors and reduce the outbursts of reactive oxygen species, thus reducing the damage caused by S. rolfsii at the base of the plant's stem and also enhancing the root activity of the infected plant, thereby promoting root growth. It could also inhibit fungal growth, unblock the vascular bundles and stomata, maintain a balance of material and energy exchange within the plant, and thus restore the damaged plant to its normal growth capacity. All the results will provide an adequate reference for the prevention and control of stem rot disease on peppers with thifluzamide.

A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models.

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its anti-fibrotic profile, validated in multiple in vivo studies. Its safety and tolerability as well as pharmacokinetics were validated in a randomized, double-blinded, placebo-controlled phase I clinical trial (NCT05154240) involving 78 healthy participants. A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.

Insights into the role of the N6-methyladenosine reader IGF2BP3 in the progression of oral squamous cell carcinoma and its connection to cell-cycle control.

The genome of oral squamous cell carcinoma (OSCC) has been extensively characterized via bulk sequencing, revealing a multitude of genetic changes. The gene IGF2BP3, which encodes for the insulin-like growth factor 2 mRNA-binding protein 3, has been observed to be highly expressed in several types of cancer. This finding suggests that IGF2BP3 may play a significant role in the initiation and advancement of cancer. Nevertheless, the mechanisms by which IGF2BP3 contribute to OSCC are yet to be fully understood. In this study, we have observed that IGF2BP3 exhibits overexpression in OSCC. Based on our findings from bulk sequencing analysis, we have concluded that IGF2BP3 could potentially serve as a biomarker for predicting poor prognosis in OSCC. Moreover, it has been demonstrated that IGF2BP3 exhibits a significant association with the initiation and advancement of tumors both in vivo and in vitro. The evaluation of IGF2BP3 expression levels in relation to the cell cycle stage was conducted using single-cell RNA sequencing data. Tumor cells characterized by elevated IGF2BP3 expression demonstrated a higher percentage of cells in the G2/M transition phase. This study presents new findings indicating that the molecular target IGF2BP3 can serve as a prognostic indicator for tumors and has an impact on the development and progression of OSCC by influencing the regulation of the cell cycle.

Biphasic Fermentation of Trapa bispinosa Shells by Ganoderma sinense and Characterization of Its Polysaccharides and Alcoholic Extract and Analysis of Their Bioactivity.

BACKGROUND: Trapa bispinosa shells (TBs) and its flesh (TBf) have been recognized for their medicinal properties, including antioxidant, antitumor, and immunomodulatory effects. Despite these benefits, TBs are often discarded as waste material, and their applications remain to be further explored. METHODS: In this study, we optimized the solid-state fermentation process of Ganoderma sinense (GS) with TBs using a response surface experiment methodology to obtain the fermented production with the highest water extract rate and DPPH free radical scavenging activity. We prepared and characterized pre-fermentation purified polysaccharides (P1) and post-fermentation purified polysaccharides (P2). Alcoholic extracts before (AE1) and after (AE2) fermentation were analyzed for active components such as polyphenols and flavonoids using UPLC-QTOF-MS/MS (ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry). Mouse macrophages (RAW 264.7) were employed to compare the immune-stimulating ability of polysaccharides and the antioxidant activity of AE1 and AE2. RESULTS: Optimal fermentation conditions comprised a duration of 2 days, a temperature of 14 °C, and a humidity of 77%. The peak water extract yield and DPPH free radical scavenging rate of the water extract from TBs fermented by GS were observed under these conditions. The enhanced activity may be attributed to changes in the polysaccharide structure and the components of the alcoholic extract. The P2 treatment group indicated more secretion of RAW 264.7 cells of NO, iNOS, IL-2, IL-10, and TNF-α than P1, which shows that the polysaccharides demonstrated increased immune-stimulating ability, with their effect linked to the NF-кB pathway. Moreover, the results of the AE2 treatment group indicated that secretion of RAW 264.7 cells of T-AOC and T-SOD increased and MDA decreased, which shows that the alcoholic extract demonstrated enhanced antioxidant activity, with its effect linked to the Nrf2/Keap1-ARE pathway. CONCLUSIONS: Biphasic fermentation of Trapa bispinosa shells by Ganoderma sinense could change the composition and structure of the polysaccharides and the composition of the alcoholic extract, which could increase the products' immunomodulatory and antioxidant activity.

Prediction of pulmonary infection in patients with severe myelitis by NPAR combined with spinal cord lesion segments.

Objectives: To investigate the risk factors of pulmonary infection in patients with severe myelitis and construct a prediction model. Methods: The clinical data of 177 patients with severe myelitis at admission from the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2022 were retrospectively analyzed. The predicting factors associated with pulmonary infection were screened by multivariate logistic regression analysis, and the nomogram model was constructed, and the predictive efficiency of the model was evaluated, which was verified by calibration curve, Hosmer-Lemeshow goodness-of-fit test and decision curve analysis. Results: Of the 177 patients with severe myelitis, 38 (21.5%) had pulmonary infection. Multivariate logistic regression analysis showed that neutrophil percentage to albumin ratio (NPAR) (OR = 6.865, 95%CI:1.746-26.993, p = 0.006) and high cervical cord lesion (OR = 2.788, 95%CI:1.229-6.323, p = 0.014) were independent risk factors for pulmonary infection, and the combined nomogram could easily predict the occurrence of pulmonary infection, with a C-index of 0.766 (95% CI: 0.678-0.854). The calibration curve, Hosmer-Lemeshow goodness-of-fit test (χ2 = 9.539, p = 0.299) and decision curve analysis showed that the model had good consistency and clinical applicability. Conclusion: The nomogram model constructed based on NPAR combined with high cervical cord lesion at admission has good clinical application value in predicting pulmonary infection in patients with severe myelitis, which is conducive to clinicians' evaluation of patients.

Perturbations in gut and respiratory microbiota in COVID-19 and influenza patients: a systematic review and meta-analysis.

Objectives: Coronavirus disease-19 (COVID-19)/influenza poses unprecedented challenges to the global economy and healthcare services. Numerous studies have described alterations in the microbiome of COVID-19/influenza patients, but further investigation is needed to understand the relationship between the microbiome and these diseases. Herein, through systematic comparison between COVID-19 patients, long COVID-19 patients, influenza patients, no COVID-19/influenza controls and no COVID-19/influenza patients, we conducted a comprehensive review to describe the microbial change of respiratory tract/digestive tract in COVID-19/influenza patients. Methods: We systematically reviewed relevant literature by searching the PubMed, Embase, and Cochrane Library databases from inception to August 12, 2023. We conducted a comprehensive review to explore microbial alterations in patients with COVID-19/influenza. In addition, the data on α-diversity were summarized and analyzed by meta-analysis. Results: A total of 134 studies comparing COVID-19 patients with controls and 18 studies comparing influenza patients with controls were included. The Shannon indices of the gut and respiratory tract microbiome were slightly decreased in COVID-19/influenza patients compared to no COVID-19/influenza controls. Meanwhile, COVID-19 patients with more severe symptoms also exhibited a lower Shannon index versus COVID-19 patients with milder symptoms. The intestinal microbiome of COVID-19 patients was characterized by elevated opportunistic pathogens along with reduced short-chain fatty acid (SCFAs)-producing microbiota. Moreover, Enterobacteriaceae (including Escherichia and Enterococcus) and Lactococcus, were enriched in the gut and respiratory tract of COVID-19 patients. Conversely, Haemophilus and Neisseria showed reduced abundance in the respiratory tract of both COVID-19 and influenza patients. Conclusion: In this systematic review, we identified the microbiome in COVID-19/influenza patients in comparison with controls. The microbial changes in influenza and COVID-19 are partly similar.

Both protein and non-protein components in extracellular vesicles of human seminal plasma improve human sperm function via CatSper-mediated calcium signaling.

STUDY QUESTION: What is the significance and mechanism of human seminal plasma extracellular vesicles (EVs) in regulating human sperm functions? SUMMARY ANSWER: EV increases the intracellular Ca2+ concentrations [Ca2+]i via extracellular Ca2+ influx by activating CatSper channels, and subsequently modulate human sperm motility, especially hyperactivated motility, which is attributed to both protein and non-protein components in EV. WHAT IS KNOWN ALREADY: EVs are functional regulators of human sperm function, and EV cargoes from normal and asthenozoospermic seminal plasma are different. Pre-fusion of EV with sperm in the acidic and non-physiological sucrose buffer solution could elevate [Ca2+]i in human sperm. CatSper, a principle Ca2+ channel in human sperm, is responsible for the [Ca2+]i regulation when sperm respond to diverse extracellular stimuli. However, the role of CatSper in EV-evoked calcium signaling and its potential physiological significance remain unclear. STUDY DESIGN, SIZE, DURATION: EV isolated from the seminal plasma of normal and asthenozoospermic semen were utilized to investigate the mechanism by which EV regulates calcium signal in human sperm, including the involvement of CatSper and the responsible cargoes in EV. In addition, the clinical application potential of EV and EV protein-derived peptides were also evaluated. This is a laboratory study that went on for more than 5 years and involved more than 200 separate experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen donors were recruited in accordance with the Institutional Ethics Committee on human subjects of the Affiliated Hospital of Nantong University and Jiangxi Maternal and Child Health Hospital. The Flow NanoAnalyzer, western blotting, and transmission electron microscope were used to systematically characterize seminal plasma EV. Sperm [Ca2+]i responses were examined by fluorimetric measurement. The whole-cell patch-clamp technique was performed to record CatSper currents. Sperm motility parameters were assessed by computer-assisted sperm analysis. Sperm hyperactivation was also evaluated by examining their penetration ability in viscous methylcellulose media. Protein and non-protein components in EV were analyzed by liquid chromatography-mass spectrum. The levels of prostaglandins, reactive oxygen species, malonaldehyde, and DNA integrity were detected by commercial kits. MAIN RESULTS AND THE ROLE OF CHANCE: EV increased [Ca2+]i via an extracellular Ca2+ influx, which could be suppressed by a CatSper inhibitor. Also, EV potentiated CatSper currents in human sperm. Furthermore, the EV-in [Ca2+]i increase and CatSper currents were absent in a CatSper-deficient sperm, confirming the crucial role of CatSper in EV induced Ca2+ signaling in human sperm. Both proteins and non-protein components of EV contributed to the increase of [Ca2+]i, which were important for the effects of EV on human sperm. Consequently, EV and its cargos promoted sperm hyperactivated motility. In addition, seminal plasma EV protein-derived peptides, such as NAT1-derived peptide (N-P) and THBS-1-derived peptide (T-P), could activate the sperm calcium signal and enhance sperm function. Interestingly, EV derived from asthenozoospermic semen caused a lower increase of [Ca2+]i than that isolated from normal seminal plasma (N-EV), and N-EV significantly improved sperm motility and function in both asthenozoospermic samples and frozen-thawed sperm. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was an in vitro study and caution must be taken when extrapolating the physiological relevance to in vivo regulation of sperm. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that the CatSper-mediated-Ca2+ signaling is involved in EV-modulated sperm function under near physiological conditions, and EV and their derivates are a novel CatSper and sperm function regulators with potential for clinical application. They may be developed to improve sperm motility resulting from low [Ca2+]i response and/or freezing and thawing. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Natural Science Foundation of China (32271167), the Social Development Project of Jiangsu Province (BE2022765), the Nantong Social and People's Livelihood Science and Technology Plan (MS22022087), the Basic Science Research Program of Nantong (JC22022086), and the Jiangsu Innovation and Entrepreneurship Talent Plan (JSSCRC2021543). The authors declare no conflict of interest.

Electrokinetic Analyses Uncover the Rate-Determining Step of Biomass-Derived Monosaccharide Electroreduction on Copper.

Electrochemical biomass conversion holds promise to upcycle carbon sources and produce valuable products while reducing greenhouse gas emissions. To this end, deep insight into the interfacial mechanism is essential for the rational design of an efficient electrocatalytic route, which is still an area of active research and development. Herein, we report the reduction of dihydroxyacetone (DHA)-the simplest monosaccharide derived from glycerol feedstock-to acetol, the vital chemical intermediate in industries, with faradaic efficiency of 85±5 % on a polycrystalline Cu electrode. DHA reduction follows preceding dehydration by coordination with the carbonyl and hydroxyl groups and the subsequent hydrogenation. The electrokinetic profile indicates that the rate-determining step (RDS) includes a proton-coupled electron transfer (PCET) to the dehydrated intermediate, revealed by coverage-dependent Tafel slope and isotopic labeling experiments. An approximate zero-order dependence of H+ suggests that water acts as the proton donor for the interfacial PCET process. Leveraging these insights, we formulate microkinetic models to illustrate its origin that Eley-Rideal (E-R) dominates over Langmuir-Hinshelwood (L-H) in governing Cu-mediated DHA reduction, offering rational guidance that increasing the concentration of the adsorbed reactant alone would be sufficient to promote the activity in designing practical catalysts.

Silica-induced macrophage pyroptosis propels pulmonary fibrosis through coordinated activation of relaxin and osteoclast differentiation signaling to reprogram fibroblasts.

Silica nanoparticle (SiNP) exposure induces severe pulmonary inflammation and fibrosis, but the pathogenesis remains unclear, and effective therapies are currently lacking. To explore the mechanism underlying SiNPs-induced pulmonary fibrosis, we constructed in vivo silica exposure animal models and in vitro models of silica-induced macrophage pyroptosis and fibroblast transdifferentiation. We found that SiNP exposure elicits upregulation of pulmonary proteins associated with pyroptosis, including NLRP3, ASC, IL-1ß, and GSDMD, while the immunofluorescence staining co-localized NLRP3 and GSDMD with macrophage-specific biomarker F4/80 in silica-exposed lung tissues. However, the NLRP3 inhibitor MCC950 and classical anti-fibrosis drug pirfenidone (PFD) were found to be able to alleviate silica-induced collagen deposition in the lungs. In in vitro studies, we exposed the fibroblast to a conditioned medium from silica-induced pyroptotic macrophages and found enhanced expression of α-SMA, suggesting increased transdifferentiation of fibroblast to myofibroblast. In line with in vivo studies, the combined treatment of MCC950 and PFD was demonstrated to inhibit the expression of α-SMA and attenuate fibroblast transdifferentiation. Mechanistically, we adopted high throughput RNA sequencing on fibroblast with different treatments and found activated signaling of relaxin and osteoclast differentiation pathways, where the expression of the dysregulated genes in these two pathways was examined and found to be consistently altered both in vitro and in vivo. Collectively, our study demonstrates that SiNP exposure induces macrophage pyroptosis, which subsequently causes fibroblast transdifferentiation to myofibroblasts, in which the relaxin and osteoclast differentiation signaling pathways play crucial roles. These findings may provide valuable references for developing new therapies for pulmonary fibrosis.

Combined ROS Responsive Polydopamine-Coated Berberine Nanoparticles Effective Against Ulcerative Colitis in Mouse Model.

Introduction: Enhancing the efficacy of berberine (BBR) in the treatment of ulcerative colitis (UC) through the development of dopamine-coated berberine nanoparticles (PDA@BBR NPs) with ROS-responsive and adhesive properties. Methods: Berberine nanoparticles (BBR NPs) were synthesized using the nonsolvent precipitation method, and their surfaces were coated with polydopamine (PDA) through oxidative polymerization. The PDA@BBR NPs were characterized by transmission electron microscopy (TEM), size analysis, and zeta potential analysis. Drug loading and encapsulation efficiency were analyzed using fluorescence spectroscopy. The responsiveness of these nanoparticles to reactive oxygen species (ROS) was assessed in vitro, while their adhesive properties and therapeutic efficacy on UC were evaluated in vivo. Results: Physicochemical property studies showed that PDA coated BBR NPs nanoparticles have good dispersion and stability. In vitro results showed that PDA@BBR NPs could prolong the retention time of the drug at the colonic site and could realize the gradual drug release under ROS environment. In addition, animal studies showed that PDA@BBR NPs exhibited significant anti-inflammatory effects on DSS-induced colitis and effectively reduced intestinal mucosal damage. Conclusion: PDA@BBR NPs are ROS-responsive nanoparticles that adhere well and have a high drug loading capacity. They have shown therapeutic effects in mice with UC, indicating that this formulation may be a promising treatment option.

Lipoamide Attenuates Hypertensive Myocardial Hypertrophy Through PI3K/Akt-Mediated Nrf2 Signaling Pathway.

The process of myocardial hypertrophy in hypertension can lead to excessive activation of oxidative stress. Lipoamide (ALM) has significant antioxidant and anti-inflammatory effects. This study aimed to investigate the effects of ALM on hypertension-induced cardiac hypertrophy, as well as explore its underlying mechanisms. We evaluated the effects of ALM on spontaneously hypertensive rats and rat cardiomyocytes treated with Ang II. We found that ALM was not effective in lowering blood pressure in SHR, but it attenuated hypertension-mediated cardiac fibrosis, oxidative stress, inflammation, and hypertrophy in rats. After that, in cultured H9C2 cells stimulated with Ang II, ALM increased the expression of antioxidant proteins that were decreased in the Ang II group. ALM also alleviated cell hypertrophy and the accumulation of ROS, while LY294002 partially abrogated these effects. Collectively, these results demonstrate that ALM could alleviate oxidative stress in cardiac hypertrophy, potentially through the activation of the PI3K/Akt-mediated Nrf2 signaling pathway.

Design, Synthesis, and Target Identification of Novel Phenylalanine Derivatives by Drug Affinity Responsive Target Stability (DARTS) in Xanthomonas oryzae pv Oryzae.

The increasing resistance displayed by plant phytopathogenic bacteria to conventional pesticides has heightened the urgency for the exploration of novel antibacterial agents possessing distinct modes of action (MOAs). In this study, a series of novel phenylalanine derivatives with the unique structure of acylhydrazone dithioether have been designed and synthesized. Bioassay results demonstrated that most target compounds exhibited excellent in vitro antibacterial activity against Xanthomonas oryzae pv oryzae (Xoo) and Xanthomonas axonopodis pv citri (Xac). Among them, the EC50 values of L3, L4, L6, L21, and L22 against Xoo were 7.4, 9.3, 6.7, 8.9, and 5.1 µg/mL, respectively, superior to that of bismerthiazol (BT) and thiodiazole copper (TC) (41.5 and >100 µg/mL); the EC50 values of L3, L4, L5, L6, L7, L8, L20, L21, and L22 against Xac were 5.6, 2.5, 6.2, 4.1, 4.2, 6.4, 6.3, 3.6, and 5.2 µg/mL, respectively, superior to that of BT and TC (43.3 and >100 µg/mL). An unmodified drug affinity responsive target stability (DARTS) technology was used to investigate the antibacterial MOAs of active compound L22, and the 50S ribosomal protein L2 (RL2) as an unprecedented target protein in Xoo cells was first discovered. The target protein RL2 was then expressed and purified. Furthermore, the in vitro interactions by microscale thermophoresis (Kd = 0.050 µM) and fluorescence titration (Ka = 1.4 × 105 M-1) experiments also demonstrated a strong binding force between compound L22 and RL2. Overall, these results not only facilitate the development of novel antibacterial agents but also establish a reliable method for exploring the targets of bactericides.

Defects in lead halide perovskite light-emitting diodes under electric field: from behavior to passivation strategies.

Lead halide perovskites (LHPs) are emerging semiconductor materials for light-emitting diodes (LEDs) owing to their unique structure and superior optoelectronic properties. However, defects that initiate degradation of LHPs through external stimuli and prompt internal ion migration at the interfaces remain a significant challenge. The electric field (EF), which is a fundamental driving force in LED operation, complicates the role of these defects in the physical and chemical properties of LHPs. A deeper understanding of EF-induced defect behavior is crucial for optimizing the LED performance. In this review, the origins and characterization of defects are explored, indicating the influence of EF-induced defect dynamics on LED performance and stability. A comprehensive overview of recent defect passivation approaches for LHP bulk films and nanocrystals (NCs) is also provided. Given the ubiquity of EF, a summary of the EF-induced defect behavior can enhance the performance of perovskite LEDs and related optoelectronic devices.

Exosomes derived from programmed cell death: mechanism and biological significance.

Exosomes are nanoscale extracellular vesicles present in bodily fluids that mediate intercellular communication by transferring bioactive molecules, thereby regulating a range of physiological and pathological processes. Exosomes can be secreted from nearly all cell types, and the biological function of exosomes is heterogeneous and depends on the donor cell type and state. Recent research has revealed that the levels of exosomes released from the endosomal system increase in cells undergoing programmed cell death. These exosomes play crucial roles in diseases, such as inflammation, tumors, and autoimmune diseases. However, there is currently a lack of systematic research on the differences in the biogenesis, secretion mechanisms, and composition of exosomes under different programmed cell death modalities. This review underscores the potential of exosomes as vital mediators of programmed cell death processes, highlighting the interconnection between exosome biosynthesis and the regulatory mechanisms governing cell death processes. Furthermore, we accentuate the prospect of leveraging exosomes for the development of innovative biomarkers and therapeutic strategies across various diseases.

Thrombospondin-1-mediated crosstalk between autophagy and oxidative stress orchestrates repair of blast lung injury.

Coal mining carries inherent risks of catastrophic gas explosions capable of inflicting severe lung injury. Using complementary in vivo and in vitro models, we explored mechanisms underlying alveolar epithelial damage and repair following a gas explosion in this study. In a rat model, the gas explosion was demonstrated to trigger inflammation and injury within the alveolar epithelium. The following scRNA-sequencing revealed that alveolar epithelial cells exhibited the most profound transcriptomic changes after gas explosion compared to other pulmonary cell types. In the L2 alveolar epithelial cells, the blast was found to cause autophagic flux by inducing autophagosome formation, LC3 lipidation, and p62 degradation. Transcriptomic profiling of the L2 cells identified PI3K-Akt and p53 pathways as critical modulators governing autophagic and oxidative stress responses to blast damage. Notably, Thrombospondin-1 (Thbs1) was determined for the first time as a pivotal node interconnecting these two pathways. The findings of this study illuminate intricate mechanisms of alveolar epithelial injury and recovery after blast trauma, highlighting autophagic and oxidative stress responses mediated by Thbs1-associated PI3K-Akt and p53 pathways as high-value therapeutic targets, and strategic modulation of these pathways in future studies may mitigate lung damage by reducing oxidative stress while engaging endogenous tissue repair processes like autophagy.

Melatonin as an immunomodulator in CD19-targeting CAR-T cell therapy: managing cytokine release syndrome.

BACKGROUND: Chimeric antigen receptor CAR-T cell therapies have ushered in a new era of treatment for specific blood cancers, offering unparalleled efficacy in cases of treatment resistance or relapse. However, the emergence of cytokine release syndrome (CRS) as a side effect poses a challenge to the widespread application of CAR-T cell therapies. Melatonin, a natural hormone produced by the pineal gland known for its antioxidant and anti-inflammatory properties, has been explored for its potential immunomodulatory effects. Despite this, its specific role in mitigating CAR-T cell-induced CRS remains poorly understood. METHODS: In this study, our aim was to investigate the potential of melatonin as an immunomodulatory agent in the context of CD19-targeting CAR-T cell therapy and its impact on associated side effects. Using a mouse model, we evaluated the effects of melatonin on CAR-T cell-induced CRS and overall survival. Additionally, we assessed whether melatonin administration had any detrimental effects on the antitumor efficacy and persistence of CD19 CAR-T cells. RESULTS: Our findings demonstrate that melatonin effectively mitigated the severity of CAR-T cell-induced CRS in the mouse model, leading to improved overall survival outcomes. Remarkably, melatonin administration did not compromise the antitumor effectiveness or persistence of CD19 CAR-T cells, indicating its compatibility with therapeutic goals. These results suggest melatonin's potential as an immunomodulatory compound to alleviate CRS without compromising the therapeutic benefits of CAR-T cell therapy. CONCLUSION: The study's outcomes shed light on melatonin's promise as a valuable addition to the existing treatment protocols for CAR-T cell therapies. By attenuating CAR-T cell-induced CRS while preserving the therapeutic impact of CAR-T cells, melatonin offers a potential strategy for optimizing and refining the safety and efficacy profile of CAR-T cell therapy. This research contributes to the evolving understanding of how to harness immunomodulatory agents to enhance the clinical application of innovative cancer treatments.

Encapsulation and assessment of therapeutic cargo in engineered exosomes: a systematic review.

Exosomes are nanoscale extracellular vesicles secreted by cells and enclosed by a lipid bilayer membrane containing various biologically active cargoes such as proteins, lipids, and nucleic acids. Engineered exosomes generated through genetic modification of parent cells show promise as drug delivery vehicles, and they have been demonstrated to have great therapeutic potential for treating cancer, cardiovascular, neurological, and immune diseases, but systematic knowledge is lacking regarding optimization of drug loading and assessment of delivery efficacy. This review summarizes current approaches for engineering exosomes and evaluating their drug delivery effects, and current techniques for assessing exosome drug loading and release kinetics, cell targeting, biodistribution, pharmacokinetics, and therapeutic outcomes are critically examined. Additionally, this review synthesizes the latest applications of exosome engineering and drug delivery in clinical translation. The knowledge compiled in this review provides a framework for the rational design and rigorous assessment of exosomes as therapeutics. Continued advancement of robust characterization methods and reporting standards will accelerate the development of exosome engineering technologies and pave the way for clinical studies.

Single-cell RNA sequencing reveals the heterogeneity of epithelial cell and fibroblast cells from non- to metastatic lymph node OTSCC.

Lymph node metastasis (LNM) is one of the common features of oral tongue squamous cell carcinoma (OTSCC). LNM is also taken as a sign of advanced OTSCC and poor survival rate. Recently, single-cell RNA sequencing has been applied in investigating the heterogeneity of tumor microenvironment and discovering the potential biomarkers for helping the diagnosis and prognosticating. Pathogenesis of LNM in OTSCC remains unknown. Specifically, cancer-associated fibroblasts (CAFs) and epithelial tumor cells could foster the progression of tumors. Thus, in this study, we aimed to comprehensively analyze the roles of subpopulations of CAFs and epithelial tumor cells in lymph node metastatic OTSCC using the integration of OTSCC single-cell RNA sequencing datasets. Four distinct subtypes of CAFs, namely vascular CAFs, myofibroblast CAFs, inflammatory CAFs, and growth arrest CAFs were successfully discovered in LNM tumor and confirmed the roles of GAS and PTN pathways in the progression of tumor metastasis. In addition, NKAIN2+ epithelial cells and FN1+ epithelial cells specifically exhibited an upregulation of PTN, NRG, MIF, and SPP1 signaling pathways in the metastatic OTSCC. In doing so, we put forth some potential biomarkers that could be utilized for the purpose of diagnosing and prognosticating OTSCC during its metastatic phase and tried to confirm by immunofluorescence assays.

B-embedded disulfide-bridged π-conjugated compounds: structures and optical tuning.

Two novel B-embedded disulfide-bridged π-conjugated compounds (BS-CZ and BS-N) bearing different electron donor groups (phenyl carbazole and triphenylamine) have been prepared and show different optical mechanisms. The compound BS-CZ exhibits significant multiple resonance thermal activation delayed fluorescence (MR-TADF) properties with a small singlet-triplet energy gap (ΔEST = 0.16 eV) and a narrow half-peak full width (FWHM = 33 nm), while the compound BS-N shows traditional fluorescence luminescence (FL) characteristics with a larger ΔEST (0.28 eV) and FWHM (57 nm). Time-dependent density functional theory (TD-DFT) calculations show that the lowest excited singlet state (S1) of the compound BS-CZ exhibits local excited (LE) state characteristics, while the charge transfer (CT) state characteristics can be found in S1 of the compound BS-N. Considering good optical performance, the compound BS-CZ is used as an emitting layer of the organic light-emitting diode device and achieved saturated blue emission (473 nm) with a narrow FWHM (39 nm), and CIE color coordinates of (0.12, 0.21). This work provides an important strategy for the optical mechanism regulation and photoelectric applications of B-embedded disulfide-bridged π-conjugated molecules.

Psychological evaluation of Asian female patients with rhinoplasty.

BACKGROUND: Patients requiring plastic surgery exhibit more abnormal psychological trends (e.g., body dysmorphic disorder [BDD], depression, and anxiety) than those requiring other surgeries. However, there are only a few domestic studies on the psychological aspects of the population requiring plastic surgery. Therefore, we analyzed the psychological characteristics and psychological impact of rhinoplasty in female patients. METHODS: In this study, patients were classified into 2 groups: 151 males and 60 females. The self-rating scale of body image (SSBI), self-rating anxiety scale, self-rating depression scale, and postoperative satisfaction questionnaire were used to examine the patients before and after surgery. The results were analyzed using t-test, analysis of variance, chi-square test, paired rank sum test, and Pearson correlation analysis. RESULTS: The total prevalence of BDD in female patients who underwent rhinoplasty was 7.3%. The prevalence of anxiety disorders was 31.8% and that of depression was 45.0%. Female patients with BDD were more likely to exhibit depression (55.5%) and anxiety (36.4%). The SSBI score was related to marital status (p = 0.001) and history of rhinoplasty (p = 0.000). Moreover, there was a significant negative correlation between preoperative BDD score and postoperative satisfaction (r = -0.392, p = 0.002) as well as between the previous history of rhinoplasty and postoperative satisfaction (r = -0.603, p = 0.000). CONCLUSION: Pathological psychologies such as anxiety, depression, and BDD are common in patients scheduled to undergo rhinoplasty, and BDD is more likely to be associated with depression. Rhinoplasty has little psychological impact on patients, i.e., it neither causes improvement nor deterioration. Female patients who have undergone rhinoplasty should be considered to a have high risk of BDD. Although the outcomes of surgery are generally quite positive, patients diagnosed with BDD are more likely to be dissatisfied.