FOXO1 reshapes neutrophils to aggravate acute brain damage and promote late depression after traumatic brain injury.

BACKGROUND: Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. METHODS: Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. RESULTS: We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. CONCLUSIONS: FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.

MI-MZI based distributed optical fiber sensor for location and pattern recognition.

This research addressed the drawbacks of the conventional hybrid structure and processing technique by presenting a novel distributed fiber optic sensor based on a hybrid Michelson and Mach-Zehnder interferometer. The sensor can achieve blind spot free positioning and has a wide response frequency, additionally its structure is not complex. It can obtain two phase signals from each of the two interferometers by using a demodulation method that uses a 3 × 3 optical coupler. To determine the position of the disturbance, we computed cross-correlations on the two signals following basic mathematical techniques. Markov Transition Field was used to transform the phase signals-which had been filtered by a band pass filter-into two-dimensional images. Tagged photos built a dataset, which is then fed into a neural network to identify patterns. Experiments have shown that the frequency response capacity of the structure was verified, and it was able to achieve location within 0-30 km with location errors of ±85 m. In a six-category pattern recognition, the testing set accuracy was 98.74%.

Multiscale architecture design of 3D printed biodegradable Zn-based porous scaffolds for immunomodulatory osteogenesis.

Reconciling the dilemma between rapid degradation and overdose toxicity is challenging in biodegradable materials when shifting from bulk to porous materials. Here, we achieve significant bone ingrowth into Zn-based porous scaffolds with 90% porosity via osteoinmunomodulation. At microscale, an alloy incorporating 0.8 wt% Li is employed to create a eutectoid lamellar structure featuring the LiZn4 and Zn phases. This microstructure optimally balances high strength with immunomodulation effects. At mesoscale, surface pattern with nanoscale roughness facilitates filopodia formation and macrophage spreading. At macroscale, the isotropic minimal surface G unit exhibits a proper degradation rate with more uniform feature compared to the anisotropic BCC unit. In vivo, the G scaffold demonstrates a heightened efficiency in promoting macrophage polarization toward an anti-inflammatory phenotype, subsequently leading to significantly elevated osteogenic markers, increased collagen deposition, and enhanced new bone formation. In vitro, transcriptomic analysis reveals the activation of JAK/STAT pathways in macrophages via up regulating the expression of Il-4, Il-10, subsequently promoting osteogenesis.

A Combined Method of Seismic Monitoring and Transient Electromagnetic Detection for the Evaluation of Hydraulic Fracturing Effect in Coal Burst Prevention.

In order to mitigate the risk of roof-dominated coal burst in underground coal mining, horizontal long borehole staged hydraulic fracturing technology has been prevailingly employed to facilitate the weakening treatment of the hard roof in advance. Such weakening effect, however, can hardly be evaluated, which leads to a lack of a basis in which to design the schemes and parameters of hydraulic fracturing. In this study, a combined underground-ground integrated microseismic monitoring and transient electromagnetic detection method was utilized to carry out simultaneous evaluations of the seismic responses to each staged fracturing and the apparent resistivity changes before and after all finished fracturing. On this basis, the comparable and applicable fracturing effects on coal burst prevention were evaluated and validated by the distribution of microseismic events and their energy magnitude during the mining process. Results show that the observed mining-induced seismic events are consistent with the evaluation results obtained from the combined seismic-electromagnetic detection method. However, there is a limited reduction effect on resistivity near the fractured section that induces far-field seismic events. Mining-induced seismic events are concentrated primarily within specific areas, while microseismic events in the fractured area exhibit high frequency but low energy overall. This study validates the rationality of combined seismic-electromagnetic detection results and provides valuable insights for optimizing fracturing construction schemes as well as comprehensively evaluating outcomes associated with underground directional long borehole staged hydraulic fracturing.

Safety, tolerability, and pharmacokinetics of aildenafil citrate tablets, a novel oral PDE5 inhibitor, in healthy Chinese volunteers after multiple-dose administration.

Background: Aildenafil citrate is a potent and selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, developed for the treatment of erectile dysfunction (ED). Aim: This study aimed to assess the pharmacokinetics, safety, and tolerability of aildenafil citrate tablets after multiple doses in healthy Chinese males. Methods: Twenty participants were divided into 2 groups, 10 participants each. Participants were administered multiple doses of aildenafil citrate tablets at 30 and 60 mg. Outcomes: The safety evaluation was based on clinical symptoms and adverse events. Concentrations of aildenafil and its key metabolites (M1, M5, and M12) in human serum were measured by liquid chromatography-tandem mass spectrometry. Results: Pharmacokinetic analysis showed rapid absorption and elimination of aildenafil, with a median time to maximum serum concentration of 1 hour and mean terminal half-lives of 2.75 and 3.26 hours in the respective dose groups. The mean maximum concentration was proportional to the aildenafil dose in the range of 30 to 60 mg, although the area under the curve was not proportional for serum concentration vs time 0 to the last measurable time point (24 hours). Multiple doses of aildenafil were well tolerated, with 60.0% of men experiencing treatment-emergent adverse events, notably myalgia and fatigue, particularly in the 60-mg group. Clinical Implications: Aildenafil citrate tablets demonstrated favorable tolerability with once-daily administration over the clinical dose range. The occurrence of myalgia and fatigue was more prevalent in the 60-mg group. From a pharmacokinetic perspective, optimal administration of aildenafil citrate tablets appears to be 1 hour before sexual intercourse in men with ED. Strengths and Limitations: This study presents robust safety and pharmacokinetic data at expected therapeutic doses, unaffected by clinical factors. The efficacy of aildenafil citrate tablets warrants further validation in individuals with ED. Conclusion: Aildenafil citrate tablets exhibited good tolerability in healthy Chinese males following multiple doses at 30 and 60 mg. The 60-mg group showed an increased incidence of myalgia and fatigue, suggesting the need for heightened clinical vigilance. The mean maximum concentration, but not the area under the curve, displayed dose proportionality within the 30- to 60-mg dose range, and no significant drug accumulation was observed with repeated daily administration. Clinical Trial Registration: CTR20192473 (http://www.chinadrugtrials.org.cn).

Tumor microenvironment characteristics and prognostic role of m6A modification in lung squamous cell carcinoma.

Background: It has recently been determined that N6-methyladenosine (m6A) RNA methylation regulators have prominent effects on several cancers. However, the potential role of m6A modification in lung squamous cell carcinoma (LUSC) remains unclear. Methods: We evaluated the modification pattern of m6A and studied the biological function of m6A regulators in LUSC. Then, we constructed the m6Ascore to predict the prognosis of LUSC and analyzed the relationship between the m6Ascore and tumor mutation burden, immune cell infiltration, and immunotherapy. Result: In the unsupervised consensus cluster analysis, three different m6Aclusters were identified, which correspond to an immune activation state, a moderate immune activation state, and an immune tolerance state. Forty-two genes related to the m6A phenotype were used to construct the m6Ascore; subsequently, multiple validations of the m6Ascore were carried out to determine the relationship between the score and immune cell infiltration and response to CTLA-4/PD-1 inhibitor treatment. Further analysis revealed that the m6Ascore could effectively predict the prognosis of LUSC and that the m6A phenotype-related genes, FAM162A and LOM4, might be potential biomarkers. Conclusion: These findings highlight the potential role of m6A modification in the prognosis, TME, and immunotherapy of LUSC and have profound implications for developing more effective personalized treatment strategies for LUSC.

Comparative Analysis of the Chloroplast Genomes of Eight Species of the Genus Lirianthe Spach with Its Generic Delimitation Implications.

Based on Sima and Lu's system of the family Magnoliaceae, the genus Lirianthe Spach s. l. includes approximately 25 species, each with exceptional landscaping and horticultural or medical worth. Many of these plants are considered rare and are protected due to their endangered status. The limited knowledge of species within this genus and the absence of research on its chloroplast genome have greatly impeded studies on the relationship between its evolution and systematics. In this study, the chloroplast genomes of eight species from the genus Lirianthe were sequenced and analyzed, and their phylogenetic relationships with other genera of the family Magnoliaceae were also elucidated. The results showed that the chloroplast genome sizes of the eight Lirianthe species ranged from 159,548 to 159,833 bp. The genomes consisted of a large single-copy region, a small single-copy region, and a pair of inverted repeat sequences. The GC content was very similar across species. Gene annotation revealed that the chloroplast genomes contained 85 protein-coding genes, 37 tRNA genes, and 8 rRNA genes, totaling 130 genes. Codon usage analysis indicated that codon usage was highly conserved among the eight Lirianthe species. Repeat sequence analysis identified 42-49 microsatellite sequences, 16-18 tandem repeats, and 50 dispersed repeats, with microsatellite sequences being predominantly single-nucleotide repeats. DNA polymorphism analysis revealed 10 highly variable regions located in the large single-copy and small single-copy regions, among which rpl32-trnL, petA-psbJ, and trnH-psbA were the recommended candidate DNA barcodes for the genus Lirianthe species. The inverted repeat boundary regions show little variation between species and are generally conserved. The result of phylogenetic analysis confirmed that the genus Lirianthe s. l. is a monophyletic taxon and the most affinal to the genera, Talauma and Dugandiodendron, in Sima and Lu's system and revealed that the genus Lirianthe s. s. is paraphyletic and the genus Talauma s. l. polyphyletic in Xia's system, while Magnolia subsection Gwillimia is paraphyletic and subsection Blumiana polyphyletic in Figlar and Nooteboom's system. Morphological studies found noticeable differences between Lirianthe species in aspects including leaf indumentum, stipule scars, floral orientation, tepal number, tepal texture, and fruit dehiscence. In summary, this study elucidated the chloroplast genome evolution within Lirianthe and laid a foundation for further systematic and taxonomic research on this genus.

Emerging polymeric materials for treatment of oral diseases: design strategy towards a unique oral environment.

Oral diseases are prevalent but challenging diseases owing to the highly movable and wet, microbial and inflammatory environment. Polymeric materials are regarded as one of the most promising biomaterials due to their good compatibility, facile preparation, and flexible design to obtain multifunctionality. Therefore, a variety of strategies have been employed to develop materials with improved therapeutic efficacy by overcoming physicobiological barriers in oral diseases. In this review, we summarize the design strategies of polymeric biomaterials for the treatment of oral diseases. First, we present the unique oral environment including highly movable and wet, microbial and inflammatory environment, which hinders the effective treatment of oral diseases. Second, a series of strategies for designing polymeric materials towards such a unique oral environment are highlighted. For example, multifunctional polymeric materials are armed with wet-adhesive, antimicrobial, and anti-inflammatory functions through advanced chemistry and nanotechnology to effectively treat oral diseases. These are achieved by designing wet-adhesive polymers modified with hydroxy, amine, quinone, and aldehyde groups to provide strong wet-adhesion through hydrogen and covalent bonding, and electrostatic and hydrophobic interactions, by developing antimicrobial polymers including cationic polymers, antimicrobial peptides, and antibiotic-conjugated polymers, and by synthesizing anti-inflammatory polymers with phenolic hydroxy and cysteine groups that function as immunomodulators and electron donors to reactive oxygen species to reduce inflammation. Third, various delivery systems with strong wet-adhesion and enhanced mucosa and biofilm penetration capabilities, such as nanoparticles, hydrogels, patches, and microneedles, are constructed for delivery of antibiotics, immunomodulators, and antioxidants to achieve therapeutic efficacy. Finally, we provide insights into challenges and future development of polymeric materials for oral diseases with promise for clinical translation.

Bibliometric and visualized analysis of hydrogels in organoids research.

Over the past decades, there has been ongoing effort to develop complex biomimetic tissue engineering strategies for in vitro cultivation and maintenance of organoids. The defined hydrogels can create organoid models for various organs by changing their properties and various active molecules. An increasing number of researches has been done on the application of hydrogels in organoids, and a large number of articles have been published on the topic. Although there have been existing reviews describing the application of hydrogels in the field of organoids, there is still a lack of comprehensive studies summarizing and analyzing the overall research trends in this field. The citation can be used as an indicator of the scientific influence of an article in its field. This study aims to evaluate the application of hydrogels in organoids through bibliometric analysis, and to predict the hotspots and developing trends in this field.

Age-related bone diseases: Role of inflammaging.

Bone aging is characterized by an imbalance in the physiological and pathological processes of osteogenesis, osteoclastogenesis, adipogenesis, and chondrogenesis, resulting in exacerbated bone loss and the development of age-related bone diseases, including osteoporosis, osteoarthritis, rheumatoid arthritis, and periodontitis. Inflammaging, a novel concept in the field of aging research, pertains to the persistent and gradual escalation of pro-inflammatory reactions during the aging process. This phenomenon is distinguished by its low intensity, systemic nature, absence of symptoms, and potential for management. The mechanisms by which inflammaging contribute to age-related chronic diseases, particularly in the context of age-related bone diseases, remain unclear. The precise manner in which systemic inflammation induces bone aging and consequently contributes to the development of age-related bone diseases has yet to be fully elucidated. This article primarily examines the mechanisms underlying inflammaging and its association with age-related bone diseases, to elucidate the potential mechanisms of inflammaging in age-related bone diseases and offer insights for developing preventive and therapeutic strategies for such conditions.

Modular Protein Fibers with Outstanding High-Strength and Acid-Resistance Performance Mediated by Copper Ion Binding and Imine Networking.

Engineered protein fibers are promising biomaterials with diverse applications due to their tunable protein structure and outstanding mechanical properties. However, it remains challenging at the molecular level to achieve satisfied mechanical properties and environmental tolerance simultaneously, especially under extreme acid conditions. Herein, the construction of artificial fibers comprising chimeric proteins made of rigid amyloid peptide and flexible cationic elastin-like protein (ELP) module is reported. The amyloid peptide readily assembles into highly organized ß-sheet structures that can be further strengthened by the coordination of Cu2+ , while the flexible ELP module allows the formation of imine-based crosslinking networks. These double networks synergistically enhance the mechanical properties of the fibers, leading to a high tensile strength and toughness, overwhelming many reported recombinant spidroin fibers. Notably, the coordination of Cu2+ with serine residues could stabilize ß-sheet structures in the fibers under acidic conditions, which makes the fibers robust against acid, thus enabling their successful utilization in gastric perforation suturing. This work highlights the customization of double networks at the molecular level to create tailored high-performance protein fibers for various application scenarios.

Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy.

Melittin, a classical antimicrobial peptide, is a highly potent antitumor agent. However, its significant toxicity seriously hampers its application in tumor therapy. In this study, we developed novel melittin analogs with pH-responsive, cell-penetrating and membrane-lytic activities by replacing arginine and lysine with histidine. After conjugation with camptothecin (CPT), CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions. Notably, we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus. CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity. Collectively, the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

Nicotine destructs dental stem cell-based periodontal tissue regeneration.

Background/purpose: Nicotine is a widely known addictive and toxic substance in cigarette that exacerbates periodontitis. However, its deleterious effects on dental stem cells and subsequent implications in tissue regeneration remain unclear. This study aimed to explore the effects of nicotine on the regenerative capacity of human periodontal ligament stem cells (hPDLSCs) based on transcriptomics and proteomics, and determined possible targeted genes associated with smoking-related periodontitis. Materials and methods: hPDLSCs were treated with different concentrations of nicotine ranging from 10-3 to 10-8 M. Transcriptomics and proteomics were performed and confirmed employing Western blot, 5-ethynyl-2'-deoxyuridine (EdU), and alkaline phosphatase (ALP) staining. A ligature-induced periodontitis mouse model was established and administrated with nicotine (16.2 µg/10 µL) via gingival sulcus. The bone resorption was assessed by micro-computed tomography and histological staining. Key genes were identified using multi-omics analysis with verifications in hPDLSCs and human periodontal tissues. Results: Based on enrichments analysis, nicotine-treated hPDLSCs exhibited decreased proliferation and differentiation abilities. Local administration of nicotine in mouse model significantly aggravated bone resorption and undermined periodontal tissue regeneration by inhibiting the endogenous dental stem cells regenerative ability. HMGCS1, GPNMB, and CHRNA7 were hub-genes according to the network analysis and corelated with proliferation and differentiation capabilities, which were also verified in both cells and tissues. Conclusion: Our study investigated the destructive effects of nicotine on the regeneration of periodontal tissues from aspects of in vitro and in vivo with the supporting information from both transcriptome and proteome, providing novel targets into the molecular mechanisms of smoking-related periodontitis.

The influence and therapeutic effect of microbiota in systemic lupus erythematosus.

Systemic erythematosus lupus (SLE) is an autoimmune disease involving multiple organs that poses a serious risk to the health and life of patients. A growing number of studies have shown that commensals from different parts of the body and exogenous pathogens are involved in SLE progression, causing barrier disruption and immune dysregulation through multiple mechanisms. However, they sometimes alleviate the symptoms of SLE. Many factors, such as genetic susceptibility, metabolism, impaired barriers, food, and sex hormones, are involved in SLE, and the microbiota drives the development of SLE either by depending on or interacting with these factors. Among these, the crosstalk between genetic susceptibility, metabolism, and microbiota is a hot topic of research and is expected to lay the groundwork for the amelioration of the mechanism, diagnosis, and treatment of SLE. Furthermore, the microbiota has great potential for the treatment of SLE. Ideally, personalised therapeutic approaches should be developed in combination with more specific diagnostic methods. Herein, we provide a comprehensive overview of the role and mechanism of microbiota in lupus of the intestine, oral cavity, skin, and kidney, as well as the therapeutic potential of the microbiota.

Two new 2-(2-phenylethyl)chromone derivatives and two sesquiterpenes from agarwood of Aquilaria sinensis with anti-inflammatory activity.

Two new 2-(2-phenylethyl)chromones (1-2), two new sesquiterpenes (12-13), and twelve known compounds (3-11, 14-16) were isolated from agarwood of Aquilaria sinensis. These structures were confirmed by HRESIMS, 1D and 2D NMR spectra. The absolute configurations of two new sesquiterpenes were determined by comparing the experimental and calculated ECD spectra. Among them, 7,8-dihydroxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (2) was the first time found that the hydroxyl groups at both C-7/C-8 in agarwood. And Aseudesm B (13), the aldehyded methyl group at C-5 of eucalyptane sesquiterpenes was first discovered in natural products. In the bioassays, all compounds were evaluated for their inhibitory activity against lipopolysaccharide-activated nitric oxide (NO) production in RAW264.7 cells. Compounds 2-5, 7, 9-10, and 13-14 revealed notable inhibitory effects against NO production with IC50 values ranging from 4.0 to 13.0 µM.

Ulcerative colitis with autoimmune thyroid disease results in bilateral auricular ossificans：a case.

Background: Patients with ulcerative colitis (UC) often exhibit susceptibilities to multiple autoimmune diseases such as Sjogren's syndrome, primary sclerosing cholangitis, systemic lupus erythematosus, and insulin-dependent diabetes mellitus. This propensity likely stems from common pathogenic mechanisms underlying immune-mediated conditions. This report highlights the occurrence of autoimmune thyroid disease during UC exacerbations. Notably, the patient displayed petrified auricles.Case Summary.A 57-year-old male complained of sustained abdominal pain, diarrhea, hematochezia, and mucus for a duration of 20 days. The diagnosis of UC was confirmed via colonoscopy, histopathological examination, and small bowel MRE. Clinical evaluations revealed bilateral ectopic ossification in his ears, which appeared to develop over an unspecified timeframe. Imaging and histological evaluations substantiated the ectopic ossification diagnosis while eliminating the possibility of adrenal insufficiency. The presented case offers a unique instance of bilateral auricular ossification, which is hypothesized to result from hyperthyroidism. Conclusion: Our case report underscores the necessity of enhancing awareness of the rare complications associated with UC. Medical practitioners should recognize the potential overlap of autoimmune thyroid disorders in UC patients. It is imperative to test for thyroid-related antibodies in such individuals, irrespective of overt thyroid dysfunction.

Benzyl Deuteriodifluoromethyl Sulfoxide: An Easily Accessible and Stable Reagent for Direct Deuterodifluoromethylthiolation.

A new, stable and scalable reagent based on a sulfoxide skeleton for direct deuteriodifluoromethylthiolation has been developed. The reagent displays excellent reactivities toward Tf2O promoted C-H deuteriodifluoromethylthiolation of electron-rich arenes, indoles, alkenes, and intramolecular lactonization of 2-alkynylbenzoates. Moreover, high deuteration rates and good to excellent yields were achieved under metal-free reaction conditions. As a result, a wide range of deuteriodifluoromethylthilolated compounds were prepared, enabling further applications in drug discovery.

No Incidence of Liver Cancer Was Observed in A Retrospective Study of Patients with Aristolochic Acid Nephropathy.

OBJECTIVE: To assess the risk of aristolochic acid (AA)-associated cancer in patients with AA nephropathy (AAN). METHODS: A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014. Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer. The primary endpoint was the incidence of liver cancer, and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014. RESULTS: A total of 337 patients diagnosed with AAN were included in this study. From the initiation of taking AA to the termination of follow-up, 39 patients were diagnosed with cancer. No cases of liver cancer were observed throughout the entire follow-up period, with urinary cancer being the predominant type (34/39, 87.17%). Logistic regression analysis showed that age, follow-up period, and diabetes were potential risk factors, however, the dosage of the drug was not significantly associated with urinary cancer. CONCLUSIONS: No cases of liver cancer were observed at the end of follow-up. However, a high prevalence of urinary cancer was observed in AAN patients. Establishing a direct causality between AA and HCC is challenging.

A first-in-human study of Brozopentyl Sodium, following single and multiple ascending intravenous infusion in Chinese healthy volunteers.

BACKGROUND: Brozopentyl Sodium (BZP), a novel agent for ischemic stroke, has shown promising results in preclinical pharmacological studies, prompting the initiation of the first-in-human investigation. PURPOSE: This study aimed to assess the safety, tolerability, and pharmacokinetic (PK) characteristics of BZP in Chinese healthy volunteers. METHODS: The study consisted of two parts. Part I was a single-center, randomized, single-blinded, placebo-controlled, single-ascending study with six BZP dose cohorts (SAD: 25, 50, 100, 200, 300, and 400 mg). Part II was a single-center, randomized, single-blinded, placebo-controlled, multi-dose- and dose-elevated study with three BZP dose cohorts (MAD: 50, 100, and 200 mg). Doses were administered once daily on days 1 and 7 and twice daily on days 2-6. The PK properties of BZP and its bioactive metabolites, BNBP, were assessed. Safety and tolerability evaluations were also conducted. RESULTS: In the SAD study, BZP reached peak plasma concentrations (Tmax) at the end of administration, with median Tmax values ranging from 1 to 1.03 h, while BNBP reached Tmax between 1.25 to 1.38 h. The terminal half-lives (T1/2) were approximately 8 h for BZP and 15 h for BNBP. In the MAD study, steady-state plasma concentrations of BZP were reached by day 5. There was minimal accumulation of both BZP and BNBP after 7 days of administration. The area under the plasma concentration-time curve from 0 to time of the last measurable concentration (AUC0-t) and maximum plasma drug concentration (Cmax) showed dose-proportional increases for BZP but not for BNBP in both study parts. Single and multiple doses of BZP demonstrated a good safety profile and were well-tolerated. CONCLUSION: BZP displayed safety, good tolerability and predictable PK characteristics following both single and multiple ascending intravenous administrations. These findings provide a basis for further clinical development of BZP for ischemic stroke patients.

Sphingolipids: drivers of cardiac fibrosis and atrial fibrillation.

Sphingolipids (SLs) are vital constituents of the plasma membrane of animal cells and concurrently regulate numerous cellular processes. An escalating number of research have evinced that SLs assume a crucial part in the progression of tissue fibrosis, a condition for which no efficacious cure exists as of now. Cardiac fibrosis, and in particular, atrial fibrosis, is a key factor in the emergence of atrial fibrillation (AF). AF has become one of the most widespread cardiac arrhythmias globally, with its incidence continuing to mount, thereby propelling it to the status of a major public health concern. This review expounds on the structure and biosynthesis pathways of several pivotal SLs, the pathophysiological mechanisms of AF, and the function of SLs in cardiac fibrosis. Delving into the influence of sphingolipid levels in the alleviation of cardiac fibrosis offers innovative therapeutic strategies to address cardiac fibrosis and AF.