Borneol acts as an adjuvant agent to enhance the oral absorption of Panax notoginseng saponins in rats: Effect of optical configuration and compatibility ratios.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng saponins (PNS), as the main active component of Panax notoginseng, shows broad pharmacological effects but with low oral bioavailability. Borneol (BO) is commonly used as an adjuvant drug in the field of traditional Chinese medicine, which has been proven to facilitate the absorption of ginsenosides such as Rg1 and Rb1 in vivo. The presence of chiral carbons has resulted in three optical isomers of BO commercially available in the market, all of which are documented by national standards. AIM OF THE STUDY: This study aimed to investigate the role of BO in promoting the oral absorption of PNS from the perspective of optical configuration and compatibility ratios. MATERIALS AND METHODS: In this study, an ultra-performance liquid chromatography coupled with triple quadrupole-linear ion trap tandem mass spectrometry (UPLC-QTRAP-MS/MS) method was validated and applied to determine the concentrations of five main saponins in PNS in rat plasma. The kinetic characteristics of PNS were compared when co-administered with BO based on optical isomerism and different compatibility ratios. RESULTS: The results showed that BO promoted the exposure of PNS in rats. Three forms of BO, namely d-borneol (DB), l-borneol (LB), and synthetic borneol (SB), exhibited different promotion strengths. SB elevated PNS exposure in rats more than DB or LB. It is also interesting to note that under different compatibility ratios, SB can exert a strong promoting effect only when PNS and BO were combined in a 1:1 ratio (PNS 75 mg/kg; BO 75 mg/kg). As a pharmacokinetic booster, the dosage of BO is worthy of consideration and should follow the traditional medication principles of Chinese medicine. CONCLUSIONS: This study shed new light on the compatible use of PNS and BO from the perspective of "configuration-dose-influence" of BO. The results provide important basis for the clinical application and selection of BO.

Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial.

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180-365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients' improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).

Functional Green-Emitting Mn2+-doped Zinc Germanate Persistent Luminescent Nanoparticles for Dual-Mode Immunochromatographic Detection.

Immunochromatography is a commonly used immediate detection technique, using signal labels to generate detection signals for rapid medical diagnosis. However, its detection sensitivity is affected by background fluorescence caused by the excitation light source. We have developed an immunochromatographic test strip using Zn2GeO4:Mn2+ (ZGM) persistent luminescent nanoparticles (PLNPs) for immediate fluorescence detection and highly sensitive persistent luminescence (PersL) detection without background fluorescence interference. ZGM emits a strong green light when exposed to ultraviolet (UV) excitation, and its green PersL can persist for over 30 min after the excitation light is turned off. We modified the surface of ZGM with heparin-binding protein (HBP) antibodies to create immunochromatographic test strips for the detection of HBP as the target analyte. Under UV excitation, the chromatography test paper can be visually observed at concentrations as low as 25 ng/mL. After the excitation light source is switched off, PersL can achieve a detection limit of 4.7 ng/mL without background interference. This dual-mode immunochromatographic detection, based on ZGM, shows great potential for in vitro diagnostic applications.

[Phenotypic and genetic analysis of a Chinese pedigree affected with Hereditary antithrombin deficiency due to a novel variant of SERPINC1 gene].

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Hereditary antithrombin deficiency. METHODS: A pedigree diagnosed at the the Second Affiliated Hospital of Wenzhou Medical University, Yuying Children's Hospital in June, 2020 was selected as the study subject. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and thrombin time (TT) of the probands and their pedigree members were determined using a STA-R automatic coagulation analyzer. Antithrombin activity (AT: A) and antithrombin antigen (AT: Ag) in plasma were determined with chromogenic substrate and immunonephelometry assays. All exons and flanking sequences of the anticoagulant protein gene SERPINC1 were amplified by PCR and subjected to Sanger sequencing. Candidate variants were verified with bioinformatic tools (PolyPhen-2, SIFT, Mutation Taster and PYMOL) to explore their effect on the function and structural conformation of the protein. RESULTS: The probands (II-2, II-10), their brother (II-5) and sons (III-1, III-8) had shown normal PT, APTT, FIB, and TT, but significantly decreased AT: A and AT: Ag, with their levels being 34%, 57%, 56%, 48%, 53% and 13.51 mg/dL, 13.44 mg/dL, 18.39 mg/dL, 17.36 mg/dL, 17.71 mg/dL, respectively. The remaining pedigree members had normal values. Sanger sequencing revealed that the probands and all affected pedigree members had harbored a heterozygous c.851T>C (p.Met284Thr) missense variant in exon 5 of the SERPINC1 gene. Bioinformatic analysis and simulation suggested that the variant has resulted in alteration of hydrogen bonds at the c.851 position, which may affect the structure of the protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS1+PM1+PM5+PP1+PP4). CONCLUSION: The probands and other affected members were all diagnosed with type I hereditary AT deficiency, for which the c.851T>C (p.Met284Thr) variant of the SERPINC1 gene may be accountable.

Near-Infrared Persistent Luminescence Nanoprobe for Early Detection of Atherosclerotic Plaque.

Atherosclerosis (AS) is a crucial contributor to various cardiovascular diseases (CVDs), which seriously threaten human life and health. Early and accurate recognition of AS plaques is essential for the prevention and treatment of CVD. Herein, we introduce an AS-targeting nanoprobe based on near-infrared (NIR) persistent luminescence nanoparticles (PLNPs), developing a highly sensitive NIR persistent luminescence (PersL) AS plaque imaging technique and successfully realizing early AS plaque detection. The nanoprobe exhibits good monodispersity and regular spherical morphology and also owns exceptional NIR PersL performance upon repetitive irradiation by biological window light. The surface-conjugated antibody (anti-osteopontin) endowed nanoprobe excellent targeting ability to foam cells within plaques. After intravenously injected nanoprobe into AS model mice, the highly sensitive PersL imaging technique can accurately detect AS plaques prior to ultrasonography (US) and magnetic resonance imaging (MRI). Specifically, the NIR PersL imaging reveals AS plaques at the earliest within 2 weeks, with higher signal-to-background ratio (SBR) up to 5.72. Based on this technique, the nanoprobe has great potential for applications in the prevention and treatment of CVD, the study of AS pathogenesis, and the screening of anti-AS drugs.

Efficacy of antioxidant supplementation in improving endocrine, hormonal, inflammatory, and metabolic statuses of PCOS: a meta-analysis and systematic review.

Background and aim: A large number of recent studies have reported on the use of antioxidants in patients with polycystic ovary syndrome (PCOS). This study aimed to evaluate the antioxidant effects on PCOS. Methods: We searched PubMed, Embase, Web of Science, and The Cochrane Library to identify randomized controlled trials investigating the use of antioxidants in treating PCOS. Statistical analysis was performed using Review Manager 5.4. Stata17.0 software was used to conduct sensitivity analyses. Results: This meta-analysis included 49 articles and 62 studies. The sample comprised 1657 patients with PCOS from the antioxidant group and 1619 with PCOS from the placebo group. The meta-analysis revealed that the fasting blood glucose levels [standardized mean difference (SMD): -0.31, 95% confidence interval (CI): -0.39 to -0.22, P < 0.00001], the homeostatic model assessment of insulin resistance (SMD: -0.68, 95% CI: -0.87 to -0.50], P < 0.00001), and insulin levels (SMD: -0.68, 95% CI: -0.79 to -0.58, P < 0.00001) were significantly lower in patients with PCOS taking antioxidants than those in the placebo group. Further, total cholesterol levels (SMD: -0.38, 95% CI: -0.56 to -0.20, P < 0.001), low-density lipoprotein cholesterol levels (SMD: -0.24, 95% CI: -0.37 to -0.10, P = 0.0008), and very low-density lipoprotein levels (SMD: -0.53, 95% CI: -0.65 to -0.41, P < 0.00001) were lower in patients with PCOS taking antioxidant supplements compared with the placebo group. Total testosterone (TT) level (SMD: -0.78, 95% CI: -1.15 to -0.42, P < 0.0001), dehydroepiandrosterone level (SMD: -0.42, 95% CI: -0.58 to -0.25, P < 0.00001), and mean standard deviation modified Ferriman-Gallway (MF-G scores) (SMD: -0.63, 95% CI: -0.98 to -0.28, P = 0.0004) were lower in patients taking antioxidant supplements. C-reactive protein (CRP) levels (SMD: -0.48, 95% CI: -0.63 to -0.34, P < 0.000001), body mass index [mean difference (MD): -0.27, 95% CI: -0.50 to -0.03, P = 0.03], weight (MD: -0.73, 95% CI: -1.35 to -0.11, P = 0.02), and diastolic blood pressure (MD: -3.78, 95% CI: -6.30 to -1.26, P = 0.003) were significantly lower. Moreover, the levels of sex hormone-binding protein (SMD: 0.23, 95% CI: 0.07-0.38, P = 0.004), high-density lipoprotein cholesterol (SMD: 0.11, 95% CI: 0.01-0.20, P = 0.03), total antioxidant capacity (SMD: 0.59, 95% CI: 0.31-0.87, P < 0.0001), and quantitative insulin sensitivity index (SMD: 0.01, 95% CI: 0.01-0.02, P < 0.00001) were higher in patients with PCOS who took antioxidant supplements compared with the placebo group. Antioxidant supplements did not affect other analyzed parameters in these patients, including follicle-stimulating hormone, free androgen index, nitric oxide, glutathione, malondialdehyde, and diastolic blood pressure. Conclusions: Antioxidants are beneficial in treating PCOS. Our study might provide a new treatment strategy for patients with clinical PCOS. We hope that more high-quality studies evaluating the effects of antioxidants on patients with PCOS will be conducted in the future. Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023448088.

Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice.

A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72-deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72-mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72-deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72-deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72-deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD.

Interpretable deep learning model for major depressive disorder assessment based on functional near-infrared spectroscopy.

BACKGROUND: Major depressive disorder (MDD) affects a substantial number of individuals worldwide. New approaches are required to improve the diagnosis of MDD, which relies heavily on subjective reports of depression-related symptoms. AIM: Establish an objective measurement and evaluation of MDD. METHODS: Functional near-infrared spectroscopy (fNIRS) was used to investigate the brain activity of MDD patients and healthy controls (HCs). Leveraging a sizeable fNIRS dataset of 263 HCs and 251 patients with MDD, including mild to moderate MDD (mMDD; n = 139) and severe MDD (sMDD; n = 77), we developed an interpretable deep learning model for screening MDD and staging its severity. RESULTS: The proposed deep learning model achieved an accuracy of 80.9% in diagnostic classification and 78.6% in severity staging for MDD. We discerned five channels with the most significant contribution to MDD identification through Shapley additive explanations (SHAP), located in the right medial prefrontal cortex, right dorsolateral prefrontal cortex, right superior temporal gyrus, and left posterior superior frontal cortex. The findings corresponded closely to the features of haemoglobin responses between HCs and individuals with MDD, as we obtained a good discriminative ability for MDD using cortical channels that are related to the disorder, namely the frontal and temporal cortical channels with areas under the curve of 0.78 and 0.81, respectively. CONCLUSION: Our study demonstrated the potential of integrating the fNIRS system with artificial intelligence algorithms to classify and stage MDD in clinical settings using a large dataset. This approach can potentially enhance MDD assessment and provide insights for clinical diagnosis and intervention.

GnRH antagonist protocol versus progestin-primed ovarian stimulation in patients with polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: The aim of this meta-analysis was comparing the efficacy of GnRH antagonist (GnRH-ant) protocol and progestin-primed ovarian stimulation (PPOS) in polycystic ovarian syndrome (PCOS) women. METHODS: A search was conducted from PubMed, Embase, The Cochrane library, Web of Science, and Scopus databases to collect clinical papers regarding GnRH-ant protocol and PPOS protocol from inception to September 2023. Subsequently, the retrieved documents were screened, and the content of the documents that conformed to the requirements was extracted. Moreover, statistical meta-analyses were conducted using the RevMan 5.4 software. Furthermore, with the use of a star-based system and the Cochrane handbook, the methodological quality of the covered papers was evaluated on the Ottawa-Newcastle scale. RESULTS: A total of eight papers were covered in the meta-analysis, with 2156 PCOS women enrolled (i.e., 1085 patients in the GnRH-ant protocol group and 1071 patients in the PPOS group). As indicated by the meta-analysis results, the PPOS group was correlated with a lower risk of ovarian hyperstimulation syndrome (OHSS) (SMD = 9.24, [95% CI: (2.50, 34.21)], P = 0.0009), more gonadotropin (Gn) dose (SMD = - 0.34, [95% CI: (- 0.56, - 0.13)], P = 0.002) compared with GnRH-ant group. No statistical difference was identified on the oocytes condition and pregnancy outcomes. CONCLUSIONS: As revealed by the data of this study, the progesterone protocol is comparable with the GnRH-ant protocol in oocytes condition and clinical outcomes. The progestin-primed ovarian stimulation could serve as an alternative for polycystic ovarian syndrome women who have failed in GnRH antagonist protocol. The above-described conclusions should be verified by more high-quality papers due to the limitation of the number and quality of included papers. TRIAL REGISTRATION: PROSPERO registration: CRD42023411284.

RhoA suppresses pseudorabies virus replication in vitro.

The porcine pseudorabies virus (PRV) is one of the most devastating pathogens and brings great economic losses to the swine industry worldwide. Viruses are intracellular parasites that have evolved numerous strategies to subvert and utilize different host processes for their life cycle. Among the different systems of the host cell, the cytoskeleton is one of the most important which not only facilitate viral invasion and spread into neighboring cells, but also help viruses to evade the host immune system. RhoA is a key regulator of cytoskeleton system that may participate in virus infection. In this study, we characterized the function of RhoA in the PRV replication by chemical drugs treatment, gene knockdown and gene over-expression strategy. Inhibition of RhoA by specific inhibitor and gene knockdown promoted PRV proliferation. On the contrary, overexpression of RhoA or activation of RhoA by chemical drug inhibited PRV infection. Besides, our data demonstrated that PRV infection induced the disruption of actin stress fiber, which was consistent with previous report. In turn, the actin specific inhibitor cytochalasin D markedly disrupted the normal fibrous structure of intracellular actin cytoskeleton and decreased the PRV replication, suggesting that actin cytoskeleton polymerization contributed to PRV replication in vitro. In summary, our data displayed that RhoA was a host restriction factor that inhibited PRV replication, which may deepen our understanding the pathogenesis of PRV and provide further insight into the prevention of PRV infection and the development of anti-viral drugs.

Pyrroloquinoline quinone inhibits PCSK9-NLRP3 mediated pyroptosis of Leydig cells in obese mice.

Abnormal lipid metabolism and chronic low-grade inflammation are the main traits of obesity. Especially, the molecular mechanism of concomitant deficiency in steroidogenesis-associated enzymes related to testosterone (T) synthesis of obesity dominated a decline in male fertility is still poorly understood. Here, we found that in vivo, supplementation of pyrroloquinoline quinone (PQQ) efficaciously ameliorated the abnormal lipid metabolism and testicular spermatogenic function from high-fat-diet (HFD)-induced obese mice. Moreover, the transcriptome analysis of the liver and testicular showed that PQQ supplementation not only inhibited the high expression of proprotein convertase subtilisin/Kexin type 9 (PCSK9) but also weakened the NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis, which both played a negative role in T synthesis of Leydig Cells (LCs). Eventually, the function and the pyroptosis of LCs cultured with palmitic acid in vitro were simultaneously benefited by suppressing the expression of NLRP3 or PCSK9 respectively, as well the parallel effects of PQQ were affirmed. Collectively, our data revealed that PQQ supplementation is a feasible approach to protect T synthesis from PCSK9-NLRP3 crosstalk-induced LCs' pyroptosis in obese men.

Nicotinamide Mononucleotide Improves Spermatogenic Disorders in Aluminum-Exposed Rats by Modulating the Glycolytic Pathway.

This study aimed to investigate the protective effect of nicotinamide mononucleotide (NMN) on testicular spermatogenesis in aluminum chloride (AlCl3)-exposed rats and to elucidate the potential underlying mechanism. The results indicated that AlCl3-induced testicular damage, leading to reduced sperm quality, increased apoptosis, decreased cell proliferation, and impaired Sertoli cell function in rats. Additionally, glycolytic metabolism was observed to be hindered. However, after NMN treatment, there was a noticeable improvement in testicular damage among the rats, marked by increased sperm quality, reduced apoptosis, enhanced cell proliferation, improved Sertoli cell function, and an activated glycolytic metabolism. The findings of this study suggest that NMN alleviates testicular spermatogenesis impairment induced by AlCl3 exposure through the inhibition of spermatogenic cell apoptosis, promotion of spermatogenic cell proliferation, and activation of glycolytic pathways. The study contributes an experimental foundation for potential future clinical applications of NMN in cases of AlCl3-exposed spermatogenic dysfunction.

Assessing the utilization of antimicrobial agents in pediatric pneumonia during the era of the 13-valent pneumococcal conjugate vaccine: A retrospective, single-center study.

BACKGROUND AND PURPOSE: Pneumonia and bronchopneumonia are the most common infectious diseases in children. This study aimed to analyze changes in causative pathogens and antibiotic use for bronchopneumonia or pneumonia after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in children. METHODS: This retrospective study was conducted from 2009 to 2019. Hospitalized children aged 6 months-3 years with a discharge diagnosis of bronchopneumonia or pneumonia were included to analyze changes in the potential mismatch between the diagnosed pathogen and antibiotic use. RESULTS: The cohort comprised 1100 patients, including 648 (59%) and 452 (41%) with a discharge diagnosis of bronchopneumonia and pneumonia, respectively. The trend of viral pneumonia increased every year (rs = 0.101, p < 0.05) Antibiotics were administered in 97% patients, with an increasing annual trend in macrolide use (rs = 0.031, p = 0.009). Regarding antibiotic utilization, no significant variations were observed in the days of therapy (DOT) (rs = 0.076, p = 0.208) or length of therapy (LOT) (rs = -0.027, p = 0.534) per patient-year throughout the study duration. Interestingly, the LOT for combined therapy with macrolides and first-line beta-lactams was high (rs = 0.333, p = 0.028). In viral pneumonia treatment, neither the DOT nor LOT exhibited significant variations (rs = -0.006, p = 0.787 and rs = -0.156, p = 0.398). CONCLUSION: After the introduction of PCV13 in Taiwan, no decrease in antibiotic use has been observed among children aged 6 months-3 years with a discharge diagnosis of bronchopneumonia and pneumonia.

Comparative volatiles profiling in milk-flavored white tea and traditional white tea Shoumei via HS-SPME-GC-TOFMS and OAV analyses.

White tea is a mildly fermented tea processed with withering and drying. Milk-flavored white tea has a unique milk flavor compared to the traditional white tea. Little is known about the aromas that make white tea taste milky. Here we conducted the volatile profiling via headspace solid-phase microextraction (HS-SPME)-gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) and chemometrics to explore the key volatiles making milk-flavored white tea taste milky. Sixty-seven volatiles were identified, with 7 volatiles (OAV > 1 and VIP > 1) were characterized as the typical aromas. Green and light fruity scent volatiles, such as methyl salicylate, benzyl alcohol, and phenylethyl alcohol, were richer in TFs than MFs. Strong fruity and cheese aromas, such as dihydro-5-pentyl-2(3H)-furanone, 2-pentyl-furan, (E)-6,10-dimethyl-5,9-undecadien-2-one, and hexanal, were more abundant in MFs than TFs. Dihydro-5-pentyl-2(3H)-furanone, recognized as coconut and creamy aroma, should be the essential volatile for milky flavor. Also, (E)-6,10-dimethyl-5,9-undecadien-2-one and 2-pentyl-furan may contribute to the milk scent formation.

Icariin Ameliorates Spermatogenesis Disorder in Obese Mice Induced by High-Fat Diet through Regulating the Glycolytic Pathway.

SCOPE: Obesity is a global threat for male infertility, which can cause spermatogenic dysfunction. However, there are no available drugs for the treatment of obesity-induced spermatogenesis dysfunction. This study characterizes the protective effects of icariin (ICA) on spermatogenesis dysfunction in obese mice. METHODS AND RESULTS: Obese mice are induced by a high-fat diet to determine whether ICA has a protective effect. ICA treatment reduces body weight and the proportion of abnormal sperm, brings about a recovery of sperm count, and the number of spermatogenic cells. ICA treatment improves histopathological changes of the testes and inhibits testicular apoptosis, as evidenced by reduced the expression of Bax and increased the expression of Bcl-2, PCNA, WT1, GATA-4, vimentin, HK2, PKM2, and LDHA in the testes. In vitro, TM4 cells are treated with 0.4 mm palmitic acid (PA) to induce Sertoli cell injury, and are then utilized for ICA treatment. ICA improves PA-induced decreased TM4 cells viability, reduces the levels of lactate, and increases the levels of pyruvate and the expression of HK2, PKM2, and LDHA and restores the glycolytic process in vitro. CONCLUSION: ICA ameliorates spermatogenic dysfunction in obese mice by regulating glycolytic activity, providing effective strategies for obesity treatment.

Species difference in toxicokinetics and safety assessment of senecionine N-oxide in a UDP-glucuronosyltransferase 1A4 humanized mouse model.

Pyrrolizidine alkaloids (PAs) are naturally occurring hepatotoxins, and herbs containing PAs are of high concern. PAs are normally found in tertiary amines and N-oxide forms (PA N-oxides), yet the latter are less evaluated for their toxicokinetics. As a continuation of our investigation into the safety assessment of PA-containing herbal medicines, the toxicity and toxicokinetic characteristics of senecionine N-oxide (a representative toxic PA N-oxide) were investigated by using the UDP-glucuronosyltransferase 1A4 humanized mouse model (hUGT1A4 mouse model) and compared with those in wild-type mice simultaneously. Results show that the toxicity caused by senecionine N-oxide exposure was evidently decreased in hUGT1A4 mice as approved by pathology and biochemistry assays. In addition, a N-glucuronidation conjugate was exclusively found in hUGT1A4 mice but not in wild-type (WT) mice. In vitro studies proved that senecionine N-oxide initially reduced to the corresponding tertiary amine alkaloid (senecionine) and then underwent N-glucuronidation via human UGT1A4. The variation in toxicokinetic characteristics was also observed between hUGT1A4 mice and WT mice with a notably enhanced clearance of senecionine N-oxide and senecionine, and accordingly less formation of pyrrole-protein adducts in hUGT1A4 mice, which finally led to the detoxification of senecionine N-oxide exposure in hUGT1A4 mice. Our results provided the first in vivo toxicity data and toxicokinetic characteristics of senecionine N-oxide in a humanized animal model and revealed that human UGT1A4 plays an important role in the detoxification of senecionine N-oxide.

Analysis of risk and protective factors associated with retinal nerve fiber layer defect in a Chinese adult population.

AIM: To investigate the risk and protective factors associated with the retinal nerve fiber layer defect (RNFLD) in a Chinese adult population. METHODS: This study was a cross-sectional population-based investigation including employees and retirees of a coal mining company in Kailuan City, Hebei Province. All the study participants underwent a comprehensive systemic and ophthalmic examination. RNFLD was diagnosed on fundus photographs. Binary logistic regression was used to investigate the risk and protective factors associated with the RNFLD. RESULTS: The community-based study included 14 440 participants. There were 10 473 participants in our study, including 7120 males (68.0%) and 3353 females (32.0%). The age range was 45-108y, averaging 59.56±8.66y. Totally 568 participants had RNFLD and the prevalence rate was 5.42%. A higher prevalence of RNFLD was associated with older age [P<0.001, odds ratio (OR): 1.032; 95% confidence interval (CI): 1.018-1.046], longer axial length (P=0.010, OR: 1.190; 95%CI: 1.042-1.359), hypertension (P=0.007, OR: 0.639; 95%CI: 0.460-0.887), and diabetes mellitus (P=0.019, OR: 0.684; 95%CI: 0.499-0.939). The protective factors of RNFLD were visual acuity (P=0.038, OR: 0.617; 95%CI: 0.391-0.975), and central anterior chamber depth (P=0.046, OR: 0.595; 95%CI: 0.358-0.990). CONCLUSION: In our cross-sectional community-based study, with an age range of 45-108y, RNFLD is associated with older age, longer axial length, hypertension, and diabetes mellitus. The protective factors of RNFLD are visual acuity and central anterior chamber depth. These can help to predict and evaluate RNFLD related diseases and identify high-risk populations early.

ortho-C(sp3)-H arylation of aromatic aldehydes using 2-amino-N-methyl-acetamide as a L,L-type transient directing group.

Pd-catalyzed ortho-C(sp3)-H arylation of aromatic aldehydes using 2-amino-N-methyl-acetamide as a simple, efficient and commercially available L,L-type transient directing group (TDG) is reported. The reaction exhibited excellent substrate compatibility and generated the desired products in moderate-to-high yields up to 78%. Further acid-catalyzed cyclization and dehydrative aromatization were also tested, and furnished some polycyclic aromatic hydrocarbons with excellent yields up to 96%. The X-ray crystal structure of a 2-methylbenzaldehyde ortho-C(sp3)-H palladation intermediate was obtained. Then, a plausible reaction mechanism involving the formation of a [5,6]-fused palladacycle was proposed. This approach offers valuable insights for exploiting novel L,L-type TDGs.

Building nomogram plots for predicting urinary tract infections in children less than three years of age.

BACKGROUND AND PURPOSE: Urinary tract infections (UTIs) are the most common bacterial infection in young children. This study aimed to formulate nomogram plots for clinicians to predict UTIs in children aged <3 years by evaluating the risk factors for UTIs in these children. METHODS: This retrospective study was conducted at a tertiary medical center from December 2017 to November 2020. Children less than three years of age were eligible for the study if they had undergone both urine culture and urinalysis during the study period. Mixed-effects logistic regression models with a stepwise procedure were used to determine the relationship between outcome (positive/negative UTI) and covariates of interest (e.g., weight percentile, laboratory) for each patient. Nomogram plots were constructed on the basis of significant factors. We repeated the analysis thrice to adapt it to three different medical settings: medical centers, regional hospitals, and local clinics. RESULTS: In the medical center setting, the two most significant factors were urine leukocyte count ≥100 (OR =8.87; 95% CI (Confidence Interval), 4.135-19.027) and urine nitrite level (OR =8.809; 95% CI, 5.009-15.489). The two factors showed similar significance at the regional hospital and local clinic settings. Abnormal renal echo findings were positively correlated with UTI in the medical center setting (OR =2.534; 95% CI 1.757-3.655). Three nomogram plots for the prediction of UTIs were drawn for medical centers, regional hospitals, and local clinics. CONCLUSION: Using the three nomogram plots, frontline doctors can formulate the probabilities of pediatric UTIs for better decision-making.