Noninvasive electrical stimulation as a neuroprotective strategy in retinal diseases: a systematic review of preclinical studies.

BACKGROUND: Electrical activity has a crucial impact on the development and survival of neurons. Numerous recent studies have shown that noninvasive electrical stimulation (NES) has neuroprotective action in various retinal disorders. OBJECTIVE: To systematically review the literature on in vivo studies and provide a comprehensive summary of the neuroprotective action and the mechanisms of NES on retinal disorders. METHODS: Based on the PRISMA guideline, a systematic review was conducted in PubMed, Web of Science, Embase, Scopus and Cochrane Library to collect all relevant in vivo studies on "the role of NES on retinal diseases" published up until September 2023. Possible biases were identified with the adopted SYRCLE's tool. RESULTS: Of the 791 initially gathered studies, 21 articles met inclusion/exclusion criteria for full-text review. The results revealed the neuroprotective effect of NES (involved whole-eye, transcorneal, transscleral, transpalpebral, transorbital electrical stimulation) on different retinal diseases, including retinitis pigmentosa, retinal degeneration, high-intraocular pressure injury, traumatic optic neuropathy, nonarteritic ischemic optic neuropathy. NES could effectively delay degeneration and apoptosis of retinal neurons, preserve retinal structure and visual function with high security, and its mechanism of action might be related to promoting the secretion of neurotrophins and growth factors, decreasing inflammation, inhibiting apoptosis. The quality scores of included studies ranged from 5 to 8 points (a total of 10 points), according to SYRCLE's risk of bias tool. CONCLUSION: This systematic review indicated that NES exerts neuroprotective effects on retinal disease models mainly through its neurotrophic, anti-inflammatory, and anti-apoptotic capabilities. To assess the efficacy of NES in a therapeutic setting, however, well-designed clinical trials are required in the future.

Loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation.

BACKGROUND: Inherited hyperpigmented skin disorders comprise a group of entities with considerable clinical and genetic heterogenicity. The genetic basis of a majority of these disorders remains to be elucidated. OBJECTIVES: This study aimed to identify the underlying gene for an unclarified disorder of autosomal-dominant generalized skin hyperpigmentation with or without glomuvenous malformation. METHODS: Whole-exome sequencing was performed in five unrelated families with autosomal-dominant generalized skin hyperpigmentation. Variants were confirmed using Sanger sequencing and a minigene assay was employed to evaluate the splicing alteration. Immunofluorescence and transmission electron microscopy (TEM) were used to determine the quantity of melanocytes and melanosomes in hyperpigmented skin lesions. GLMN knockdown by small interfering RNA assays was performed in human MNT-1 cells to examine melanin concentration and the underlying molecular mechanism. RESULTS: We identified five variants in GLMN in five unrelated families, including c.995_996insAACA(p.Ser333Thrfs*11), c.632 + 4delA, c.1470_1473dup(p.Thr492fs*12), c.1319G > A(p.Trp440*) and c.1613_1614insTA(Thr540*). The minigene assay confirmed that the c.632 + 4delA mutant resulted in abolishment of the canonical donor splice site. Although the number of melanocytes remained unchanged in skin lesions, as demonstrated by immunofluorescent staining of tyrosinase and premelanosome protein, TEM revealed an increased number of melanosomes in the skin lesion of a patient. The GLMN knockdown MNT-1 cells demonstrated a higher melanin concentration, a higher proportion of stage III and IV melanosomes, upregulation of microphthalmia-associated transcription factor and tyrosinase, and downregulation of phosphorylated p70S6 K vs. mock-transfected cells. CONCLUSIONS: We found that loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation. Our study implicates a potential role of glomulin in human skin melanogenesis, in addition to vascular morphogenesis.

A group of skin conditions known as 'inherited hyperpigmented skin disorders' includes some diseases with different clinical and genetic traits. The genetic basis of the majority of these diseases is not understood. To identify the gene responsible for a disease that causes darker patches of skin (hyperpigmentation) with or without the abnormal growth of blood vessels and the presence of cells named glomus cells (a glomuvenous malformation), we used genetic techniques called whole-exome sequencing and Sanger sequencing in five unrelated families with this disease. We also used a technique called a 'minigene assay' to evaluate genetic alterations in a gene called GLMN, which encodes a protein called glomulin. Immunofluorescence and transmission electron microscopy (TEM) were used to determine the number of pigment-producing cells (called melanocytes) and melanosomes (where the pigment melanin is synthesized, stored and transported) in hyperpigmented skin lesions. We identified five different variants of the GLMN gene in five unrelated families. Although the number of melanocytes remained unchanged in skin lesions, TEM revealed an increased number of melanosomes. By 'switching off' the GLMN gene, we found that skin cells produced more pigment, as well as the proteins MITF and tyrosinase; they also showed a decrease in the phosphorylated protein p-p70S6 K. Overall, we found that loss-of-function mutations in GLMN caused skin hyperpigmentation with or without abnormal blood vessels. The results suggest there could be a potential role of the protein glomulin in human skin colour and blood vessel changes.

Hospitalization, case fatality, comorbidities, and isolated pathogens of adult inpatients with pneumonia from 2013 to 2022: a real-world study in Guangzhou, China.

BACKGROUND: In the context of increasing population aging, ongoing drug-resistant pathogens and the COVID-19 epidemic, the changes in the epidemiological and clinical characteristics of patients with pneumonia remain unclear. This study aimed to assess the trends in hospitalization, case fatality, comorbidities, and isolated pathogens of pneumonia-related adult inpatients in Guangzhou during the last decade. METHODS: We retrospectively enrolled hospitalized adults who had doctor-diagnosed pneumonia in the First Affiliated Hospital of Guangzhou Medical University from January 1, 2013 to December 31, 2022. A natural language processing system was applied to automatically extract the clinical data from electronic health records. We evaluated the proportion of pneumonia-related hospitalizations in total hospitalizations, pneumonia-related in-hospital case fatality, comorbidities, and species of isolated pathogens during the last decade. Binary logistic regression analysis was used to assess predictors for patients with prolonged length of stay (LOS). RESULTS: A total of 38,870 cases were finally included in this study, with 70% males, median age of 64 (53, 73) years and median LOS of 7.9 (5.1, 12.8) days. Although the number of pneumonia-related hospitalizations showed an upward trend, the proportion of pneumonia-related hospitalizations decreased from 199.6 per 1000 inpatients in 2013 to 123.4 per 1000 in 2021, and the case fatality decreased from 50.2 per 1000 in 2013 to 23.9 per 1000 in 2022 (all P < 0.05). The most common comorbidities were chronic obstructive pulmonary disease, lung malignancy, cardiovascular diseases and diabetes. The most common pathogens were Pseudomonas aeruginosa, Candida albicans, Acinetobacter baumannii, Stenotrophomonas maltophilia, Klebsiella pneumoniae, and Staphylococcus aureus. Glucocorticoid use during hospitalization (Odd Ratio [OR] = 1.86, 95% Confidence Interval (CI): 1.14-3.06), immunosuppressant use during hospitalization (OR = 1.99, 1.14-3.46), ICU admission (OR = 16.23, 95%CI: 11.25-23.83), receiving mechanical ventilation (OR = 3.58, 95%CI: 2.60-4.97), presence of other underlying diseases (OR = 1.54, 95%CI: 1.15-2.06), and elevated procalcitonin (OR = 1.61, 95%CI: 1.19-2.19) were identified as independent predictors for prolonged LOS. CONCLUSION: The proportion of pneumonia-related hospitalizations and the in-hospital case fatality showed downward trends during the last decade. Pneumonia inpatients were often complicated by chronic underlying diseases and isolated with gram-negative bacteria. ICU admission was a significant predictor for prolonged LOS in pneumonia inpatients.

Combining small airway parameters with conventional parameters obtained during spirometry to diagnose airflow obstruction: A cross-sectional study.

BACKGROUND AND OBJECTIVE: The use of small airway parameters generated by spirometry, namely forced expiratory flow between 25% and 75% of forced vital capacity (FVC) (FEF25%-75%) and forced expiratory flow at 50% and 75% of FVC (FEF50% and FEF75%, respectively), is widely discussed. We evaluated the importance of these spirometric parameters in a large Chinese population. METHODS: We conducted a cross-sectional observational study in which spirometry and bronchodilator responsiveness (BDR) data were collected in a healthcare centre from May 2021 to August 2022 and in a tertiary hospital from January 2017 to March 2022. Discordance was assessed between the classification of test results by the large airway parameters of forced expiratory volume in 1 second (FEV1) and FEV1/FVC ratio and by the small airway parameters of FEF25%-75%, FEF75% and FEF50%. The predictive power of Z-scores of spirometric parameters for airflow limitation and BDR was assessed using receiver operating characteristic curves. RESULTS: Our study included 26,658 people. Among people with a normal FVC (n = 14,688), 3.7%, 4.5% and 3.6% of cases exhibited normal FEV1/FVC ratio but impaired FEF25%-75%, FEF75% and FEF50%, respectively, while 6.8%-7.0% of people exhibited normal FEV1 but impaired FEF25%-75%, FEF75% and FEF50%. Using the Z-scores of combining both large and small airway parameters in spirometry showed the best area under the curve for predicting airflow limitation (0.90; 95% CI 0.87-0.94) and predicting BDR (0.72; 95% CI 0.71-0.73). CONCLUSION: It is important to consider both large and small airway parameters in spirometry to avoid missing a diagnosis of airflow obstruction.

Supervised training models with or without manual lesion delineation outperform clinicians in distinguishing pulmonary cryptococcosis from lung adenocarcinoma on chest CT.

BACKGROUND: The role of artificial intelligence (AI) in the discrimination between pulmonary cryptococcosis (PC) and lung adenocarcinoma (LA) warrants further research. OBJECTIVES: To compare the performances of AI models with clinicians in distinguishing PC from LA on chest CT. METHODS: Patients diagnosed with confirmed PC or LA were retrospectively recruited from three tertiary hospitals in Guangzhou. A deep learning framework was employed to develop two models: an undelineated supervised training (UST) model utilising original CT images, and a delineated supervised training (DST) model utilising CT images with manual lesion annotations provided by physicians. A subset of 20 cases was randomly selected from the entire dataset and reviewed by clinicians through a network questionnaire. The sensitivity, specificity and accuracy of the models and the clinicians were calculated. RESULTS: A total of 395 PC cases and 249 LA cases were included in the final analysis. The internal validation results for the UST model showed a sensitivity of 85.3%, specificity of 81.0%, accuracy of 83.6% and an area under the curve (AUC) of 0.93. Similarly, the DST model exhibited a sensitivity of 88.2%, specificity of 88.1%, accuracy of 88.2% and an AUC of 0.94. The external validation of the two models yielded AUC values of 0.74 and 0.77, respectively. The average sensitivity, specificity and accuracy of 102 clinicians were determined to be 63.1%, 53.7% and 59.3%, respectively. CONCLUSIONS: Both models outperformed the clinicians in distinguishing between PC and LA on chest CT, with the UST model exhibiting comparable performance to the DST model.

Impact of anaerobic digestion on reactive nitrogen gas emissions from dairy slurry storage.

Biogas digesters are commonly used to treat animal manure/slurry, and abundant digested slurry is generated during the digestion process. Gas emissions from digested and raw slurry may vary with the change in slurry parameters after digestion, but the mechanism is not well understood. Gas emissions from raw dairy slurry (RS) and digested dairy slurry (BS) during 98 days of storage were investigated in this study to evaluate the effects of anaerobic digestion on reactive nitrogen emissions from slurry storage. Results showed that much higher N2O and NO emission and lower NH3 emission was achieved in BS than in RS. The mean gaseous emission of RS and BS accounted for 27.8% ± 6.9% and 17.1% ± 2.3% of the initial TN for NH3, 0.1% ± 0.1% and 3.5% ± 1.6% of the initial TN for N2O, and 0.0% ± 0.0% and 0.2% ± 0.0% of the initial TN for NO, respectively. Among all detected N2O-forming and reducing microbial genes, the abundance of amoA genes was the most closely related to N2O flux (r = 0.54, p < 0.01). More aerobic conditions occurred in BS, and dissolved oxygen (DO) increased to 0.4-1.6 mg L-1 after 35 days because the low organic matter of BS resulted in good infiltration of surface air into the slurry. The increased DO stimulated the growth of Nitrosomonas and the increase in amoA gene copies and contributed to the high N2O and NO emissions in BS through the nitrification process. Vulcanibacillus, Thauera, Castellaniella, and Thermomonas were the major denitrifying bacteria that occurred in BS and caused an incomplete denitrification process, which could be another reason for the increase in N2O and NO emissions from BS. Our study indicated that anaerobic digestion reduced the organic matter content of the slurry and caused an active microbial environment that facilitated the transformation of slurry N to N2O in BS storage, thus lowering the NH3 emission compared with RS storage. Therefore, aside from NH3, N2O should also be preferentially mitigated during BS storage because N2O is a greenhouse gas with high global warming potential.

De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes.

KCNMA1 encodes the large-conductance Ca2+- and voltage-activated K+ (BK) potassium channel α-subunit, and pathogenic gain-of-function variants in this gene have been associated with a dominant form of generalized epilepsy and paroxysmal dyskinesia. Here, we genetically and functionally characterize eight novel loss-of-function (LoF) variants of KCNMA1. Genome or exome sequencing and the participation in the international Matchmaker Exchange effort allowed for the identification of novel KCNMA1 variants. Patch clamping was used to assess functionality of mutant BK channels. The KCNMA1 variants p.(Ser351Tyr), p.(Gly356Arg), p.(Gly375Arg), p.(Asn449fs) and p.(Ile663Val) abolished the BK current, whereas p.(Cys413Tyr) and p.(Pro805Leu) reduced the BK current amplitude and shifted the activation curves toward positive potentials. The p.(Asp984Asn) variant reduced the current amplitude without affecting kinetics. A phenotypic analysis of the patients carrying the recurrent p.(Gly375Arg) de novo missense LoF variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other LoF variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria. Therefore, LoF KCNMA1 variants are associated with a new syndrome characterized by a broad spectrum of neurological phenotypes and developmental disorders. LoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.

Synthesis of a biotinylated heptose 1,7-bisphosphate analogue, a probe to study immunity and inflammation.

d-glycero-d-manno-Heptose-1ß,7-bisphosphate (HBP) is a bacterial metabolite that can induce a TIFA-dependent innate immune response in mammals. It was recently discovered that after HBP enters into the cytoplasm of the host cell, it is transformed into ADP-heptose-7-phosphate, which then leads to ALPK1-TIFA-dependent inflammatory response. In order to provide a molecular tool allowing the discovery of the proteins involved in this novel inflammatory pathway, we designed and synthesized a biotinylated analogue of HBP. This chemical probe displays an anomeric ß-phosphate and a phosphonate at the 7-position, and a d-configured 6-position to which is attached the biotin moiety. To do so, different synthetic strategies were explored and described in this report. Moreover, we demonstrated that the biotinylated version of HBP is still biologically active and can activate the NF-κB pathway in HEK293T cells.

Application of comprehensive u nit-based safety program model in the inter-hospital transfer of patients with critical diseases: a retrospective controlled study.

BACKGROUND: To explore the effect of applying a comprehensive unit-based safety program (CUSP) in the intrahospital transfer of patients with critical diseases. METHODS: A total of 426 critically ill patients in the first affiliated Hospital of Anhui Medical University from August 2018 to February 2019 were divided into two groups according to the time of admission. Overall, 202 patients in the control group were treated with the routine transfer method, and 224 patients in the observational group were treated with the transfer method based on the CUSP model. The safety culture assessment data of medical staff, the occurrence rate of adverse events and related causes, the time of transfer, and the satisfaction of patients' relatives to the transfer process were compared before and after implementation of the transfer model between the two groups. RESULTS: Before and after the implementation of the CUSP mode transfer program, there were significant differences in the scores of all dimensions of the safety culture assessment of medical staff (P < 0.05), and the occurrence rate of adverse events and the causes in the observational group were significantly lower than those in the control group (disease-related, staff-related, equipment-related, environment-related) (P < 0.05). The transfer time for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), operating room, and the interventional room was significantly shorter in the observational group than that in the control group (P < 0.05), while the satisfaction of relatives to the transfer process was significantly higher than those in the control group (P < 0.05). CONCLUSION: The implementation of CUSP model for the intrahospital transfer of critically ill patients can significantly shorten the in-hospital transfer time, improve the attitude of medical staff towards safety, reduce the occurrence rate of adverse events, and improve the satisfaction of patients' relatives to the transfer process.

Nonhydrolyzable Heptose Bis- and Monophosphate Analogues Modulate Pro-inflammatory TIFA-NF-κB Signaling.

d-Glycero-d-manno-heptose-1ß,7-bisphosphate (HBP) and d-glycero-d-manno-heptose-1ß-phosphate (H1P) are bacterial metabolites that were recently shown to stimulate inflammatory responses in host cells through the activation of the TIFA-dependent NF-κB pathway. To better understand structure-based activity in relation to this process, a family of nonhydrolyzable phosphonate analogues of HBP and H1P was synthesized. The inflammation modulation by which these molecules induce the TIFA-NF-κB signal axis was evaluated in vivo at a low-nanomolar concentration (6 nM) and compared to that of the natural metabolites. Our data showed that three phosphonate analogues had similar stimulatory activity to HBP, whereas two phosphonates antagonized HBP-induced TIFA-NF-κB signaling. These results open new horizons for the design of pro-inflammatory and innate immune modulators that could be used as vaccine adjuvant.

Mutation in NPPA causes atrial fibrillation by activating inflammation and cardiac fibrosis in a knock-in rat model.

Atrial fibrillation (AF) affects >30 million individuals worldwide. However, no genetic mutation from human patients with AF has been linked to inflammation. Here, we show that AF-associated human variant p.Ile138Thr in natriuretic peptide A (NPPA) encoding the atrial natriuretic peptide (ANP) causes inflammation, fibroblast activation, atrial fibrosis, and AF in knock-in (KI) rats. Variant p.Ile138Thr inhibits the interaction between ANP and its receptor natriuretic peptide receptor A and reduces intracellular cGMP levels. RNA sequencing and follow-up analyses showed that mutant ANP (mANP) activates multiple innate immunity pathways, including TNF-α, NF-κB, and IL-1ß signaling. mANP induces differentiation of cardiac fibroblasts (CFs) to myofibroblasts and promotes CF proliferation and fibrosis. These results suggest that NPPA variant p.Ile138Thr causes AF by activating TNF-α, NF-κB, and IL-1ß signaling, inflammation, and fibrosis. Multiple computational programs suggest that p.Ile138Thr is damaging or deleterious. Based on the 2015 American College of Medical Genetics and Genomics Standards and Guidelines, p.Ile138Thr can be classified as a likely pathogenic variant. Variant p.Ile138Thr was found only in Asian people in the Genome Aggregation Database and Exome Aggregation Consortium database at an averaged frequency of 0.026%. An estimated 1.15 million Asian people carry the variant and might be at risk of AF. The KI rats may provide an inflammation-based, genetic animal model for AF valuable for testing anti-inflammation or other therapies for AF.-Cheng, C., Liu, H., Tan, C., Tong, D., Zhao, Y., Liu, X., Si, W., Wang, L., Liang, L., Li, J., Wang, C., Chen, Q., Du, Y., Wang, Q. K., Ren, X. Mutation in NPPA causes atrial fibrillation by activating inflammation and cardiac fibrosis in a knock-in rat model.

UBC9 regulates cardiac sodium channel Nav1.5 ubiquitination, degradation and sodium current density.

Voltage-gated sodium channel Nav1.5 is critical for generation and conduction of cardiac action potentials. Mutations and expression level changes of Nav1.5 are associated with cardiac arrhythmias and sudden death. The ubiquitin (Ub) conjugation machinery utilizes three enzyme activities, E1, E2, and E3, to regulate protein degradation. Previous studies from us and others showed that Nedd4-2 acts as an E3 ubiquitin-protein ligase involved in ubiquitination and degradation of Nav1.5, however, more key regulators remain to be identified. In this study, we show that UBC9, a SUMO-conjugating enzyme, regulates ubiquitination and degradation of Nav1.5. Overexpression of UBC9 significantly decreased Nav1.5 expression and reduced sodium current densities, whereas knockdown of UBC9 expression significantly enhanced Nav1.5 expression and increased sodium current densities, in both HEK293 cells and primary neonatal cardiomyocytes. Overexpression of UBC9 increased ubiquitination of Nav1.5, and proteasome inhibitor MG132 blocked the effect of UBC9 overexpression on Nav1.5 degradation. Co-immunoprecipitation showed that UBC9 interacts with Nedd4-2. UBC9 with mutation C93S, which suppresses SUMO-conjugating activity of UBC9, was as active as wild type UBC9 in regulating Nav1.5 levels, suggesting that UBC9 regulates Nav1.5 expression levels in a SUMOylation-independent manner. Our findings thus identify a key structural element of the ubiquitin-conjugation machinery for Nav1.5 and provide important insights into the regulatory mechanism for ubiquitination and turnover of Nav1.5.

Novel racemosin B derivatives as new therapeutic agents for aggressive breast cancer.

Carbazole derivatives show anti-cancer activity and are of great interest for drug development. In this study, we synthesized and analyzed several new alkylamide derivatives of racemocin B, a natural indolo[3,2-a]carbazole molecule originally isolated from the green alga Caulerpa racemose. Several alkylamide derivatives were found to exhibit moderate to strong growth inhibition against human breast cancer cell lines. They induced G2/M cell cycle arrest and apoptosis in the aggressive triple-negative breast cancer cell line MDA-MB-231. Among these derivatives, compound 25 with the lowest IC50 induced cell death by suppressing autophagy. This was accompanied by inhibition of autophagic flux and accumulation of autophagy protein 1 light chain 3, LC3II, and p62. The novel alkylamide derivative offers a potential new treatment for human breast cancer.

[Summarize drug dosage forms in treatment of age-related macular degeneration disease].

In this review, the authors summarized the drugs in treatment of the age-related macular degeneration (AMD or ARMD), including the pathogenesis of the age-related macular degeneration at home and abroad, dosage forms used in the treatment, and the drugs research and development directions in the future. AMD disease is the third largest blinding diseases all over the world, with an incidence of 6.62%. The dosage form of the traditional medicine is mostly oral formulations, playing a role in body, while the newly dosage form is topical drug delivery formulation. Traditional Chinese medicine (TCM) has certain advantages in the treatment of AMD disease and the development of topical drug delivery preparations with newly preparation technologies would have a very bright prospect in the future.

ZiBu PiYin recipe prevents diabetes-associated cognitive decline in rats: possible involvement of ameliorating mitochondrial dysfunction, insulin resistance pathway and histopathological changes.

BACKGROUND: Disturbance in energy metabolism, as a key factor in diabetes-associated cognitive decline (DACD), has become a promising therapeutic target of Chinese medicine ZiBu PiYin Recipe (ZBPYR). However, it is still not clear how ZBPYR affects the mitochondrial function in DACD rats' brains, which is considered as the crucial cell organelle to supply energy for the brain. METHODS: Type 2 diabetes mellitus (T2DM) rat models were established by using high fat diet and streptozotocin (STZ) (30 mg/kg, ip). The evaluation of insulin sensitivity was performed by oral glucose tolerance and insulin tolerance test. After 7 weeks, the T2DM rats were treated with vehicle or ZBPYR for 11 weeks and morris water maze (MWM) test were used to evaluate memory function. The ultra structural changes of prefrontal cortex (PFC) and hippocampus were examined by transmission electron microscopy (TEM). The mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) were measured with JC-1 and DCFDA assay. The levels of insulin proteins were quantified by Western Blot analysis and the markers of histopathological changes were detected by immunohistochemistry. RESULTS: ZBPYR could alleviate learning and memory impairment of DACD rats. TEM showed that ZBPYR prevented mitochondrial ultra-structural alterations and number changes in the PFC and hippocampus of the DACD rats. In addition, ZBPYR significantly increased ΔΨm and lowered the levels of ROS. Further investigation indicated that ZBPYR suppressed the release of cytochrome c from mitochondria, strengthened insulin signaling and inhibited GSK3ß over-expression. These positive effects were associated with reduced Aß1-42 deposition and restored expression levels of microtubule-associated protein MAP2. CONCLUSION: ZBPYR showed excellent protective effect against DACD via ameliorating mitochondrial dysfunction, insulin resistance and histopathological changes.

Uralsaponins M-Y, antiviral triterpenoid saponins from the roots of Glycyrrhiza uralensis.

Thirteen new oleanane-type triterpenoid saponins, uralsaponins M-Y (1-13), and 15 known analogues (14-28) were isolated from the roots of Glycyrrhiza uralensis Fisch. The structures of 1-13 were identified on the basis of extensive NMR and MS data analyses. The sugar residues were identified by gas chromatography and ion chromatography coupled with pulsed amperometric detection after hydrolysis. Saponins containing a galacturonic acid (1-3) or xylose (5) residue are reported from Glycyrrhiza species for the first time. Compounds 1, 7, 8, and 24 exhibited good inhibitory activities against the influenza virus A/WSN/33 (H1N1) in MDCK cells with IC50 values of 48.0, 42.7, 39.6, and 49.1 µM, respectively, versus 45.6 µM of the positive control oseltamivir phosphate. In addition, compounds 24 and 28 showed anti-HIV activities with IC50 values of 29.5 and 41.7 µM, respectively.

Rosavin extends lifespan via the insulin/IGF-1 signaling pathway in Caenorhabditis elegans.

Rosavin, a phenylpropanoid glycoside, is the specific index component and one of the main active components of Rhodiola rosea. Currently, there are few studies describing the antiaging effect of rosavin, and most of them are mainly based on in vitro antioxidant research. Our study aimed to investigate the antiaging activities and mechanisms of rosavin in Caenorhabditis elegans. Using Caenorhabditis elegans as the model, the lifespan of Caenorhabditis elegans under various stressors (heat and juglone) and normal conditions was studied, and the antioxidant activities of rosavin were discussed. To discover the underlying mechanisms, we analyzed daf-16 nuclear localization, the expression of the sod-3p::GFP fusion protein, mRNA levels, and loss-of-function mutants of IIS-associated genes. The results showed that rosavin significantly improved the lifespan of Caenorhabditis elegans under stress and normal conditions. Rosavin can increase the expression and activity of antioxidant enzymes and suppress the generation of malondialdehyde and ROS in nematodes. Additionally, it promotes the nuclear localization of daf-16 and improves the expression of the sod-3 gene in Caenorhabditis elegans. The data revealed that rosavin activated the insulin/IGF-1 signaling pathway by downregulating the upstream components daf-2 and age-1. In summary, these results verify that rosavin could increase the lifespan of Caenorhabditis elegans through the insulin/IGF-1 signaling pathway.

Effects of Long-Term Controlled-Release Urea on Soil Greenhouse Gas Emissions in an Open-Field Lettuce System.

Controlled-release urea (CRU) fertilizers are widely used in agricultural production to reduce conventional nitrogen (N) fertilization-induced agricultural greenhouse gas emissions (GHGs) and improve N use efficiency (NUE). However, the long-term effects of different CRU fertilizers on GHGs and crop yields in vegetable fields remain relatively unexplored. This study investigated the variations in GHG emissions at four growth stages of lettuce in the spring and autumn seasons based on a five-year field experiment in the North China Plain. Four treatments were setup: CK (without N application), U (conventional urea-N application), ON (20% reduction in urea-N application), CRU (20% reduction in polyurethane-coated urea without topdressing), and DCRU (20% reduction in polyurethane-coated urea containing dicyandiamide [DCD] without topdressing). The results show that N application treatments significantly increased the GHG emissions and the lettuce yield and net yield, and DCRU exhibited the lowest N2O and CO2 emissions, the highest lettuce yield and net yield, and the highest lettuce N content of the N application treatments. When compared to U, the N2O emission peak under CRU and DCRU treatments was notably decreased and delayed, and their average N2O emission fluxes were significantly reduced by 10.20-20.72% and 17.51-29.35%, respectively, leading to a significant reduction in mean cumulative N2O emissions during the 2017-2021 period. When compared to U, the CO2 fluxes of DCRU significantly decreased by 8.0-16.54% in the seedling period, and mean cumulative CO2 emission decreased by 9.28%. Moreover, compared to U, the global warming potential (GWP) and greenhouse gas intensity (GHGI) of the DCRU treatment was significantly alleviated by 9.02-17.13% and 16.68-20.36%, respectively. Compared to U, the N content of lettuce under DCRU was significantly increased by 6.48-17.25%, and the lettuce net yield was also significantly increased by 5.41-7.71%. These observations indicated that the simple and efficient N management strategy to strike a balance between enhancing lettuce yields and reduce GHG emissions in open-field lettuce fields could be obtained by applying controlled-release urea containing DCD without topdressing.