CD38 Deficiency Protects Mouse Retinal Ganglion Cells Through Activating the NAD+/Sirt1 Pathway in Ischemia-Reperfusion and Optic Nerve Crush Models.

Purpose: The purpose of this study was to investigate the protective effect of CD38 deletion on retinal ganglion cells (RGCs) in a mouse retinal ischemia/reperfusion (I/R) model and an optic nerve crush (ONC) model, and to elucidate the underlying molecular mechanisms. Methods: Retinal I/R and ONC models were constructed in mice. PCR was used to identify the deletion of CD38 gene in mice, hematoxylin and eosin (H&E) staining was used to evaluate the changes in retinal morphology, and electroretinogram (ERG) was used to evaluate the changes in retinal function. The survival of RGCs and activation of retinal macroglia were evaluated by immunofluorescence staining. The expression of Sirt1, CD38, Ac-p65, Ac-p53, TNF-α, IL-1ß, and Caspase3 proteins in the retina was further evaluated by protein imprinting. Results: In retinal I/R and ONC models, CD38 deficiency reduced the loss of RGCs and activation of macroglia and protected the retinal function. CD38 deficiency increased the concentration of NAD+, reduced the degree of acetylation of NF-κB p65 and p53, and reduced expression of the downstream inflammatory cytokines TNFα, IL-1ß, and apoptotic protein Caspase3 in the retina in the ONC model. Intraperitoneal injection of the Sirt1 inhibitor EX-527 partially counteracted the effects of CD38 deficiency, suggesting that CD38 deficiency acts at least in part through the NAD+/Sirt1 pathway. Conclusions: CD38 plays an important role in the pathogenesis of retinal I/R and ONC injury. CD38 deletion protects RGCs by attenuating inflammatory responses and apoptosis through the NAD+/Sirt1 pathway.

Three species of rape responded to cadmium and melatonin alleviating Cd-toxicity in species-specific strategy.

Cadmium (Cd) pollution has been a significant concern in heavy metal pollution, prompting plants to adopt various strategies to mitigate its damage. While the response of plants to Cd stress and the impact of exogenous melatonin has received considerable attention, there has been limited focus on the responses of closely related species to these factors. Consequently, our investigation aimed to explore the response of three different species of rape to Cd stress and examine the influence of exogenous melatonin in this scenario. The research findings revealed distinctive responses among the investigated rape species. B. campestris showed the resistance to Cd and exhibited lower Cd absorption and sustained its physiological activity under Cd stress. In contrast, B. juncea accumulated much Cd and increased the amount of anthocyanin to mitigate the Cd-damage. Furthermore, B. napus showed the tolerance to Cd and tended to accumulate Cd in vacuoles under Cd stress, thereby decreasing the Cd damage and leading to higher activity of antioxidant enzymes and photosynthesis. Moreover, the application of exogenous melatonin significantly elevated the melatonin level in plants and mitigated Cd toxicity by promoting the activity of antioxidant enzymes, reducing Cd absorption, enhancing the chelating capacity with Cd, decreasing Cd accumulation in organelles, and reducing its fluidity. Specifically, exogenous melatonin increased the FHAc content in B. campestris, elevated the phytochelatins (PCs) level in B. napus, and stimulated photosynthesis in B. juncea. In summary, the findings underscore the species-specific responses of the three species of rape to both Cd stress and exogenous melatonin, highlighting the potential for tailored mitigation strategies based on the unique characteristics of each species.

A systematic literature review of the epidemiology and burden of herpes zoster in selected locales in Asia Pacific.

Herpes zoster (HZ) is a painful rash which typically affects older adults. This is of concern in Asia-Pacific given its aging population. As HZ epidemiology and burden are evolving, this systematic literature review aimed to update the current understanding of HZ burden and associated costs for selected Asia-Pacific locales. MEDLINE and Embase were searched for English articles of HZ studies conducted in Australia, China, Hong Kong, Japan, Korea, New Zealand, Singapore, and Taiwan. Eligible outcomes included HZ incidence and prevalence, occurrence of HZ-related complications, healthcare resource utilization, costs, and HZ-associated quality of life outcomes. This paper focused on HZ data in the general adult population (N = 90 articles). Substantial HZ-related disease and economic burden were observed in these locales, consistent with global trends. These findings reinforce the increasing burden of HZ and need for preventive strategies, which may include raising awareness and encouraging timely vaccination.

Herpes zoster, also known as shingles, is a painful rash that usually resolves after a few weeks, although some people experience serious or long-lasting complications. Shingles is common, affecting around one in every three individuals in their lifetime, and older persons are more likely to have shingles. Given the aging population in the Asia-Pacific region, shingles represents an increasingly important health issue as the proportion of older people increases. Vaccination can help prevent shingles and avoid its complications. New data on the trends and burden of shingles in this region are regularly generated. Therefore, in this study, we looked at studies from selected countries published over the past twenty years to summarize the latest available information on: how many people experience shingles in selected Asia-Pacific areas, how these individuals and societies are affected, and the related costs. Consistent with previous research, this study observed an increasing trend in the number of persons with shingles and costs of managing it, especially in older adults. In populations that are aging, there is a need for ways to reduce the risk of shingles and to lessen its burden on the healthcare system and society. Our findings can help to inform current development of strategies to reduce the risk of shingles, including education (on the burden and risk of shingles) and encouraging uptake of preventive measures.

Neoscytalidium dimidiatum causing stem canker on Hylocereus megalanthus in China.

Hylocereus megalanthus (syn. Selenecereus megalanthus), commonly known as Yanwo fruit (bird's nest fruit), is an important tropical fruit, which is popular and widely planted due to its high nutritional and economic value in southern China. In September 2022, a serious stem and fruit canker was observed on Ecuadorian variety of Yanwo fruit plant in a 0.2 ha orchard in Guangdong (N21°19'1.24" E110°7'28.49"). Almost all plants were infected and disease incidence of fruits and stems was about 80% and 90% respectively. Symptoms on the stem and fruits were small, circular or irregular, sunken, orangish brown spots that developed into cankers (Fig 1 A, B and C). Black pycnidia were embedded under the surface of the cankers at the initial stage, subsequently they became erumpent from the surface, and the infected parts rotted. Five symptomatic stems from five plants were collected, 0.2 cm2 tissues adjacent to cankers were surface sterilized and placed on potato dextrose agar (PDA) to incubate at 25 to 28 ℃. Fungal isolates each with similar morphology grew from 100% of the tissues. Colonies covered with aerial mycelium were grayish white, and then gradually turned to grayish black. Septate hyphae were hyaline to brown and constricted into arthroconidial chains. The arthroconidia were variously shaped and colored, orbicular to rectangular, hyaline to dark brown, thick-walled, and zero- to one- septate, averaging 7.7 × 3.6 µm (n>50) (Fig 1 D, E, F and G). To identify the fungus, the internal transcribed spacer region (ITS), translation elongation factor 1-alpha (tef1), beta-tubulin (tub2), histone H3 (his3) and chitin synthase (chs) gene of isolate ACCC 35488 and ACCC 35489 (Agricultural Culture Collection of China) were amplified and sequenced with primer pairs: ITS1/ITS4 (White et al. 1990), EF1-728F/EF2-rd (Carbone & Kohn 1999; O'Donnell et al.1998), TUB2Fd/ TUB4Rd（Aveskamp et al 2009）, CYLH3F/H3-1b (Crous et al. 2004) and CHS-79F/CHS-345R (Carbone & Kohn 1999) (ITS: OQ381102 and PP488350; tef1: OQ408545 and PP510454; tub2: OQ408546 and PP510455; his3: OQ408544 and PP510453; chs: OQ408543 and PP510452). Sequence Blastn results showed above 99% identical with those of Neoscytalidium dimidiatum ex-type strain CPC38666. Phylogenetic tree inferred from Maximum Likelihood analysis of the combined ITS, tub2 and tef1 sequences revealed two isolates clustered with N. dimidiatum (Fig 2). Pathogenicity was tested on healthy one-year-old cuttings and fruits of Ecuadorian variety at room temperature. Six sites were pin-pricked on each stem and fruit. Both wounded stems and fruits were inoculated with spore suspensions (106 spore/ml) and 6-mm fungal plugs respectively. Sterile water and agar were used as control. The test was repeated twice. Stems and fruits were enclosed in plastic boxes with 80% relative humidity. Symptoms described above were observed on inoculated stems and fruits at five days post inoculation (Fig 1 H and I). No symptoms developed on the controls. Neoscytaliudium dimidiatum was reisolated from the cankers with a frequency of 100% via morphological and molecular analysis. This is first report of stem and fruit canker caused by N. dimidiatum on H. megalanthus in China and this disease represents a serious risk of Yanwo fruit yield losses. This fungus is widespread occurring throughout the world causing diseases on a wide variety of plants. The finding will be helpful for its prevention and control.

Pituitary metastasis from lung adenocarcinoma: A case report.

BACKGROUND: Pituitary gland metastasis is an unusual event, and pituitary metastasis from lung adenocarcinoma is extremely rare and associated with poor prognosis. To date, approximately 15 cases have been reported. CASE SUMMARY: Here, we present the case of a 64-year-old woman with pituitary metastasis derived from lung adenocarcinoma, which was difficult to distinguish from other sellar tumors. The patient presented to the neurosurgery clinic with blurred vision and intermittent headache. During hospitalization, brain computed tomography (CT) and magnetic resonance imaging revealed a pituitary macroadenoma. Chest CT revealed irregular nodules in the basal segment of the lower lobe of the left lung, which were likely lung cancer. Positron emission tomography-CT revealed a carbohydrate metabolism tumor in the lungs and sellar region, which was considered malignant. Postoperative pathological examination of the sellar tumor revealed lung adenocarcinoma. CONCLUSION: Excision of pituitary metastases combined with radiotherapy and chemotherapy should be a priority treatment for patients with pituitary metastasis.

Occurrence of Cassava (Manihot esculenta) Leaf Spot Disease Caused by Diaporthe ueckeri in China.

Cassava (Manihot esculenta) is a perennial crop of the family Euphorbiaceae, widely cultivated due to its phytopharmacological and economic values in China. In November 2022, a leaf spot disease on cassava was observed in Zhanjiang, Guangdong, China (21.17° N, 110.18° E), with 100% disease incidence. About 80 % of leaves were covered with spots on the infected plants. Typical symptoms initially appeared as irregular water-soaked lesions that became brown and whitish with the progress of the disease, lesions gradually expanded and coalesced, causing leaf withering, drying and final fall. Tissues (4 to 5 mm) were excised from the margin of lesions, sterilized in 3% H2O2 solution for 3 min, rinsed three times with sterile water, placed on potato dextrose agar (PDA) medium (containing 50mg/L penicillin), and incubated at 25-28 °C. Ten single hypha isolates with similar morphology were obtained and further purified as single conidium subcultures. The colony was grey whitish with sparse aerial mycelium and colony diameter reached 70.4 mm after four days incubation at 25-28℃ in the dark. Black pycnidia occurring as clusters were spherical or irregular, erumpent at maturity, often with a creamy whitish, conidial cirrus extruding from ostiole after 30-days incubation. Conidiophores were hyaline, smooth, unbranched. Alpha conidia were bi-guttulate, hyaline, ellipsoidal, aseptate, with dimensions of 5.1~7.5×1.9~3.4µm (mean 6.2×2.8 µm, n>50). Beta conidia were abundant, filiform, hyaline, smooth, curved in a hooked shape, with a truncate base and dimensions of 18.5-26.4 × 0.6-1.2µm (mean 23.4 × 1.0 µm, n= 40) . Gamma conidia were not observed. The morphological characteristics were similar to those of Diaporthe ueckeri (Udayanga et al. 2015). The internal transcribed spacer (ITS) region, large subunit (LSU) rRNA sequence, actin (ACT), calmodulin (CAL), histone H3 (HIS), translation elongation factor 1-alpha (TEF1-α), and ß-tubulin (TUB) genes of a representative isolate CCAS-MS-6 (ACCC 35497) were amplified and sequenced using primer pairs: ITS5/ITS4, LR0R/LR5, ACT-512F/ACT-783R, CAL228F/CAL737R, CYLH3F/ H3-1b, EF1-728F/ EF1-986R and Bt2a/Bt2b (Gao et al 2017；Udayanga et al 2014). All sequences were deposited in GenBank (OR361671, OR361672, and OR365605-9). BLAST search showed high similarities with sequences of Diaporthe ueckeri (Tab 1). Maximum likelihood analyses of the concatenated data of CAL, HIS, ITS, TEF and TUB using Mega 11 placed CCAS-MS-6 in the D. ueckeri clade. Thus, the fungus was identified as D. ueckeri. Three one-year old healthy plants were used for pathogenicity tests in pots. Two 15-day old leaves of each plant were cleaned with 75% alcohol, three sites on each leaf were wounded, and sites on one of the leaf were covered with fungal plugs from 15-day-old cultures on PDA, and sites on the other leaf with PDA plugs as a control. All plants were kept at ambient temperature (about 28℃) and covered with plastic bags containing sterile wet cotton to maintain the humidity. Seven days after inoculation, all inoculated sites showed symptoms of necrosis, while control sites showed no symptoms. The same fungus identified on the basis of morphological and molecular criteria was reisolated from symptomatic inoculated leaves. In China, D. ueckeri had been reported to cause diseases on Eucalyptus citriodora, Camellia sinensis, and Michelia shiluensis (Gao et al 2016; Liao et al 2023; Yi et al 2018), this is the first report on M. esculenta. The definition of the disease etiology is a prerequisite to develop effective management strategies.

The current clinical landscape of neonatal respiratory failure in Jiangsu Province of China: patient demographics, NICU treatment interventions, and patient outcomes.

INTRODUCTION: Neonatal respiratory failure (NRF) is a serious condition that often has high mortality and morbidity, effective interventions can be delivered in the future by identifying the risk factors associated with morbidity and mortality. However, recent advances in respiratory support have improved neonatal intensive care units (NICUs) care in China. We aimed to provide an updated review of the clinical profile and outcomes of NRF in the Jiangsu province. METHODS: Infants treated for NRF in the NICUs of 28 hospitals between March 2019 and March 2022 were retrospectively reviewed. Data collected included baseline perinatal and neonatal parameters, NICU admission- and treatment-related data, and patient outcomes in terms of mortality, major morbidity, and survival without major morbidities. RESULTS: A total of 5548 infants with NRF were included in the study. The most common primary respiratory disorder was respiratory distress syndrome (78.5%). NRF was managed with non-invasive and invasive respiratory support in 59.8% and 14.5% of patients, respectively. The application rate of surfactant therapy was 38.5%, while that of neonatal extracorporeal membrane oxygenation therapy was 0.2%. Mortality and major morbidity rates of 8.5% and 23.2% were observed, respectively. Congenital anomalies, hypoxic-ischemic encephalopathy, invasive respiratory support only and inhaled nitric oxide therapy were found to be significantly associated with the risk of death. Among surviving infants born at < 32 weeks of gestation or with a birth weight < 1500 g, caffeine therapy and repeat mechanical ventilation were demonstrated to significantly associate with increased major morbidity risk. CONCLUSION: Our study demonstrates the current clinical landscape of infants with NRF treated in the NICU, and, by proxy, highlights the ongoing advancements in the field of perinatal and neonatal intensive care in China.

Smooth-Muscle-Cell-Specific Deletion of CD38 Protects Mice from AngII-Induced Abdominal Aortic Aneurysm through Inhibiting Vascular Remodeling.

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.

The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.

Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives.

Hepatocellular carcinoma (HCC) is a major health concern worldwide, with limited therapeutic options and poor prognosis. In recent years, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. The combination treatments based on ICIs have been the major trend in this area. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective treatment for advanced HCC. However, the majority of HCC patients obtain limited benefits. Understanding the immunological rationale and exploring novel ways to improve the efficacy of immunotherapy has drawn much attention. In this review, we summarize the latest progress in this area, the ongoing clinical trials of immune-based combination therapies, as well as novel immunotherapy strategies such as chimeric antigen receptor T cells, personalized neoantigen vaccines, oncolytic viruses, and bispecific antibodies.

Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition of glutamatergic transmission.

Status epilepticus (SE), a serious and often life-threatening medical emergency, is characterized by abnormally prolonged seizures. It is not effectively managed by present first-line anti-seizure medications and could readily develop into drug resistance without timely treatment. In this study, we highlight the therapeutic potential of CZL80, a small molecule that inhibits caspase-1, in SE termination and its related mechanisms. We found that delayed treatment of diazepam (0.5 h) easily induces resistance in kainic acid (KA)-induced SE. CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic time window to 3 h following SE, and also protected against neuronal damage. Interestingly, the effect of CZL80 on SE termination was model-dependent, as evidenced by ineffectiveness in the pilocarpine-induced SE. Further, we found that CZL80 did not terminate KA-induced SE in Caspase-1-/- mice but partially terminated SE in IL1R1-/- mice, suggesting the SE termination effect of CZL80 was dependent on the caspase-1, but not entirely through the downstream IL-1ß pathway. Furthermore, in vivo calcium fiber photometry revealed that CZL80 completely reversed the neuroinflammation-augmented glutamatergic transmission in SE. Together, our results demonstrate that caspase-1 inhibitor CZL80 terminates diazepam-resistant SE by blocking glutamatergic transmission. This may be of great therapeutic significance for the clinical treatment of refractory SE.

Equity, diversity, and inclusion in the Multinational Association for Supportive Care in Cancer: a global membership survey.

Equity, diversity, and inclusion (EDI) are essential for healthcare organizations since they allow for the development of programs and initiatives that bring together diverse perspectives and knowledge. Global multidisciplinary organizations, such as the Multinational Association for Supportive Care in Cancer (MASCC), need to understand the perspective of their members regarding EDI to identify opportunities to enhance diversity and inclusiveness and to better meet the needs of members from different backgrounds and resources. The MASCC Health Disparities Committee designed a survey to identify issues related to disparities faced by MASCC members when providing supportive care to patients with cancer and to examine the EDI landscape within the organization. Here, we report results related to EDI initiatives within the organization. Two-hundred and eighteen MASCC members responded to the survey (response rate 10.2%). The results indicated that respondents were generally satisfied with how MASCC manages leadership, membership, and organization-related EDI issues. Opportunities for improvement noted by respondents included developing strategies to foster a more diverse membership, improving communication regarding diversity in the organization, and increasing EDI content in educational sessions and publications. The results of this survey represent the first attempt at understanding how to improve EDI within MASCC and will be utilized to guide further initiatives and programs.

Quantum ghost imaging of a vector field.

Quantum ghost image technique utilizing position or momentum correlations between entangled photons can realize nonlocal reconstruction of the image of an object. In this work, based on polarization entanglement, we experimentally demonstrate quantum ghost imaging of vector images by using a geometric phase object. We also provide a corresponding theoretical analysis. Additionally, we offer a geometrical optics path explanation of ghost imaging for vector fields. The proposed strategy offers new insights into the fundamental development of ghost imaging and also holds great promise for developing complex structured ghost imaging techniques. Our work expanding the principle of ghost imaging to spatially varying vector beams will lead to interesting developments of this field.

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients.

PURPOSE: Our preclinical studies showed that lycopene enhanced the anti-prostate cancer efficacy of docetaxel in animal models. A phase I trial (NCT0149519) was conducted to identify an optimum dose of synthetic lycopene in combination with docetaxel (and androgen blockade [androgen deprivation therapy, ADT]), and to evaluate its effect on the safety and pharmacokinetics of docetaxel in men with metastatic prostate cancer. METHODS: Subjects were treated with 21-day cycles of 75 mg/m2 docetaxel (and ADT), plus lycopene at 30, 90 or 150 mg/day. A Bayesian model averaging continual reassessment method was used to guide dose escalation. Pharmacokinetics of docetaxel and multiple correlative studies were carried out. RESULTS: Twenty-four participants were enrolled, 18 in a dose escalation cohort to define the maximum tolerated dose (MTD), and six in a pharmacokinetic cohort. Docetaxel/ADT plus 150 mg/day synthetic lycopene resulted in dose-limiting toxicity (pulmonary embolus) in one out of 12 participants with an estimated probability of .106 and thus was chosen as the MTD. Lycopene increased the AUCinf and Cmax of plasma docetaxel by 9.5% and 15.1%, respectively. Correlative studies showed dose-related changes in circulating endothelial cells and vascular endothelial growth factor A, and reduction in insulin-like growth factor 1R phosphorylation, associated with lycopene therapy. CONCLUSIONS: The combination of docetaxel/ADT and synthetic lycopene has low toxicity and favourable pharmacokinetics. The effects of lycopene on biomarkers provide additional support for the toxicity-dependent MTD definition. HIGHLIGHTS: The maximum tolerated dose was identified as 150 mg/day of lycopene in combination with docetaxel/ADT for the treatment of metastatic prostate cancer patients. Small increases in plasma exposure to docetaxel were observed with lycopene co-administration. Mechanistically significant effects were seen on angiogenesis and insulin-like growth factor 1 signalling by lycopene co-administration with docetaxel/ADT.

New Insights into the Umami and Sweet Taste of Oolong Tea: Formation of Enhancer N-(1-carboxyethyl)-6-(hydroxymethyl) pyridinium-3-ol (Alapyridaine) in Roasting Via Maillard Reaction.

Roasting is pivotal for enhancing the flavor of Wuyi rock tea (WRT). A study investigated a novel compound that enhances the umami taste of WRT. Metabolomics of Shuixian tea (SXT) and Rougui tea (RGT) under light roasting (LR), medium roasting (MR), and heavy roasting (HR) revealed significant differences in nonvolatiles compounds. Compared LR reducing sugars and amino acids notably decreased in MR and HR, with l-alanine declining by 69%. Taste-guided fractionation identified fraction II-B as having high umami and sweet intensities. A surprising taste enhancer, N-(1-carboxyethyl)-6-(hydroxymethyl) pyridinium-3-ol (alapyridaine), was discovered and identified. It formed via the Maillard reaction, positively correlated with roasting in SXT and RGT. Alapyridaine levels were highest in SXT among the five oolong teas. Roasting tea with glucose increased alapyridaine levels, while EGCG inhibited its formation. HR-WRT exhibited enhanced umami and sweet taste, highlighting alapyridaine's impact on WRT's flavor profile. The formation of alapyridaine during the roasting process provides new insights into the umami and sweet perception of oolong tea.

Myeloid Deletion of Cdc42 Protects Liver From Hepatic Ischemia-Reperfusion Injury via Inhibiting Macrophage-Mediated Inflammation in Mice.

BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (HIRI) often occurs in liver surgery, such as partial hepatectomy and liver transplantation, in which myeloid macrophage-mediated inflammation plays a critical role. Cell division cycle 42 (Cdc42) regulates cell migration, cytoskeleton rearrangement, and cell polarity. In this study, we explore the role of myeloid Cdc42 in HIRI. METHODS: Mouse HIRI models were established with 1-hour ischemia followed by 12-hour reperfusion in myeloid Cdc42 knockout (Cdc42mye) and Cdc42flox mice. Myeloid-derived macrophages were traced with RosamTmG fluorescent reporter under LyzCre-mediated excision. The experiments for serum or hepatic enzymic activities, histologic and immunologic analysis, gene expressions, flow cytometry analysis, and cytokine antibody array were performed. RESULTS: Myeloid deletion of Cdc42 significantly alleviated hepatic damages with the reduction of hepatic necrosis and inflammation, and reserved hepatic functions following HIRI in mice. Myeloid Cdc42 deficiency suppressed the infiltration of myeloid macrophages, reduced the secretion of proinflammatory cytokines, restrained M1 polarization, and promoted M2 polarization of myeloid macrophages in livers. In addition, inactivation of Cdc42 promoted M2 polarization via suppressing the phosphorylation of STAT1 and promoting phosphorylation of STAT3 and STAT6 in myeloid macrophages. Furthermore, pretreatment with Cdc42 inhibitor, ML141, also protected mice from hepatic ischemia-reperfusion injury. CONCLUSIONS: Inhibition or deletion of myeloid Cdc42 protects liver from HIRI via restraining the infiltration of myeloid macrophages, suppressing proinflammatory response, and promoting M2 polarization in macrophages.

Efficacy and safety of eszopiclone combined with drug therapy in the treatment of insomnia after stroke: A network meta-analysis and systematic review.

OBJECTIVE: To evaluate the efficacy and safety of multi-drug therapy based on eszopiclone in the treatment of insomnia after stroke using a network meta-analysis method and to provide evidence for clinical practice. METHOD: Computer searches of PubMed, Excerpt Medica Database (Embase), Cochrane Library Central Register of Controlled Trials, APA PsycInfo, CNKI, WanFang, Sinomed and other databases were performed to search for clinical randomized controlled studies (RCTs) on multi-drug therapy based on eszopiclone in the treatment of insomnia patients after stroke. The search time was from the establishment of each database until July 2023. The bias risk assessment tool recommended by Cochrane was used to evaluate the quality of the included RCTs. Stata 14.0 was applied to perform network meta-analysis using Review Manager 5.3 software for traditional meta-analysis. RESULT: Eighteen RCTs and 1646 patients were ultimately included, involving 11 treatment options. The results of the network meta-analysis showed that the ranking of Pittsburgh Sleep Quality Index (PSQI) decline was eszopiclone combined with sweet dream oral liquid (ESZ+SDOL)>eszopiclone combined with a shugan jieyu capsule (ESZ+SGJYC)>eszopiclone combined with agomelatine (ESZ+AGO)>eszopiclone combined with flupentixol and melitracen tablets (ESZ+FMT)>eszopiclone combined with yangxue qingnao granules (ESZ+YXQNG)>eszopiclone combined with mirtazapine (ESZ+MIR)>ESZ>FMT; the modified Edinburgh Scandinavia Stroke Scale (MESSS) decline ranking was ESZ+SDOL>ESZ+AGO>ESZ; and the clinical total effective rate ranking was eszopiclone combined with a xuefu zhuyu capsule (ESZ+XFZYC)>ESZ+MIR>ESZ+SGJYC>ESZ+SDOL> ESZ+FMT>ESZ+YXQNG>ESZ>FMT. In terms of clinical adverse reactions, in addition to ESZ therapy, ESZ+ESC had the highest number of adverse reactions, with abdominal pain being the most common. ESZ+YXQNG had the most types of adverse reactions, with 8 types. CONCLUSION: Multi-drug therapy based on eszopiclone can effectively improve the sleep quality of patients with insomnia after stroke, and ESZ+SDOL has significant efficacy and safety. However, due to the limitations of this study, efficacy ranking cannot fully explain the superiority or inferiority of clinical efficacy. In the future, more multicentre, large sample, double-blind randomized controlled trials are needed to supplement and demonstrate the results of this study.

SOX9 Induces Orbital Fibroblast Activation in Thyroid Eye Disease Via MAPK/ERK1/2 Pathway.

Purpose: To evaluate the expression of sry-box transcription factor 9 (SOX9) in orbital fibroblasts (OFs) of thyroid eye disease (TED) and to find its potential role and underlying mechanism in orbital fibrosis. Methods: OFs were cultured from orbital connective tissues obtained from patients with TED (n = 10) and healthy controls (n = 6). SOX9 was depleted by small interfering RNA or overexpressed through lentivirus transduction in OFs. Fibroblast contractile activity was measured by collagen gel contraction assay and proliferation was examined by EdU assay. Transcriptomic changes were assessed by RNA sequencing. Results: The mRNA and protein levels of SOX9 were significantly higher in OFs cultured from patients with TED than those from healthy controls. Extracellular matrix-related genes were down-regulated by SOX9 knockdown and up-regulated by SOX9 overexpression in TED-OFs. SOX9 knockdown significantly decrease the contraction and the antiapoptotic ability of OFs, whereas the overexpression of SOX9 increased the ability of transformation, migration, and proliferation of OFs. SOX9 knockdown suppressed the expression of phosphorylated ERK1/2, whereas its overexpression showed the opposite effect. Epidermal growth factor receptor (EGFR) is one of the notably down-regulated genes screened out by RNA sequencing. Chromatin immunoprecipitation-qPCR demonstrated SOX9 binding to the EGFR promoter. Conclusions: A high expression of SOX9 was found in TED-OFs. SOX9 can activate OFs via MAPK/ERK1/2 signaling pathway, which in turn promotes proliferation and differentiation of OFs. EGFR was a downstream target gene of SOX9. SOX9/EGFR can be considered as therapeutic targets for the treatment of orbital fibrosis in TED.

Comparison contrast-enhanced CT with contrast-enhanced US in diagnosing combined hepatocellular-cholangiocarcinoma: a propensity score-matched study.

OBJECTIVES: To develop and compare noninvasive models for differentiating between combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and HCC based on serum tumor markers, contrast-enhanced ultrasound (CEUS), and computed tomography (CECT). METHODS: From January 2010 to December 2021, patients with pathologically confirmed cHCC-CCA or HCC who underwent both preoperative CEUS and CECT were retrospectively enrolled. Propensity scores were calculated to match cHCC-CCA and HCC patients with a near-neighbor ratio of 1:2. Two predicted models, a CEUS-predominant (CEUS features plus tumor markers) and a CECT-predominant model (CECT features plus tumor markers), were constructed using logistic regression analyses. Model performance was evaluated by the area under the curve (AUC), sensitivity, specificity, and accuracy. RESULTS: A total of 135 patients (mean age, 51.3 years ± 10.9; 122 men) with 135 tumors (45 cHCC-CCA and 90 HCC) were included. By logistic regression analysis, unclear boundary in the intratumoral nonenhanced area, partial washout on CEUS, CA 19-9 > 100 U/mL, lack of cirrhosis, incomplete tumor capsule, and nonrim arterial phase hyperenhancement (APHE) volume < 50% on CECT were independent factors for a diagnosis of cHCC-CCA. The CECT-predominant model showed almost perfect sensitivity for cHCC-CCA, unlike the CEUS-predominant model (93.3% vs. 55.6%, p < 0.001). The CEUS-predominant model showed higher diagnostic specificity than the CECT-predominant model (80.0% vs. 63.3%; p = 0.020), especially in the ≤ 5 cm subgroup (92.0% vs. 70.0%; p = 0.013). CONCLUSIONS: The CECT-predominant model provides higher diagnostic sensitivity than the CEUS-predominant model for CHCC-CCA. Combining CECT features with serum CA 19-9 > 100 U/mL shows excellent sensitivity. CRITICAL RELEVANCE STATEMENT: Combining lack of cirrhosis, incomplete tumor capsule, and nonrim arterial phase hyperenhancement (APHE) volume < 50% on CECT with serum CA 19-9 > 100 U/mL shows excellent sensitivity in differentiating cHCC-CCA from HCC. KEY POINTS: 1. Accurate differentiation between cHCC-CCA and HCC is essential for treatment decisions. 2. The CECT-predominant model provides higher accuracy than the CEUS-predominant model for CHCC-CCA. 3. Combining CECT features and CA 19-9 levels shows a sensitivity of 93.3% in diagnosing cHCC-CCA.

Human amniotic MSCs-mediated anti-inflammation of CD206hiIL-10hi macrophages alleviates isoproterenol-induced ventricular remodeling in mice.

BACKGROUND: Human amniotic mesenchymal stem cells (hAMSCs) derived from amniotic membrane have multilineage differentiation, immunosuppressive, and anti-inflammation which makes them suitable for the treatment of various diseases. OBJECTIVE: This study aimed to explore the therapeutic effect and molecular mechanism of hAMSCs in ventricular remodeling (VR). METHODS: hAMSCs were characterized by a series of experiments such as flow cytometric analysis, immunofluorescence, differentiative induction and tumorigenicity. Mouse VR model was induced by isoproterenol (ISO) peritoneally, and the therapeutic effects and the potential mechanisms of hAMSCs transplantation were evaluated by echocardiography, carboxy fluorescein diacetate succinimidyl ester (CFSE) labeled cell tracing, histochemistry, qRT-PCR and western blot analysis. The co-culturing experiments were carried out for further exploring the mechanisms of hAMSCs-derived conditioned medium (CM) on macrophage polarization and fibroblast fibrosis in vitro. RESULTS: hAMSCs transplantation significantly alleviated ISO-induced VR including cardiac hypertrophy and fibrosis with the improvements of cardiac functions. CFSE labeled hAMSCs kept an undifferentiated state in heart, indicating that hAMSCs-mediated the improvement of ISO-induced VR might be related to their paracrine effects. hAMSCs markedly inhibited ISO-induced inflammation and fibrosis, seen as the increase of M2 macrophage infiltration and the expressions of CD206 and IL-10, and the decreases of CD86, iNOS, COL3 and αSMA expressions in heart, suggesting that hAMSCs transplantation promoted the polarization of M2 macrophages and inhibited the polarization of M1 macrophages. Mechanically, hAMSCs-derived CM significantly increased the expressions of CD206, IL-10, Arg-1 and reduced the expressions of iNOS and IL-6 in RAW264.7 macrophages in vitro. Interestingly, RAW264.7-CM remarkably promoted the expressions of anti-inflammatory factors such as IL-10, IDO, and COX2 in hAMSCs. Furthermore, the CM derived from hAMSCs pretreated with RAW264.7-CM markedly inhibited the expressions of fibrogenesis genes such as αSMA and COL3 in 3T3 cells. CONCLUSION: Our results demonstrated that hAMSCs effectively alleviated ISO-induced cardiac hypertrophy and fibrosis, and improved the cardiac functions in mice, and the underlying mechanisms might be related to inhibiting the inflammation and fibrosis during the ventricular remodeling through promoting the polarization of CD206hiIL-10hi macrophages in heart tissues. Our study strongly suggested that by taking the advantages of the potent immunosuppressive and anti-inflammatory effects, hAMSCs may provide an alternative therapeutic approach for prevention and treatment of VR clinically.