Intermittent Changes in Temperature and Humidity Repress Gray Mold in Tomato.

Environmental temperature and humidity play a vital role in plant-pathogen interactions, which profoundly affect the occurrence of crop diseases. However, the specific methods and mechanisms through which intermittent changes in temperature and humidity mitigate plant diseases remain unclear. In this study, six temperature and humidity combinations were set, the disease severity of tomatoes and biomass of Botrytis cinerea were analyzed, and the infection process of pathogens was observed using an optical microscope. Furthermore, dual RNA-seq analysis was performed to explore the interactions between plants and pathogens. Results showed that the 24 hours postinoculation (hpi)-12 h day (regulation was performed at 24 hpi for 12 h after inoculation during the day) treatment reduced the gray mold severity and biomass of B. cinerea in plants by the greatest amount and effectively inhibited the growth of mycelia. The 24 hpi-12 h day treatment induced the upregulation of light reactions, photorespiration, and Calvin cycle-related genes in tomatoes, whereas fungal genes related to the biosynthesis of sesquiterpene botrydial and polyketide botcinic acid were downregulated. Overall, we identified the optimal combination of temperature and humidity changes to inhibit the development of tomato gray mold and preliminarily explored the interactions between tomato and B. cinerea under temperature and humidity changes. This work has practical importance and provides a theoretical basis for the ecological control of plant diseases.

NRF2 overexpression in mesenchymal stem cells induces stem-cell marker expression and enhances osteoblastic differentiation.

Hypoxic environment has been suggested in stem cell culturing as their physiologic niche requires oxygen tension to maintain stemness. The administration of cobalt chloride (CoCl2) was widely applied in mimicking hypoxia for its economic advantages and convenience. We confirmed that CoCl2 could maintain stemness and promote the osteogenesis capacity of MSCs. However, CoCl2 could induce the apoptosis and hinder the proliferation of MSCs. To find out a potential method maintaining their stemness without threatening their survival, we analyzed the database of Gene Expression Omnibus (GEO) and proposed that NRF2 (nuclear factor erythroid-derived 2-like 2) might be the potential target. We found that knocking down NRF2 expression in MSCs impaired the expression of stem cell markers and the osteogenesis process even under hypoxic environment, but with NRF2 overexpression, the proliferation of MSCs was increased with significantly reduced rate of apoptosis. Therefore, our findings suggested that overexpressing NRF2 could be a potential method for maintaining stemness and preventing apoptosis in MSCs under oxidative stress.

RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway.

Background and Aims: Hepatic ischemia-reperfusion injury (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aimed to investigate the pathogenesis of RAMP1 in HIRI. Methods: We established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hypoxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conducted in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function. Results: Liver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was promoted in RAMP1-KO mice via the induction of hepatocyte apoptosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experiments. Conclusions: Our findings suggest that RAMP1 protects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention.

Case Report: Primary hepatic neuroendocrine tumor: two cases report with literature review.

Background & Aims: Primary hepatic neuroendocrine tumors (PHNETs) are rare malignant liver tumors that present diagnostic challenges owing to their rarity and absence of specific clinical features. This study aimed to investigate the characteristics of this rare liver tumor to enhance our understanding of the disease, improve diagnostic accuracy, and explore standardized diagnostic and treatment approaches. Case description: During physical examination, two elderly women, aged 64 and 74 years, were found to have liver masses. 18F-FDG Positron Emission Tomography-Computed Tomography (18F-FDG PET-CT) and Ga68-DOTATATE PET-CT scans of both individuals revealed multiple liver masses that were initially suspected to be hepatic neuroendocrine tumors. Subsequent puncture pathology confirmed the diagnosis of neuroendocrine tumors. Furthermore, in Case 1, the tumor was also detected by 18F-FDG PET-CT in the lung, suggesting a metastatic tumor, in conjunction with liver immunohistochemistry and imaging findings. Laboratory tests revealed no significant abnormalities in liver function or autoimmune liver disease indicators, and there was no evidence of viral hepatitis infection. However, partial hepatectomy was not indicated for cases with distant metastasis or multiple space-occupying lesions. Individualized treatment approaches have been developed for such situations. A large portion of the tumor underwent Transarterial Embolization (TAE), and targeted combination chemotherapy or endocrine therapy was administered based on the pathological results. During regular follow-ups a 13 and 12 months, the tumor remained stable. The patients' quality of life was good, and their psychological well-being was healthy. They led active lifestyles, demonstrated a thorough understanding of their disease and its progression, and actively cooperated during the follow-up process. Conclusion: Our findings suggest that a combination of serological, radiological, and immunohistochemical examinations can aid in the diagnosis of PHNET. In addition, we determined that TAE combined with drug therapy could be an effective method for controlling PHNET progression. Regular postoperative follow-ups are important for monitoring the prognosis and tumor progression status of patients with PHNET.

Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC.

BACKGROUND: Emerging evidence indicates that the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) axis plays a pivotal role in intrinsic antitumor immunity. Previous studies demonstrate that the conventional chemotherapy agent, teniposide, effectively promotes the therapeutic efficacy of programmed cell death protein-1 antibody (PD-1 Ab) through robust cGAS-STING activation. Unfortunately, the cGAS expression of tumor cells is reported to be severely suppressed by the hypoxic status in solid tumor. Clinically, enhancing chemotherapy-induced, DNA-activated tumor STING signaling by alleviating tumor hypoxia might be one possible direction for improving the currently poor response rates of patients with hepatocellular carcinoma (HCC) to PD-1 Ab. METHODS: Teniposide was first screened out from several chemotherapy drugs according to their potency in inducing cGAS-STING signaling in human HCC cells. Teniposide-treated HCC cells were then cultured under hypoxia, normoxia or reoxygenation condition to detect change in cGAS-STING signaling. Next, oxaliplatin/teniposide chemotherapy alone or combined with hyperbaric oxygen (HBO) therapy was administered on liver orthotopic mouse tumor models, after which the tumor microenvironment (TME) was surveyed. Lastly, teniposide alone or combined with HBO was performed on multiple mouse tumor models and the subsequent anti-PD-1 therapeutic responses were observed. RESULTS: Compared with the first-line oxaliplatin chemotherapy, teniposide chemotherapy induced stronger cGAS-STING signaling in human HCC cells. Teniposide-induced cGAS-STING activation was significantly inhibited by hypoxia inducible factor 1α in an oxygen-deficient environment in vitro and the inhibition was rapidly removed via effective reoxygenation. HBO remarkably enhanced the cGAS-STING-dependent tumor type Ⅰ interferon and nuclear factor kappa-B signaling induced by teniposide in vivo, both of which contributed to the activation of dendritic cells and subsequent cytotoxic T cells. Combined HBO with teniposide chemotherapy improved the therapeutic effect of PD-1 Ab in multiple tumor models. CONCLUSIONS: By combination of two therapies approved by the Food and Drug Administration, we safely stimulated an immunogenic, T cell-inflamed HCC TME, leading to further sensitization of tumors to anti-PD-1 immunotherapy. These findings might enrich therapeutic strategies for advanced HCC andwe can attempt to improve the response rates of patients with HCC to PD-1 Ab by enhancing DNA-activated STING signaling through effective tumor reoxygenation.

Challenges and advances in clinical applications of mesenchymal stromal cells.

Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.

YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury.

Hepatic ischemia-reperfusion injury (IRI) is the most common cause of liver damage leading to surgical failures in hepatectomy and liver transplantation. Extensive inflammatory reactions and oxidative responses are reported to be the major processes exacerbating IRI. The involvement of Yes-associated protein (YAP) in either process has been suggested, but the role and mechanism of YAP in IRI remain unclear. In this study, we constructed hepatocyte-specific YAP knockout (YAP-HKO) mice and induced a hepatic IRI model. Surprisingly, the amount of serum EVs decreased in YAP-HKO compared to WT mice during hepatic IRI. Then, we found that the activation of YAP increased EV secretion through F-actin by increasing membrane formation, while inhibiting the fusion of multivesicular body (MVB) and lysosomes in hepatocytes. Further, to explore the essential elements of YAP-induced EVs, we applied mass spectrometry and noticed CD47 was among the top targets highly expressed on hepatocyte-derived EVs. Thus, we enriched CD47+ EVs by microbeads and applied the isolated CD47+ EVs on IRI mice. We found ameliorated IRI symptoms after CD47+ EV treatment in these mice, and CD47+ EVs bound to CD172α on the surface of dendritic cells (DCs), which inhibited DC activation and the cascade of inflammatory responses. Our data showed that CD47-enriched EVs were released in a YAP-dependent manner by hepatocytes, which could inhibit DC activation and contribute to the amelioration of hepatic IRI. CD47+ EVs could be a potential strategy for treating hepatic IRI.

Achievement of complete response to nivolumab in a patient with advanced sarcomatoid hepatocellular carcinoma: A case report.

BACKGROUND: Sarcomatoid hepatocellular carcinoma (SHC) is a rare subtype of hepatocellular carcinoma (HCC), with a high recurrence rate after surgery. In addition to limited effective treatment for the advanced stage of SHC, the prognosis of patients with this malignancy is worse than that of patients with conventional HCC. CASE SUMMARY: We present the case of a 54-year-old man with SHC who underwent radical segmental hepatectomy, which relapsed 4 mo after surgery due to lymphatic metastasis in the porta hepatis. Although a second surgery was performed, new metastasis developed in the mediastinal lymph nodes. Therefore, sorafenib and lenvatinib were sequentially administered as first- and second-line systemic therapies, respectively. However, progressive disease was confirmed based on a recurrent hepatic lesion and new metastatic lesion in the abdominal cavity. Percutaneous transhepatic cholangial drainage was performed to alleviate the biliary obstruction. Because the tumor was strongly positive for programmed death-ligand 1, the patient was started on nivolumab. Imaging studies revealed that after two cycles of immunotherapy, the metastatic lesions decreased to undetectable levels. CONCLUSION: The patient experienced continuous complete remission for 8 mo. Immune checkpoint inhibitors are useful for the treatment of advanced SHC.

Association of sex hormone-binding globulin with nonalcoholic fatty liver disease in Chinese adults.

BACKGROUND: Sex hormone-binding globulin (SHBG), a glycoprotein synthesized by hepatocytes, has been linked to insulin resistance and hepatic lipid metabolism and is suggested to be associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the association of SHBG with NAFLD in Chinese adults. METHODS: We conducted a community-based, cross-sectional study in China involving 2912 participants aged 40-75 years old. All participants underwent detection for hepatic fat infiltration by ultrasound in addition to providing complete medical history and undergoing physical and blood biochemical examinations. The association of serum SHBG with the presence of NAFLD was reported by adjusted odds ratio after applying logistic regression models. To further explore the relationship between SHBG and NAFLD, mRNA expression of SHBG and hepatocyte nuclear factor 4-α (HNF4α), as well as intrahepatic triglycerides, were determined from the liver tissues of 32 subjects with different degrees of steatosis. RESULTS: Serum SHBG levels in patients with NAFLD (median, 43.8 nmol/L; interquartile range, 33.4-56.8 nmol/L) were significantly lower than those in non-NAFLD subjects (median, 63.4 nmol/L; interquartile range, 47.6-83.1 nmol/L). Serum SHBG levels were inversely correlated with WHR, trunk fat percentage, glucose, HOMA-IR, TG, UA and DHEAS, and were positively correlated with HDL-C levels (all p <  0.001). Logistic regression analysis indicated that serum SHBG levels were negatively associated with the presence of NAFLD in all subjects, as well as the subgroups stratified by sex, BMI and HOMA-IR (all p <  0.05). In human liver tissues, SHBG and HNF4α mRNA expression decreased along with the elevated grade of hepatic steatosis. Both SHBG and HNF4α mRNA expression levels were negatively correlated with intrahepatic triglycerides. CONCLUSIONS: These results demonstrate that SHBG levels were negatively associated with the presence of NAFLD in middle-aged and elderly Chinese adults.