Redesigning a S-nitrosylated pyruvate-dependent GABA transaminase 1 to generate high-malate and saline-alkali-tolerant tomato.

Although saline-alkali stress can improve tomato quality, the detailed molecular processes that balance stress tolerance and quality are not well-understood. Our research links nitric oxide (NO) and γ-aminobutyric acid (GABA) with the control of root malate exudation and fruit malate storage, mediated by aluminium-activated malate transporter 9/14 (SlALMT9/14). By modifying a specific S-nitrosylated site on pyruvate-dependent GABA transaminase 1 (SlGABA-TP1), we have found a way to enhance both plant's saline-alkali tolerance and fruit quality. Under saline-alkali stress, NO levels vary in tomato roots and fruits. High NO in roots leads to S-nitrosylation of SlGABA-TP1/2/3 at Cys316/258/316, reducing their activity and increasing GABA. This GABA then reduces malate exudation from roots and affects saline-alkali tolerance by interacting with SlALMT14. In fruits, a moderate NO level boosts SlGABA-TP1 expression and GABA breakdown, easing GABA's block on SlALMT9 and increasing malate storage. Mutants of SlGABA-TP1C316S that do not undergo S-nitrosylation maintain high activity, supporting malate movement in both roots and fruits under stress. This study suggests targeting SlGABA-TP1Cys316 in tomato breeding could significantly improve plant's saline-alkali tolerance and fruit quality, offering a promising strategy for agricultural development.

Efficacy and safety of Shenbai Granules for recurrent colorectal adenoma: A multicenter randomized controlled trial.

BACKGROUND: Colorectal adenoma is benign glandular tumor of colon, the precursor of colorectal cancer. But no pharmaceutical medication is currently available to treat and prevent adenomas. PURPOSE: To evaluate efficacy of Shenbai Granules, an herbal medicine formula, in reducing the recurrence of adenomas. STUDY DESIGN: This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted by eight hospitals in China. METHODS: Patients who had received complete polypectomy and were diagnosed with adenomas within the recent 6 months were randomly assigned (1:1) to receive either Shenbai granules or placebo twice a day for 6 months. An annual colonoscopy was performed during the 2-year follow-up period. The primary outcome was the proportion of patients with at least one adenoma detected in the modified intention-to-treat (mITT) population during follow-up for 2 years. The secondary outcomes were the proportion of patients with sessile serrated lesions and other specified polypoid lesions. The data were analyzed using logistic regression. RESULTS: Among 400 randomized patients, 336 were included in the mITT population. We found significant differences between treatment and placebo groups in the proportion of patients with at least one recurrent adenoma (42.5 % vs. 58.6 %; OR, 0.47; 95 % CI, 0.29-0.74; p = 0.001) and sessile serrated lesion (1.8 % vs. 8.3 %; OR, 0.20; 95 % CI, 0.06-0.72; p = 0.01). There was no significant difference in the proportion of patients developing polypoid lesions (70.7 % vs. 77.5 %; OR, 1.43; 95 % CI, 0.88-2.34; p = 0.15) or high-risk adenomas (9.0 % vs. 13.6 %; OR, 0.63; 95 % CI, 0.32-1.25; p = 0.18). CONCLUSION: Shenbai Granules significantly reduced the recurrence of adenomas, indicating that they could be an effective option for adenomas. Future studies should investigate its effects in larger patient populations and explore its mechanism of action to provide more comprehensive evidence for the use of Shenbai Granules in adenoma treatment.

Genetic engineering of drought and salt tolerant tomato via S-nitrosylated Δ1-pyrroline-5-carboxylate reductase.

Drought and soil salinization substantially impact agriculture. While proline's role in enhancing stress tolerance is known, the exact molecular mechanism by which plants process stress signals and control proline synthesis under stress is still not fully understood. In tomato (Solanum lycopersicum L.), drought and salt stress stimulate nitric oxide (NO) production, which boosts proline synthesis by activating Δ1-pyrroline-5-carboxylate synthetase (SlP5CS) and Δ1-pyrroline-5-carboxylate reductase (SlP5CR) genes and the P5CR enzyme. The crucial factor is stress-triggered NO production, which regulates the S-nitrosylation of SlP5CR at Cys-5, thereby increasing its NAD(P)H affinity and enzymatic activity. S-nitrosylation of SlP5CR enables tomato plants to better adapt to changing NAD(P)H levels, boosting both SlP5CR activity and proline synthesis during stress. By comparing tomato lines genetically modified to express different forms of SlP5CR, including a variant mimicking S-nitrosylation (SlP5CRC5W), we found that SlP5CRC5W plants show superior growth and stress tolerance. This is attributed to better P5CR activity, proline production, water use efficiency, reactive oxygen species scavenging, and sodium excretion. Overall, this study demonstrates that tomato engineered to mimic S-nitrosylated SlP5CR exhibits enhanced growth and yield in drought and salt stress conditions, highlighting a promising approach for stress-tolerant tomato cultivation.

The Effects of Exogenous 2,4-Epibrassinolide on the Germination of Cucumber Seeds under NaHCO3 Stress.

This investigation focused on the suppressive impact of varying NaHCO3 concentrations on cucumber seed germination and the ameliorative effects of 2,4-Epibrassinolide (EBR). The findings revealed a negative correlation between NaHCO3 concentration and cucumber seed germination, with increased NaHCO3 concentrations leading to a notable decline in germination. Crucially, the application of exogenous EBR significantly counteracted this inhibition, effectively enhancing germination rates and seed vigor. Exogenous EBR was observed to substantially elevate the activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD), thereby mitigating oxidative damage triggered under NaHCO3 stress conditions. Additionally, EBR improved enzyme activity under alkaline stress conditions and reduced starch content in the seeds. Pertinently, EBR upregulated genes that were associated with gibberellin (GA) synthesis (GA20ox and GA3ox), and downregulated genes that were linked to abscisic acid (ABA) synthesis (NCED1 and NCED2). This led to an elevation in GA3 concentration and a reduction in ABA concentration within the cucumber seeds. Therefore, this study elucidates that alleviating oxidative stress, promoting starch catabolism, and regulating the GA and ABA balance are key mechanisms through which exogenous EBR mitigates the suppression of cucumber seed germination resulting from alkaline stress.

IFN-γ promotes radioresistant Nestin-expressing progenitor regeneration in the developing cerebellum by augmenting Shh ligand production.

BACKGROUND: Patients with brain tumors, especially pediatric brain tumors such as cerebellar medulloblastoma, always suffer from the severe side effects of radiotherapy. Regeneration of neural cells in irradiation-induced cerebellar injury has been reported, but the underlying mechanism remains elusive. METHODS: We established an irradiation-induced developing cerebellum injury model in neonatal mice. Microarray, KEGG analysis and semi in vivo slice culture were performed for mechanistic study. RESULTS: Nestin-expressing progenitors (NEPs) but not granule neuron precursors (GNPs) were resistant to irradiation and able to regenerate after irradiation. NEPs underwent less apoptosis but similar DNA damage following irradiation compared with GNPs. Subsequently, they started to proliferate and contributed to granule neurons regeneration dependent on the sonic hedgehog (Shh) pathway. In addition, irradiation increased Shh ligand provided by Purkinje cells. And microglia accumulated in the irradiated cerebellum producing more IFN-γ, which augmented Shh ligand production to promote NEP proliferation. CONCLUSIONS: NEP was radioresistant and regenerative. IFN-γ was increased post irradiation to upregulate Shh ligand, contributing to NEP regeneration. Our study provides insight into the mechanisms of neural cell regeneration in irradiation injury of the developing cerebellum and will help to develop new therapeutic targets for minimizing the side effects of radiotherapy for brain tumors.

Efficacy and safety of endoscopic retrograde cholangiopancreatography in recurrent pancreatitis of pediatric asparaginase-associated pancreatitis.

BACKGROUND: Asparaginase (ASP) is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL); ASP-associated pancreatitis (AAP) is the main adverse reaction of ASP. Recurrent pancreatitis is a complication of AAP, for which medication is ineffective. AIM: To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in treating recurrent pancreatitis due to AAP. METHODS: From May 2018 to August 2021, ten children (five males and five females; age range: 4-13 years) with AAP were treated using ERCP due to recurrent pancreatitis. Clinical data of the ten children were collected, including their sex, age, weight, ALL risk grading, clinical symptoms at the onset of pancreatitis, time from the first pancreatitis onset to ERCP, ERCP operation status, and postoperative complications. The symptomatic relief, weight change, and number of pancreatitis onsets before and after ERCP were compared. RESULTS: The preoperative symptoms were abdominal pain, vomiting, inability to eat, weight loss of 2-7 kg, and 2-9 pancreatitis onsets. After the operation, nine of ten patients did not develop pancreatitis, had no abdominal pain, could eat normally; the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP, but eating was not affected. The postoperative weight gain was 1.5-8 kg. There was one case of post ERCP pancreatitis and two cases of postoperative infections; all recovered after medication. CONCLUSION: ERCP improved clinical symptoms and reduced the incidence of pancreatitis, and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP.

Comparison of the short- and long-term prognosis of early-onset colorectal cancer compared with later-onset colorectal cancer: A systematic review and meta-analysis.

Background and Aims: The annual incidence of early-onset colorectal cancer (EOCRC) is increasing at an alarming rate. The prognosis of EOCRC remains controversial, and whether the early onset is a risk factor for colorectal cancer remains unclear. Methods: We searched four electronic bibliographic databases from database inception to April 25, 2022 for studies that included both early- and later-onset patients and performed a prognostic analysis. Random-effects models were used to summarize the prognostic information extracted by the investigators, including overall survival (OS), cancer-special survival (CSS), and disease-free survival (DFS). Network meta-analysis (NMA) was used to compare patients' long-term prognoses in different age subgroups. Results: After 694 reports were screened, 13 studies were included in the final analysis, with a total of 448,781 CRC cases. In the meta-analysis of the 5-year OS, EOCRC had a better prognosis compared to LOCRC (hazard ratio [HR] 0.87, 95% confidence interval [CI], 0.74-0.99; relative risk [RR] 0.83, 95% CI, 0.78-0.89). No difference in prognosis was found between the two groups in terms of 5-year CSS (RR 0.99, 95% CI, 0.93-1.05), 5-year DFS (RR 0.90, 95% CI, 0.74-1.09), and short-term OS. In the NMA, patients aged <30 years had the worst outcome (surface under the cumulative ranking curve [SUCRA], 15.8%) in 5-year OS; consistent results were observed in the analysis of 5-year CSS (<30 years, SUCRA 4.5%), but the difference was not statistically significant. Conclusion: Although patients with early-onset CRC had better OS than those with later-onset CRC, there was no difference in the CSS. Meanwhile, the trend for survival was worse in younger patients, especially in those ages 18-29 years. Thus, more attention should be paid to early diagnosis and treatment of EOCRC. Systematic Review and Meta­Analysis Registration: The systematic review and Meta-analysis protocol was registered with PROSPERO (registration number CRD42022334697).

External use of mirabilite to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis in children: A multicenter randomized controlled trial.

BACKGROUND: Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Currently, there is no suitable treatment for post-ERCP pancreatitis (PEP) prophylaxis. Few studies have prospectively evaluated interventions to prevent PEP in children. AIM: To assess the efficacy and safety of the external use of mirabilite to prevent PEP in children. METHODS: This multicenter, randomized controlled clinical trial enrolled patients with chronic pancreatitis scheduled for ERCP according to eligibility criteria. Patients were randomly divided into the external use of mirabilite group (external use of mirabilite in a bag on the projected abdominal area within 30 min before ERCP) and blank group. The primary outcome was the incidence of PEP. The secondary outcomes included the severity of PEP, abdominal pain scores, levels of serum inflammatory markers [tumor necrosis factor-alpha (TNF-α) and serum interleukin-10 (IL-10)], and intestinal barrier function markers [diamine oxidase (DAO), D-lactic acid, and endotoxin]. Additionally, the side effects of topical mirabilite were investigated. RESULTS: A total of 234 patients were enrolled, including 117 in the external use of mirabilite group and the other 117 in the blank group. The pre-procedure and procedure-related factors were not significantly different between the two groups. The incidence of PEP in the external use of mirabilite group was significantly lower than that in the blank group (7.7% vs 26.5%, P < 0.001). The severity of PEP decreased in the mirabilite group (P = 0.023). At 24 h after the procedure, the visual analog scale score in the external use of mirabilite group was lower than that in the blank group (P = 0.001). Compared with those in the blank group, the TNF-α expressions were significantly lower and the IL-10 expressions were significantly higher at 24 h after the procedure in the external use of mirabilite group (P = 0.032 and P = 0.011, respectively). There were no significant differences in serum DAO, D-lactic acid, and endotoxin levels before and after ERCP between the two groups. No adverse effects of mirabilite were observed. CONCLUSION: External use of mirabilite reduced the PEP occurrence. It significantly alleviated post-procedural pain and reduced inflammatory response. Our results favor the external use of mirabilite to prevent PEP in children.

Karrikin increases tomato cold tolerance via strigolactone and the abscisic acid signaling network.

As a class of biostimulants, karrikins (KARs) were first identified from plant-derived smoke to regulate plant growth, development, and stress tolerance. However, the roles of KARs in plant cold tolerance and their crosstalk with strigolactones (SLs) and abscisic acid (ABA) remain elusive. We studied the interaction among KAR, SLs, and ABA in cold acclimatization with KAI2-, MAX1-, SnRK2.5-silenced, or cosilenced plant materials. KAI2 is involved in smoke-water- (SW-) and KAR-mediated cold tolerance. MAX1 acts downstream of KAR in cold acclimation. ABA biosynthesis and sensitivity are regulated by KAR and SLs, which improve cold acclimation through the SnRK2.5 component. The physiological mechanisms of SW and KAR in improving growth, yield, and tolerance under a long-term sublow temperature environment were also studied. SW and KAR were shown to improve tomato growth and yield under sublow temperature conditions by regulating nutritional uptake, leaf temperature control, photosynthetic defense, ROS scavenging, and CBF transcriptional activation. Together, SW, which functions via the KAR-mediated SL and ABA signaling network, has potential application value for increasing cold tolerance in tomato production.

S-nitrosylation of ACO homolog 4 improves ethylene synthesis and salt tolerance in tomato.

Crop loss due to soil salinization is a global threat to agriculture. Nitric oxide (NO) and ethylene involve in multiple plant tolerance. However, their interaction in salt resistance remains largely elusive. We tested the mutual induction between NO and ethylene, and then identified an 1-aminocyclopropane-1-carboxylate oxidase homolog 4 (ACOh4) that influences ethylene synthesis and salt tolerance through NO-mediated S-nitrosylation. Both NO and ethylene positively responded to salt stress. Furthermore, NO participated in salt-induced ethylene production. Salt tolerance evaluation showed that function of NO was abolished by inhibiting ethylene production. Conversely, function of ethylene was little influenced by blocking NO generation. ACO was identified as the target of NO to control ethylene synthesis. In vitro and in vivo results suggested that ACOh4 was S-nitrosylated at Cys172, resulting in its enzymatic activation. Moreover, ACOh4 was induced by NO through transcriptional manner. Knockdown of ACOh4 abolished NO-induced ethylene production and salt tolerance. At physiological status, ACOh4 positively regulates the Na+ and H+ efflux, and keeps K+ /Na+ homeostasis by promoting salt-resistive genes' transcripts. Our findings validate a role of NO-ethylene module in salt tolerance and uncover a novel mechanism of how NO promoting ethylene synthesis against adversity.

Effects of linalool on Botrytis cinerea growth and control of tomato gray mold.

We examined the antifungal characteristics of linalool against Botrytis cinerea using plate inhibition assay and spore germination assay, and assessed the capacity of linalool in controlling tomato gray mold disease via tomato pot inoculation assay. The results showed that linalool exhibited strong inhibitive effects on mycelial growth of B. cinerea, with an EC50 value of 0.581 mL·L-1. In the spore germination test, linalool treatment inhibited spore germination in a dose-dependent manner. The electric conductivity and the malondialdehyde (MDA) contents were significantly increased in linalool-treated B. cinerea than that of the control, indicating that linalool induced oxidative damage and destroyed the cell membrane integrity in B. cinerea. The activities of the superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) in the linalool-treated B. cinerea were decreased significantly by 27.4%, 68.9% and 26.0%, respectively, suggesting that linalool inhibited the antioxidant activity of B. cinerea. In the pot experiment, the diameter of lesions in linalool-treated tomatoes was significantly smaller than that of the control. The activities of SOD, POD, CAT, polyphenol oxidase, and phenylalnine ammonialyase in the linalool-treated tomatoes increased, while the MDA content decreased, suggesting that linalool could alleviate the oxidative damage caused by B. cinerea and promote plant disease resistance. In summary, linalool had inhibitory effect on the growth of B. cinerea and could control gray mold disease in tomatoes. These findings could lay the foundation for developing bota-nical antifungal agents for management of tomato gray mold disease.

Long-term outcomes of endoscopic papillary large-balloon dilation (12-15 mm) with or without limited sphincterotomy for removal of bile duct stones.

BACKGROUND: Limited endoscopic sphincterotomy with large balloon dilation (ES-LBD) and endoscopic papillary large-balloon dilation (EPLBD) have been proven safe and effective for removal of bile duct stones. However, the long-term outcomes are not clear. The aim of this study was to assess the long-term outcomes of EPLBD (12-15 mm) with or without limited sphincterotomy for removal of common bile duct (CBD) stones. METHODS: Patients with EPLBD or ES-LBD referred for the removal of bile-duct stones between June 2008 and August 2020 were retrospectively reviewed. Complete stone clearance, endoscopic retrograde cholangiopancreatography (ERCP)-related adverse events, and late biliary complications during long-term follow-up were analyzed. RESULTS: Basic patient characteristics were not significantly different between the groups that underwent EPLBD (n = 168) and ES-LBD (n = 57). EPLBD compared with ES-LBD resulted in similar outcomes in terms of overall successful stone removal (99.4% vs. 100%, P = 1.00) and ERCP-related adverse events (7.7% vs. 5.3%, P = 0.77). The mean duration of the follow-up were 113.6 months and 106.7 months for patients with EPLBD and ES-LBD, respectively (P = 0.13). There was no significant difference between EPLBD and ES-LBD in the incidence of stone recurrence [20 (11.9%) vs. 9 (15.8%); P = 0.49]. Multivariate analysis showed that a diameter of CBD ≥ 15 mm (OR = 3.001; 95% CI: 1.357-6.640; P = 0.007) was an independent risk factor for stone recurrence. CONCLUSIONS: The application of a large balloon (12-15 mm) via EPLBD is an effective and safe alternative to ES-LBD for extraction of large CBD stones. Endoscopic sphincterotomy prior to EPLBD may be unnecessary. A diameter of CBD ≥ 15 mm is a risk factor of stone recurrence.

Phytomelatonin and plant mineral nutrition.

Plant mineral nutrition is critical for agricultural productivity and for human nutrition; however, the availability of mineral elements is spatially and temporally heterogeneous in many ecosystems and agricultural landscapes. Nutrient imbalances trigger intricate signalling networks that modulate plant acclimation responses. One signalling agent of particular importance in such networks is phytomelatonin, a pleiotropic molecule with multiple functions. Evidence indicates that deficiencies or excesses of nutrients generally increase phytomelatonin levels in certain tissues, and it is increasingly thought to participate in the regulation of plant mineral nutrition. Alterations in endogenous phytomelatonin levels can protect plants from oxidative stress, influence root architecture, and influence nutrient uptake and efficiency of use through transcriptional and post-transcriptional regulation; such changes optimize mineral nutrient acquisition and ion homeostasis inside plant cells and thereby help to promote growth. This review summarizes current knowledge on the regulation of plant mineral nutrition by melatonin and highlights how endogenous phytomelatonin alters plant responses to specific mineral elements. In addition, we comprehensively discuss how melatonin influences uptake and transport under conditions of nutrient shortage.

Complement C3a activates astrocytes to promote medulloblastoma progression through TNF-α.

BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor in children. Approximately one-third of MB patients remain incurable. Understanding the molecular mechanism of MB tumorigenesis is, therefore, critical for developing specific and effective treatment strategies. Our previous work demonstrated that astrocytes constitute the tumor microenvironment (TME) of MB and play an indispensable role in MB progression. However, the underlying mechanisms by which astrocytes are regulated and activated to promote MB remain elusive. METHODS: By taking advantage of Math1-Cre/Ptch1loxp/loxp mice, which spontaneously develop MB, primary MB cells and astrocytes were isolated and then subjected to administration and coculture in vitro. Immunohistochemistry was utilized to determine the presence of C3a in MB sections. MB cell proliferation was evaluated by immunofluorescent staining. GFAP and cytokine expression levels in C3a-stimulated astrocytes were assessed by immunofluorescent staining, western blotting, q-PCR and ELISA. C3a receptor and TNF-α receptor expression was determined by PCR and immunofluorescent staining. p38 MAPK pathway activation was detected by western blotting. Transplanted MB mice were treated with a C3a receptor antagonist or TNF-α receptor antagonist to investigate their role in MB progression in vivo. RESULTS: We found that complement C3a, a fragment released from intact complement C3 following complement activation, was enriched in both human and murine MB tumor tissue, and its receptor was highly expressed on tumor-associated astrocytes (TAAs). We demonstrated that C3a activated astrocytes and promoted MB cell proliferation via the p38 MAPK pathway. Moreover, we discovered that C3a upregulated the production of proinflammatory cytokines, such as IL-6 and TNF-α in astrocytes. Application of the conditioned medium of C3a-stimulated astrocytes promoted MB cell proliferation, which was abolished by preincubation with a TNF-α receptor antagonist, indicating a TNF-α-dependent event. Indeed, we further demonstrated that administration of a selective C3a receptor or TNF-α receptor antagonist to mice subcutaneously transplanted with MB suppressed tumor progression in vivo. CONCLUSIONS: C3a was released during MB development. C3a triggered astrocyte activation and TNF-α production via the p38 pathway, which promoted MB cell proliferation. Our findings revealed the novel role of C3a-mediated TNF-α production by astrocytes in MB progression. These findings imply that targeting C3a and TNF-α may represent a potential novel therapeutic approach for human MB.

GABA keeps nitric oxide in balance by regulating GSNOR to enhance disease resistance of harvested tomato against Botrytis cinerea.

Gamma-aminobutyric acid (GABA), a widely distributed metabolite in prokaryotes and eukaryotes, has many functions for plants in stress responses. In this study, hypotonic treatment with 10 mmol L-1 GABA in cherry tomato induced resistance to Botrytis cinerea with markedly lower disease incidence and lesion diameter, led to endogenous nitric oxide (NO) tansient accumulation before inoculation the pathogen then decrease after inoculation, and enhanced the content of arginine (Arg) and glutamic acid (Glu). The resistance of fruit treated with a NO scavenger, carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), was significantly reduced. Moreover, the enzyme activity and gene expression of S-nitrosoglutathione reductase (GSNOR) were enhanced following endogenous NO increased. The endogenous NO level was excessively high after treatment with a GSNOR scavenger, N6022, making the fruit more susceptible to pathogen. Similarly, after break down of SlGSNOR, fruit had much higher endogenous NO and lower disease resistance. However, overexpression of SlGSNOR exhibited opposite consequences. These results suggest that a suitable level of NO is beneficial for enhancing disease resistance, and GABA can help tomatoes maintain NO equilibrium by regulating GSNOR.

Efficacy and safety of Elian Granules in treating chronic atrophic gastritis: study protocol for a randomized, double-blind, placebo-controlled, multicenter clinical trial.

BACKGROUND: Multifocal atrophic gastritis and intestinal metaplasia are considered to be important links in the gastric precancerous cascade. However, there are no specific drugs for these conditions. Although many studies have shown that traditional Chinese medicine is effective with no serious side effects, these studies have not been scientifically rigorous trials. Our aim is to design a high-quality trial for a Chinese patent medicine, Elian Granules, to investigate its efficacy and safety in treating patients with chronic atrophic gastritis with or without intestinal metaplasia. METHODS: This is a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. A total of 240 participants will be assigned to a treatment or placebo control group in a 1:1 ratio. The experimental drug or placebo will be taken with boiling water, two small bags (24.2 g) each time, twice a day, half an hour after a meal, for 24 weeks. The primary outcome is the observation of histological changes in the gastric mucosa of patients with atrophic gastritis with or without intestinal metaplasia after 6 months based on the OLGA/OLGIM staging systems. The secondary outcomes include the assessment of dyspepsia and quality of life based on the dyspepsia symptom score and the quality-of-life scale. DISCUSSION: This study is designed to evaluate the efficacy and safety of Elian Granules in a randomized, double-blind, placebo-controlled, multicenter manner. This trial may not only provide evidence for a phase III clinical trial, but also an alternative option for the treatment of chronic atrophic gastritis (CAG). TRIAL REGISTRATION: Registry Platform For Evidence-Based Traditional Chinese Medicine ChiMCTR2000003929 . Registered on 13 September 2020.

γ-Aminobutyric acid (GABA) improves pesticide detoxification in plants.

It is important to ensure food safety to study the technology and mechanism of pesticide residues degradation in crops. Though γ-aminobutyric acid (GABA) has been widely reported to involve in plant stress resistance, whether exogenous application or endogenous regulation of GABA by gene-editing technology can promote the pesticide detoxification is not clear in plants. Using tomato and chlorothalonil (CHT) as research models, we discovered that exogenous application of GABA or endogenous elevation of GABA by knockout of pyruvate-dependent GABA transaminase promoted both CHT metabolism and plant stress tolerance to CHT. This is closely related to the active adaptation of GABA to CHT stress by regulating the plant GABA shunt pathway and polyamine pathway. The transcriptome data revealed 17 target genes that may be closely related to the involvement of GABA in CHT metabolism, including 4 peroxidases, 5 glycosyltransferases, 4 glutathione S-transferases, and 4 ABC transporters. In addition, the glutathione detoxification pathway and antioxidative enzyme also actively participated in the GABA-induced CHT detoxification process, which played an important role in relieving CHT stress. As a result, GABA significantly increased the photosynthetic capacity of tomato leaves under CHT stress. While studying photosynthesis, we unexpectedly found that GABA promotes stomatal closure in terms of decreased stomatal conductance and stomatal diameter. This result implies that GABA can reduce CHT absorption by regulating stomatal movement in leaves. Together, we provided a novel viewpoint that foliar application of GABA or metabolic engineering of GABA is an effective approach to reduce the risk of pesticide contamination in crop production.

The role and significance of magnetic resonance imaging and miRNA-125b expression level in diagnosis of head and neck squamous cell carcinoma.

Introduction: Diagnosis of head and neck squamous cell carcinoma (SCC) is an important challenge for clinicians, and finding new approaches to better diagnosis is the basis of a new area of cancer research. Aim: To investigate the diagnostic value and significance of MRI combined with miRNA-125 expression in head and neck SCC. Material and methods: Sixty patients with head and neck SCC were selected as the tumour group, and 20 healthy volunteers as the control group. All subjects were examined by magnetic resonance imaging (MRI) perfusion imaging. Peripheral venous blood was collected from all patients and healthy volunteers. The expression level of miRNA-125 in serum was detected by RT-qPCR, and the levels of interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and transforming growth factor ß1 (TGF-ß1) in serum were detected. Meanwhile, tumour tissues and adjacent non-tumour tissues of patients were collected to detect the mRNA expression level of ERBB2. Results: Compared with the control group, the expression level of miRNA-125b in serum of patients decreased with a statistically significant difference (p < 0.05). Compared with adjacent non-tumour tissues, the expression level of ERBB2 mRNA in tumour tissues of patients was significantly increased, with a statistically significant difference (p < 0.05). MiRNA-125b in serum was negatively correlated with tumour size and number of metastatic foci (p < 0.05). The results of enzyme-linked immunosorbent assay showed that the levels of IL-2, TNF-α, and TGF-ß1 in the patient's serum increased while the levels of IFN-γ decreased significantly, with a statistically significant difference (p < 0.05). Conclusions: Detection of miRNA-125b expression level is complementary to MRI diagnosis of head and neck SCC.

Over-activation of EFTUD2 correlates with tumor propagation and poor survival outcomes in hepatocellular carcinoma

PurposeElongation factor Tu GTP-binding domain containing 2 (EFTUD2) is an essential constituent of U5 small nuclear ribonucleoproteins (snRNPs) and plays a crucial role in spliceosome activation and cancer. The mechanism of EFTUD2 on carcinogenesis and development of liver cancer still need further study.MethodsBioinformatic analysis was performed to find differential expressed genes and related pathways. Western blotting and quantitative PCR assays were used to verify the EFTUD2 expression in HCC cell lines and tumor tissues of liver cancer patients. Transfection of shRNAs in SKHEP1 and Huh7 cell lines was conducted to explore the mechanisms of EFTUD2 in HCC. CCK-8 method, colony formation, and cell cycle detection kit were used to detect the proliferation. A tumor model in nude mice was used to explore the role of EFTUD2 in liver cancer in vivo.ResultsBased on the tumor tissues and para-tumor tissues in our HCC patients, we identified EFTUD2 as highly expressed in HCC tissues (P < 0.001). Bioinformatic analysis from the TCGA database also supported this biological phenomenon (P = 1.911e−17). Furtherly, the results of clinical specimens and TCGA data suggested that higher EFTUD2 expression levels correlated with high histologic grades, high pathological grades, and poor survival prognoses in HCC patients. And knockdown of EFTUD2 suppressed cell proliferation and colony formation in vitro. In vivo, knockdown of EFTUD2 constrained the tumor growing and expansion derived from SKHEP1 cells and induced a decrease in the tumor volume and tumor weight resected from nude mice. Furthermore, RNA sequencing based on EFTUD2 knockdown revealed that EFTUD2 affected target genes concerned with the cell cycle. Flow cytometric analyses in the SKHEP1 cell model revealed that knockdown significantly suppressed cell cycle course and caused cell cycle arrest in the G1 phase. CyclinD1 proteins were also inhibited by knocking down of EFTUD2.

Clinical characteristics and endoscopic treatment of pancreatitis caused by pancreaticobiliary malformation in Chinese children.

OBJECTIVES: We aimed to describe the clinical characteristics of pediatric patients with pancreatitis caused by pancreaticobiliary malformation and to evaluate the efficacy and safety of magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of the disease. METHODS: Medical records of pediatric patients with pancreatitis related to pancreaticobiliary malformation diagnosed by ERCP and treated in our hospital between April 2008 and December 2020 were retrospectively reviewed. Clinical manifestations, laboratory indicators, genetic testing results and imaging findings including MRCP were collected. RESULTS: Of the 148 patients with pancreaticobiliary malformation-related pancreatitis, 90 (60.8%) had pancreaticobiliary maljunction (PBM), 52 (35.1%) had pancreatic divisum (PD), and six (4.1%) had annular pancreas (AnnP). Compared with the PD group, patients with PBM were younger (P < 0.001), and were more likely to have jaundice (P < 0.001) and fever (P = 0.034). Genetic mutation was found in 51.6% of patients with PD, 50.0% with AnnP, and 15.0% with PBM. Diagnostic rate of PBM, PD, and AnnP using MRCP was 46.7%, 15.4%, and 100%, respectively. In total, 87.8% of patients had symptomatic improvement after endoscopic treatment. ERCP-related complications were observed in 28 out of the 260 procedures, including post-ERCP pancreatitis (7.7%), infection (2.3%), and gastrointestinal bleeding (0.8%). CONCLUSIONS: PBM should be considered when jaundice and fever occur in pediatric patients. Genetic testing is recommended for those with PD and AnnP. The role of MRCP is limited in identifying pancreaticobiliary malformation in children. ERCP is effective and safe for the diagnosis and treatment for pediatric pancreatitis caused by pancreaticobiliary malformation.