Helicobacter pylori antibiotic resistance profile in Chinese children with upper gastrointestinal symptoms and a literature review for developing personalized eradicating strategies.

Background: H. pylori (Helicobacter pylori) infections typically occur in early childhood. Although the prevalence of H. pylori in children is lower than that in adults, the eradication rate of this infection in children is relatively low because of resistance. In this study, we analyzed personalized treatment strategies to achieve treatment goals based on H. pylori resistance characteristics. This retrospective single-center study was conducted between January 2019 and December 2022 and enrolled 1,587 children who presented with upper gastrointestinal symptoms and underwent endoscopy. H. pylori culturing and antimicrobial susceptibility testing were performed. Results: Culture-positive results for H. pylori were obtained in 535 children. The resistance rates to clarithromycin (CLA), metronidazole (MET), and levofloxacin (LEV) were 39.8%, 78.1%, and 20.2%, respectively. None of the isolates were resistant to tetracycline (TET), amoxicillin (AMO), or furazolidone (FZD). Double resistance rates to CLA + MET, CLA + LEV, and MET + LEV were 19.1%, 3.0%, and 5.8%, respectively. Notably, triple-resistant to CLA + MET + LEV was 9.7%. Based on susceptibility tests, individualized triple therapy [proton pump inhibitor (PPI) +AMO + CLA/MET] was selected for 380 children with H. pylori sensitive to MET and/or CLA. In 155 children resistant to CLA and MET, bismuth-based quadruple therapy was recommended; for unable to receive bismuth, concomitant therapy was recommended for 14 children (<8 years of age); triple therapy with TET was recommended for 141 children (>8 years of age), with 43 children (>14 years of age) requiring FZD rather than TET. Conclusion: Resistance to H. pylori in Chinese children was relatively poor. Personalized therapy regimens should be based on susceptibility tests and avoided factors associated with treatment failure.

Effects of Continuous Nutritional Intervention on Nutritional Status and Serum Albumin During Maintenance Therapy in Children with Acute Lymphoblastic Leukemia.

Background: Nutritional imbalances can significantly impact clinical efficacy and chemotherapy tolerance in cases of acute lymphoblastic leukemia. Despite the potential significance, there is limited research in this domain, and clinicians have paid limited attention to it. Objective: This study aims to investigate the impact of continuous nutritional intervention on pediatric patients with acute lymphoblastic leukemia. Methods: A comparative analysis was conducted by dividing the children into observation and control groups, examining the effects of intermittent diet intervention and continuous nutrition intervention post-nutritional risk assessment. Results: After the intervention, the observation group exhibited a higher proportion of good nutrition and elevated serum albumin levels compared to the control group (χ2=4.79, 5.49, P = .029, 0.019, t =-2.819, -5.559, P = .01, P < .001). Additionally, the complication rate in the observation group was significantly lower than that in the control group (χ2=5.247, P = .022). Conclusions: Continuous nutrition intervention emerges as a valuable strategy for improving the nutritional status and serum albumin levels in children undergoing maintenance treatment for acute lymphoblastic leukemia. Moreover, it contributes to a noteworthy reduction in the incidence of complications.

Discovery of 2,5-diaminopyrimidine derivatives as the first series of selective monomeric degraders of B-lymphoid tyrosine kinase.

B-lymphoid tyrosine kinase (BLK) is an important knot of B cell receptor signaling, and regulates the function and development of B cells subset. Dysfunction of BLK is correlated with autoimmune diseases and cancer. There is an urgent need to develop selective BLK modulators to facilitate the studies of BLK in biological processes. Herein, we report the discovery of a series of 2,5-diaminopyrimidine-based compounds capable of selectively degrading BLK. The optimized compounds 9-11 possess weak biochemical inhibitory activities against BLK, yet they effectively degrade BLK and show high selectivity for BLK over other structurally and functionally related SRC family and TEC family kinases. Furthermore, compounds 9 and 11 demonstrate potent inhibitory activities in several B-lymphoid cell lines. As the first series of effective and selective monomeric BLK degraders, compounds 9-11 serve as valuable tools for further investigation of the functions of BLK.

Preferential, synergistic sorption and reduction of Cr(VI) from chromium-rhodamine B mixed wastewater by magnetic porous biochar derived from wasted Myriophyllum aquaticum biomass.

Eradication of heavy metals and dyes simultaneously from wastewater is urgently needed to safeguard public and environmental health. In this study, magnetic porous biochar derived from wasted Myriophyllum aquaticum (MPMaB) was synthesized by KOH-activation and co-precipitation method to treat chromate and rhodamine B (RhB)-bearing wastewater. The KOH activation significantly improved the pore structure of biochar with a high specific surface area of 937.1 m2 g-1. The sorption performance of MPMaB for Cr(VI) and RhB in single and co-solutes conditions was evaluated. In single system, a pH-dependent sorption pattern for Cr(VI) by MPMaB was revealed and the estimated sorption capability reached 175.4 mg g-1, whereas the Langmuir-based sorption capacity of RhB was 175.4 mg g-1 pH-independently. MPMaB partially transformed Cr(VI) to less toxic Cr(III) (approximately 59.3%). Synergistic sorption of Cr(VI) with the coexistence of RhB was observed, where synergistic effect ranged from 119% to 527% depending on pH. For example, the sorption capacity of Cr(VI) on MPMaB, at pH 2, augmented from 175.4 mg g-1 (single system) to 208.3 mg g-1 (binary system). Preferential sorption of Cr(VI) was found and was further confirmed by the post-sorption of Cr(VI) (or RhB) by MPMaB pre-sorbed with RhB (or chromate). Chromate sorption mechanisms mainly include electrostatic interactions and complexation, while the sorption of RhB is ascribed to π-π interactions, pore filling and hydrogen bonding. Additionally, MPMaB showed excellent reusability and maintained high removal efficiency after 5 cycles. In short, MPMaB can efficiently treat chromium and dyes-containing wastewater as sustainable and environmentally friendly adsorbent.

Discovery of Potent and Highly Selective Interleukin-2-Inducible T-Cell Kinase Degraders with In Vivo Activity.

Interleukin-2-inducible T-cell kinase (ITK) is a promising therapeutic target for human autoimmune diseases and T-cell malignant lymphomas. This paper reports the development of a series of cereblon-recruiting ITK proteolysis targeting chimeras based on a structure-based design strategy. The representative compounds 23 and 28 exhibited potent ITK degradation and IL-2 inhibition activities in Jurkat cells. Global proteomic profiling assays indicated that compounds 23 and 28 are highly selective ITK degraders. Moreover, compound 28 showed good plasma exposure levels and elicited efficient, rapid, and prolonged ITK degradation in Balb/c mice. Furthermore, it significantly suppressed IL-2 secretion stimulated by anti-CD3 antibody. Compound 28 represents the first effective and highly selective ITK degrader. Thus, 28 is a valuable tool compound for further in vitro and in vivo studies exploring the underlying biological effects and potential therapeutic utility of ITK degradation in human diseases.

A lifetime economic research of universal HLA-B*58:01 genotyping or febuxostat initiation therapy in Chinese gout patients with mild to moderate chronic kidney disease.

OBJECTIVE: To evaluate Chinese long-term economic impact of universal human leukocyte antigen B (HLA-B)*58:01 genotyping-guided urate-lowering therapy or febuxostat initiation therapy for gout patients with mild to moderate chronic kidney disease (CKD) from perspective of healthcare system. METHODS: A Markov model embedded in a decision tree was structured including four mutually exclusive health states (uncontrolled-on-therapy, controlled-on-therapy, uncontrolled-off-therapy, and death). Mainly based on Chinese real-world data, the incremental costs per quality-adjusted life years (QALYs) gained were evaluated from three groups (universal HLA-B*58:01 testing strategy, and no genotyping prior to allopurinol or febuxostat initiation therapy) at 25-year time horizon. All costs were adjusted to 2021 levels based on Chinese Consumer Price Index and were discounted by 5% annually. One-way and probability sensitivity analysis were performed. RESULTS: Among these three groups, universal HLA-B*58:01 genotyping was the most cost-effective strategy in base-case analysis according to Chinese average willingness-to-pay threshold of $37 654.50 per QALY. The based incremental cost-effectiveness ratio was $31784.55 per QALY, associated with 0.046 additional QALYs and $1463.81 increment costs per patient at a 25-year time horizon compared with no genotyping prior to allopurinol initiation strategy. Sensitivity analysis showed 64.3% robustness of these results. CONCLUSION: From Chinese perspective of healthcare system, HLA-B*58:01 genotyping strategy was cost-effective for gout patients with mild to moderate CKD in mainland China, especially in the most developed area, such as Beijing and Shanghai. Therefore, we suggest China's health authorities choose the genotyping strategy and make different recommendations according to the differences of local conditions.

Clinical and Genetic Analysis of a Patient With Coexisting 17a-Hydroxylase/17,20-Lyase Deficiency and Moyamoya Disease.

17a-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by pathogenic mutations in CYP17A1. Female patients present with hypertension, hypokalemia, and sexual infantilism while males present with sex development disorder. Moyamoya disease (MMD) is a chronic cerebrovascular disease that frequently results in intracranial ischemia or hemorrhage. The present study describes a case of 17OHD and MMD in a 27-year-old phenotypically female (46, XY) patient and discusses the clinical features and characteristics of her genetic defect. Clinical, hormonal, radiological, and genetic analyses were performed and blood samples were collected for whole-exome sequencing (WES). The results of the WES revealed a homozygous intronic mutation (c.297+2T>C) in CYP17A1, which led to combined 17a-hydroxylase/17,20-lyase deficiency, as well as novel variants in PCNT and CNOT3 that might lead to MMD. To our knowledge, this study is the first to describe 17OHD accompanied by MMD. While several cases have previously described patients with 17OHD with histories of cerebral hemorrhage or cerebral ischemia, a correlation in genetic levels between 17OHD and MMD was not found. The risk of cerebrovascular accidents should be considered in patients with 17OHD and hypertension. Cerebrovascular examination in patients with 17OHD may be beneficial for the prevention of life-threatening intracranial vascular disease.

Cx32 inhibits the autophagic effect of Nur77 in SH-SY5Y cells and rat brain with ischemic stroke.

The pathogenesis of cerebral ischemia-reperfusion (I/R) is complex. Cx32 expression has been reported to be up-regulated in ischemic lesions of aged human brain. Nevertheless, the function of Cx32 during cerebral I/R is poorly understood. Autophagy is of vital importance in the pathogenesis of cerebral I/R. In the current study, we found that oxygen-glucose deprivation/reoxygenation (OGD/R) or I/R insult significantly induced the up-regulation of Cx32 and activation of autophagy. Inhibition of Cx32 alleviated OGD/R or I/R injury, and further activated autophagy. In addition, Nur77 expression was found to be up-regulated after OGD/R or I/R. After inhibiting Cx32, the expression of Nur77 was further increased and Nur77 was translocated from nucleus to mitochondrial. Inhibition of Cx32 also activated mitophagy by promoting autophagosome formation and up-regulating the expression of mitochondrial autophagy marker molecules. Of note, in the siNur77-transfected cells, the number of dysfunctional mitochondrial was increased, and mitophagy was suppressed, which aggravated OGD/R-induced neuronal injury. In conclusion, Cx32 might act as a regulatory factor of Nur77 controlling neuronal autophagy in the brains. Understanding the mechanism of this regulatory pathway will provide new insight into the role Cx32 and Nur77 in cerebral ischemia, offering new opportunities for therapeutics.

Masitinib alleviated cerebral ischemia/reperfusion injury by inhibiting autophagy and apoptosis / 中国药科大学学报

@#To investigate the neuroprotective effect and possible mechanism of masitinib on cerebral ischemia-reperfusion injury in rats, healthy adult male Sprague-Dawley rats were divided into sham group (n = 12), model group (n = 12), masitinib low dosage group (n = 12), masitinib middle dosage group (n = 12), and masitinib high dosage group (n = 12). All rats was subjected to middle cerebral artery occlusion (MCAO) for two hours and reperfusion except sham group, and received treatment twice per day for 7 days once reperfusion started.Neurological score, infarct volume, and brain water content were detected; some autophagic markers, apoptotic and inflammatory cytokines were evaluated by Western blot and PCR after 7 d of reperfusion. Treatment with masitinib significantly ameliorated neurologic deficit, infarct volume and brain water after I/R injury. Masitinib also decreased the ratio of LC3II/I and the expression of Beclin-1 and increased the expression of p62 in the brain tissues of rats with I/R injury.Furthermore, it could inhibit apoptosis-related proteins and NF-κB expression. Masitinib could relieve the cerebral ischemia-reperfusion injury in rats through inhibiting autophagy and apoptosis.

Protein degradation through covalent inhibitor-based PROTACs.

Tremendous advancements in proteolysis targeting chimera (PROTAC) technology have been made in recent years. However, whether a covalent inhibitor-based PROTAC can be developed remains controversial. Here, we successfully developed chimeric degraders based on covalent inhibitors to degrade BTK and BLK kinases, demonstrating that covalent inhibitor-based PROTACs are viable and useful tools.

Light-Induced Protein Degradation with Photocaged PROTACs.

Induction of protein degradation is emerging as a powerful strategy to modulate protein functions and alter cellular signaling pathways. Proteolysis-targeting chimeras (PROTACs) have been used to degrade a range of diverse proteins in vitro and in vivo. Here we present a type of photo-caged PROTACs (pc-PROTACs) to induce degradation activity with light. Photo-removable blocking groups were added to a degrader of Brd4, and the resulting molecule pc-PROTAC1 showed potent degradation activity in live cells only after light irradiation. Furthermore, this molecule efficiently degraded Brd4 and induced expected phenotypic changes in zebrafish. Additionally, this approach was successfully applied to construct pc-PROTAC3 of BTK. Thus, a general strategy to induce protein degradation with light was established to augment the chemists' toolbox to study disease-relevant protein targets.

Inhibition of apoptosis signal-regulating kinase by paeoniflorin attenuates neuroinflammation and ameliorates neuropathic pain.

BACKGROUND: Neuropathic pain is a serious clinical problem that needs to be solved urgently. ASK1 is an upstream protein of p38 and JNK which plays important roles in neuroinflammation during the induction and maintenance of chronic pain. Therefore, inhibition of ASK1 may be a novel therapeutic approach for neuropathic pain. Here, we aim to investigate the effects of paeoniflorin on ASK1 and neuropathic pain. METHODS: The mechanical and thermal thresholds of rats were measured using the Von Frey test. Cell signaling was assayed using western blotting and immunohistochemistry. RESULTS: Chronic constrictive injury (CCI) surgery successfully decreased the mechanical and thermal thresholds of rats and decreased the phosphorylation of ASK1 in the rat spinal cord. ASK1 inhibitor NQDI1 attenuated neuropathic pain and decreased the expression of p-p38 and p-JNK. Paeoniflorin mimicked ASK1 inhibitor NQDI1 and inhibited ASK1 phosphorylation. Paeoniflorin decreased the expression of p-p38 and p-JNK, delayed the progress of neuropathic pain, and attenuated neuropathic pain. Paeoniflorin reduced the response of astrocytes and microglia to injury, decreased the expression of IL-1ß and TNF-α, and downregulated the expression of CGRP induced by CCI. CONCLUSIONS: Paeoniflorin is an effective drug for the treatment of neuropathic pain in rats via inhibiting the phosphorylation of ASK1, suggesting it may be effective in patients with neuropathic pain.

A DNA arithmetic logic unit for implementing data backtracking operations.

We present the application of redundant modules in the molecular cascade circuit, which can help trace the results of each logic gate. This provides a basis for finding the error position and judging the final circuit result to improve the circuit and the reliability of the system.

Penochalasin K, a new unusual chaetoglobosin from the mangrove endophytic fungus Penicillium chrysogenum V11 and its effective semi-synthesis.

A new chaetoglobosin, penochalasin K (1) bearing an unusual six-cyclic 6/5/6/5/6/13 fused ring system, along with the known analogues, chaetoglobosin C (2), penochalasin I (3), and chaetoglobosin A (4) were isolated from the solid culture of the mangrove endophytic fungus Penicillium chrysogenum V11. Their structures were elucidated by 1D, 2D NMR spectroscopic analysis and high resolution mass spectroscopic data. The absolute configuration of compound 1 was determined by comparing the theoretical and experimental electronic circular dichroism curves. Compound 1 displayed significant inhibitory activities against Colletotrichum gloeosporioides and Rhizoctonia solani (MICs=6.13, 12.26µM, respectively), which was better than those of carbendazim, and exhibited potent cytotoxicity against MDA-MB-435, SGC-7901 and A549 cells (IC50<10µM). An effective biomimetic transformation of chaetoglobosin C (2)/chaetoglobosin A (4) into penochalasin K (1)/penochalasin I (3) was developed, which provided a simple method for the semi-synthesis of chaetoglobosins with a six-cyclic 6/5/6/5/6/13 fused system formed by the connectivity of C-5 and C-2' from their corresponding epoxide analogues.

Astragaloside IV attenuates free fatty acid-induced ER stress and lipid accumulation in hepatocytes via AMPK activation.

Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) is not completely understood, the increased influx of free fatty acids (FFAs) into the liver and the FFA-induced hepatic endoplasmic reticulum (ER) stress are two crucial pathogenic processes in the initiation and development of NAFLD. In this study we investigated the effects of astragaloside IV (AS-IV), a bioactive compound purified from Astragali Radix, on FFA-induced lipid accumulation in hepatocytes and elucidated the underlying mechanisms. Human HepG2 cells and primary murine hepatocytes were exposed to FFAs (1 mmol/L, oleate/palmitate, 2:1 ratio) with or without AS-IV for 24 h. Exposure to FFAs induced marked lipid accumulation in hepatocytes, whereas co-treatment with AS-IV (100 µg/mL) significantly attenuated this phenomenon. Notably, AS-IV (50-200 µg/mL) concentration-dependently enhanced the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and SREBP-1c, inhibited the accumulation and nuclear translocation of mature SREBP-1 and subsequently decreased the mRNA levels of lipogenic genes including acc1, fas and scd1. AS-IV treatment also concentration-dependently attenuated FFA-induced hepatic ER stress evidenced by the reduction of the key markers, GRP78, CHOP and p-PERK. Pretreated the cells with the AMPK inhibitor compound C (20 µmol/L) greatly diminished these beneficial effects of AS-IV. Our results demonstrate that AS-IV attenuates FFA-induced ER stress and lipid accumulation in an AMPK-dependent manner in hepatocytes, which supports its use as promising therapeutics for hepatic steatosis.

Expression of prostaglandin E2 and EP receptors in human papillary thyroid carcinoma.

The objective of the present study is to determine the role of prostaglandin E2 (PGE2) and downstream EP receptors in the development of human papillary thyroid carcinoma (PTC). A total of 90 thyroid specimens excised from patients undergoing total or subtotal thyroidectomy in the Department of General Surgery, the Fifth Affiliated Hospital of Sun Yat-sen University, China, from August 2013 to September 2014, were analyzed. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical analyses were employed to examine the messenger RNA (mRNA) and protein expression, respectively. The expressions and significances of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), PGE2, and EP receptors in PTC and nodular goiter were investigated. The COX-2 mRNA and protein expression level significantly increased in the PTC tissues than in the paired noncarcinoma tissues adjacent to the PTC or nodular goiter tissues. The mPGES-1 protein expression was also significantly upregulated in the PTC tissues. All the four subtypes of EP receptors (EP1-4) could express in the thyroid tissues, while only the EP4 mRNA and protein levels significantly increased in the PTC tissues. The local production of PGE2 had a higher-level expression in the PTC tissues than in the noncarcinoma thyroid tissues adjacent to the PTC lesion and the benign nodular goiter tissues. The induction of PGE2 biosynthesis as well as the overexpression of EP4 in PTC suggested that this pathway might play an important role in the carcinogenesis and progression of PTC. These observations raise the possibility that pharmacological inhibition of mPGES-1 and/or EP4 may hold therapeutic promise in this common cancer.

Correlation of apolipoprotein A-I kinetics with survival and response to first-line platinum-based chemotherapy in advanced non-small cell lung cancer.

The aim of this study was to determine whether apolipoprotein A-I (ApoA-I) kinetics predict the overall survival in patients with advanced-stage non-small cell lung cancer (NSCLC) during platinum-based first-line therapy. A total of 125 NSCLC patients from January 2008 to September 2014 were retrospectively reviewed. Serum ApoA-I level was measured at baseline and thereafter at the start of each palliative chemotherapy cycle for all patients. Patients were divided into four groups according to ApoA-I kinetics. Patients whose ApoA-I ≥ 1.01 g/L and never decreased during treatment, patients whose ApoA-I ≥ 1.01 g/L and decreased (ApoA-I < 1.01 g/L) at least one time during treatment, patients whose ApoA-I < 1.01 g/L and normalized (ApoA-I ≥ 1.01) at least one time during treatment, and patients whose ApoA-I < 1.01 g/L and never normalized during treatment were assigned to non-decreased, decreased, normalized, and non-normalized ApoA-I groups, respectively. Overall survival rates were significantly different between the four groups, with 2-year survival rates of 88.6 and 17.5 % for the non-decreased and the decreased ApoA-I groups, respectively, and none survived 2 years later in the normalized and the non-normalized ApoA-I groups. When compared with the non-decreased group, the hazard ratios of death were 0.05, 0.44, and 1.73 in the normalized, decreased, and non-normalized groups, respectively (P < 0.001). Normalization of ApoA-I was associated with a low risk of progression, whereas patients with a decreased level of ApoA-I showed a progression of disease in most cases. ApoA-I can be a novel, widely available biomarker for patients with NSCLC.