Application of cefuroxime in the eradication therapy of Helicobacter pylori infection: A review article.

BACKGROUND: Helicobacter pylori infection and its associated diseases represent a significant global health concern. Patients who cannot use amoxicillin pose a therapeutic challenge and necessitate alternative medications. Preliminary research indicates that cefuroxime demonstrates promising potential for eradicating H. pylori infection, and there is a lack of comprehensive review articles on the use of cefuroxime. MATERIALS AND METHODS: This study conducts a thorough systematic literature review and synthesis. A comprehensive systematic search was conducted in PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure, China Biology Medicine disc, and Wanfang Data up to January 13, 2024. The search strategy utilized the following keywords: (Cefuroxime) AND (Helicobacter pylori OR Helicobacter nemestrinae OR Campylobacter pylori OR Campylobacter pylori subsp. pylori OR Campylobacter pyloridis OR H. pylori OR Hp) for both English and Chinese language publications. Sixteen studies from five different countries or regions were included in final literature review. RESULTS: Analysis results indicate that H. pylori is sensitive to cefuroxime, with resistance rates similar to amoxicillin being relatively low. Regimens containing cefuroxime have shown favorable eradication rates, which were comparable to those of the regimens containing amoxicillin. Regarding safety, the incidence of adverse reactions in cefuroxime-containing eradication regimens was comparable to that of amoxicillin-containing regimens or other bismuth quadruple regimens, with no significant increase in allergic reactions in penicillin-allergic patients. Regarding compliance, studies consistently report high compliance rates for regimens containing cefuroxime. CONCLUSION: Cefuroxime can serve as an alternative to amoxicillin for the patients allergic to penicillin with satisfactory efficacies, safety, and compliance.

Individualized diagnosis and eradication therapy for Helicobacter pylori infection based on gene detection of clarithromycin resistance in stool specimens: A systematic review and meta-analysis.

BACKGROUND: Empiric therapy for Helicobacter pylori infection results in significantly increased antibiotic resistance and decreased eradication efficacy. The genotypic testing of clarithromycin resistance from stool specimens is a promising method for individualized diagnosis and treatment. This study aimed to determine the status of research and application on this method through a systematic review and meta-analysis. METHODS: PubMed, Embase, MEDLINE, and WAN FANG database were searched for relevant literature. The quality of included diagnostic articles was evaluated using the quality Assessment of Diagnostic Accuracy Studies-2 tool. A bivariate random-effect model was conducted to calculate the diagnostic accuracy of genotypic testing of clarithromycin resistance. RESULTS: A total of 16 diagnostic-related were included and analyzed after exclusions. The pooled sensitivity and specificity of diagnostic meta-analysis were 0.93 (95% confidence interval [CI]: 0.90-0.96) and 0.98 (95% CI: 0.93-1.00), respectively. The area under the curve (AUC) of the summary receiver operating characteristic was 0.97 (95% CI: 0.95-0.98). The genotypic testing in stool samples had heterogeneous sensitivity (Q = 37.82, p < .01, I2  = 37.82) and specificity (Q = 60.34, p < .01, I2  = 93.72) in detecting clarithromycin resistance. Purification method, stool sample weight, real-time PCR, and antimicrobial susceptibility testing as reference accounted for the heterogeneity of pooled sensitivity, while patient age, purification method, stool sample weight, and real-time PCR for the heterogeneity of pooled specificity. CONCLUSION: The genotypic testing of clarithromycin resistance from stool specimens is an accurate, convenient, noninvasive, and rapid detection technology, providing a definitive diagnosis of clarithromycin resistance and guiding the rational antibiotic selection.

New regimens as first-line eradication therapy for Helicobacter pylori infection in patients allergic to penicillin: A randomized controlled trial.

BACKGROUND: Helicobacter pylori eradication in penicillin-allergic patients is challenging. The effective regimen is lacking in areas with high antibiotic resistance and tetracycline unavailable. Minocycline, cefuroxime, and full-dose metronidazole are promising drugs. AIMS: To compare the eradication rate, safety, and compliance among three new bismuth quadruple therapies for first-line H. pylori eradication in penicillin-allergic patients. METHODS: This randomized trial was conducted on 450 naive patients with H. pylori infection and penicillin allergy. The 14-day minocycline-metronidazole-containing (minocycline 100 mg twice daily and metronidazole 400 mg four times/day), minocycline-cefuroxime-containing (minocycline 100 mg twice daily and cefuroxime 500 mg twice daily), and cefuroxime-metronidazole-containing (cefuroxime 500 mg twice daily and metronidazole 400 mg four times/day) bismuth quadruple therapies were randomly assigned to the participants. Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed 4-8 weeks after eradication to evaluate outcome. RESULTS: The differences of eradication rates in either intention-to-treat (84.0%, 82.7%, and 23 82.0%, p = .896) or per-protocol (91.7%, 90.9%, and 88.2%, p = .599) analysis among minocycline-metronidazole, minocycline-cefuroxime, and cefuroxime-metronidazole-containing bismuth quadruple therapies were statistically insignificant. The incidence of adverse events (35.1%, 22.6%, and 28.9%) and compliance (90.5%, 91.8%, and 91.9%) were similar. Taste distortion, nausea, and anorexia were more common in metronidazole-containing regimens, and dizziness was more common in minocycline-containing regimens. The allergy was rare (~3%). CONCLUSIONS: The efficacies of three bismuth quadruple therapies containing minocycline, cefuroxime, and full-dose metronidazole (pairwise) for first-line H. pylori eradication in penicillin-allergic patients were similarly satisfactory with relatively good safety and compliance. The study was registered in the Chinese Clinical Trials Registration (ChiCTR1900023702).

Bismuth, esomeprazole, metronidazole and amoxicillin or tetracycline as a first-line regimen for Helicobacter pylori eradication: A randomized controlled trial.

BACKGROUND: Due to general unavailability and common side effects of tetracycline, the clinical application of bismuth quadruple therapy (BQT) is greatly limited. Whether amoxicillin can replace tetracycline in BQT remains unknown. This study aimed to compare the eradication rate, safety and compliance between amoxicillin-containing and tetracycline-containing BQT as a first-line regimen for Helicobacter pylori eradication. METHODS: This randomized trial was conducted on 404 naïve patients for H. pylori eradication. The participants were randomly assigned to 14-day amoxicillin-containing (bismuth potassium citrate 110 mg four times/day, esomeprazole 20 mg twice daily, metronidazole 400 mg four times/day and amoxicillin 500 mg four times/day) and tetracycline-containing (tetracycline 500 mg four times/day and the other three drugs used as above) BQT. Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed 4-8 weeks after eradication to evaluate outcome. RESULTS: As for the eradication rates of amoxicillin-containing and tetracycline-containing BQT, the results of both intention-to-treat and per-protocol analyses showed that the difference rate of the lower limit of 95% confidence interval was above -10.0% (intention-to-treat analysis: 81.7% vs. 83.2%, with a rate difference of -1.5% [-6.3% to 9.3%]; per-protocol analysis: 89.0% vs. 91.6%, -2.6% [-4.1% to 9.3%]). The incidence of adverse events in amoxicillin-containing BQT was significantly lower than tetracycline-containing BQT (29.5% vs. 39.7%). Both groups achieved relatively good compliance (92.0% vs. 89.9%). CONCLUSION: The eradication efficacy of amoxicillin-containing BQT was non-inferior to tetracycline-containing BQT as a first-line regimen for H. pylori eradication with better safety and similar compliance.

Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer.

EGFR-TKI targeted therapy is one of the most effective treatments for lung cancer patients harboring EGFR activating mutations. However, inhibition response is easily attenuated by drug resistance, which is mainly due to bypass activation or downstream activation. Herein, we established osimertinib-resistant cells by stepwise dose-escalation in vitro and an osimertinib-resistant patient-derived xenograft model through persistent treatment in vivo. Phosphorylated proteomics identified that MEK1 and AKT1/2 were abnormally activated in resistant cells compared with parental cells. Likewise, EGFR inhibition by osimertinib induced activation of MEK1 and AKT1/2, which weakened osimertinib sensitivity in NSCLC cells. Consequently, this study aimed to identify a novel inhibitor which could suppress resistant cell growth by dual targeting of MEK1 and AKT1/2. Based on computational screening, we identified that costunolide could interact with MEK1 and AKT1/2. Further exploration using in vitro kinase assays validated that costunolide inhibited the kinase activity of MEK1 and AKT1/2, which restrained downstream ERK-RSK2 and GSK3ß signal transduction and significantly induced cell apoptosis. Remarkably, the combination of osimertinib and costunolide showed synergistic or additive inhibitory effects on tumor growth in osimertinib-resistant cell lines and PDX model. Hence, this study highlights a potential therapeutic strategy for osimertinib-resistant patients through targeting of MEK1 and AKT1/2 by costunolide.

Manure application: A trigger for vertical accumulation of antibiotic resistance genes in cropland soils.

The application of livestock manure increases the dissemination risk of antibiotic resistance genes (ARGs) in farmland soil environment. However, the vertical migration behavior and driving factor of ARGs in manured soil under swine manure application remains undefined. Here, the dynamics of ARGs, mobile genetic elements (MGEs) and bacterial communities in different soil depths (0 - 80 cm) with long-term swine manure application were tracked and conducted using real-time qPCR. Results showed that long-term application of swine manure remarkably facilitated the vertical accumulation of ARGs and MGEs, in particular that the relative abundance of blaampC showed significant enrichment with increasing depth. ARGs abundance was similar in the three fields with long-term application of swine manure. (p＞0.05). Procrustes analysis indicated that microbial communities were the dominant drivers of ARGs variation in topsoil, and the changes of environmental factors played a vital role in vertical migration ARGs in cropland soils. Additionally, the variation patterns of high-risk ARGs (i.e., blaampC, blaTEM-1) were influenced by the dominant bacteria (Actinomycetes) and pH. This study illustrated that the swine manure application promoted the vertical migration of ARGs, including multidrug resistance determinants, highlighting the ecological risk caused by long-term manure application.

An unexpected second binding site for polypeptide substrates is essential for Hsp70 chaperone activity.

Heat shock proteins of 70 kDa (Hsp70s) are ubiquitous and highly conserved molecular chaperones. They play multiple essential roles in assisting with protein folding and maintaining protein homeostasis. Their chaperone activity has been proposed to require several rounds of binding to and release of polypeptide substrates at the substrate-binding domain (SBD) of Hsp70s. All available structures have revealed a single substrate-binding site in the SBD that binds a single segment of an extended polypeptide of 3-4 residues. However, this well-established single peptide-binding site alone has made it difficult to explain the efficient chaperone activity of Hsp70s. In this study, using purified proteins and site-directed mutagenesis, along with fluorescence polarization and luciferase-refolding assays, we report the unexpected discovery of a second peptide-binding site in Hsp70s. More importantly, the biochemical analyses suggested that this novel binding site, named here P2, is essential for Hsp70 chaperone activity. Furthermore, cross-linking and mutagenesis studies indicated that this second binding site is in the SBD adjacent to the first binding site. Taken together, our results suggest that these two essential binding sites of Hsp70s cooperate in protein folding.

PPI-amoxicillin dual therapy four times daily is superior to guidelines recommended regimens in the Helicobacter pylori eradication therapy within Asia: A systematic review and meta-analysis.

BACKGROUND: Systematic reviews suggested that the eradication efficacy of PPI-amoxicillin dual therapy is similar to that of other commonly used regimens. However, it might be affected by the medication frequency. Basic and clinical studies have shown that dual therapy administered four-times daily has a reliable pathophysiological basis and could achieve satisfactory efficacy. Therefore, a systematic review of RCTs of dual therapy and other regimens was conducted to clarify whether dual therapy is superior to guidelines recommended regimens. MATERIALS AND METHODS: The RCTs comparing dual therapy with other regimens were subjected to meta-analysis to evaluate the eradication rate, adverse reactions, and compliance using a random-effects model. RESULTS: Dual therapy administered four-times daily had a higher eradication rate than other regimens (intention-to-treat analysis: 89.7% vs 84.6%, OR: 1.52, 95%CI 1.08-2.14, p = 0.02; per-protocol analysis: 92.6% vs 88.2%, OR: 1.54, 95%CI 1.01-2.34, p = 0.04). In first-line therapy, according to intention-to-treat analysis, the eradication rate of dual therapy was higher than other regimens (89.8% vs 84.2%, OR: 1.63, 95%CI 1.02-2.61, p = 0.04). In per-protocol analysis, dual therapy showed better efficacy than others (92.9% vs 88.3%, OR: 1.68, 95% CI 0.98-2.89, p = 0.06), but not significantly. In salvage treatment, no significant difference was detected. The safety of dual therapy was significantly better than other regimens (19.6% vs 36.7%, p < 0.01), but no difference was observed in compliance (p = 0.58). CONCLUSION: PPI-amoxicillin dual therapy administered four-times daily has better efficacy and safety in H. pylori eradication than current guidelines recommended regimens, especially in first-line therapy, and mainly in Asia.

EPRS/GluRS promotes gastric cancer development via WNT/GSK-3ß/ß-catenin signaling pathway.

BACKGROUND: Glutamyl-prolyl-tRNA synthetase (EPRS/GluRS) is primarily part of the multi-synthetase complex that may play a key role in cancer development. However, the biological function, molecular mechanism, and inhibitor of EPRS have not been investigated in gastric cancer (GC). METHODS: Immunohistochemistry was performed to detect the expression of EPRS in human gastric tumor tissues. Knocking down of EPRS, cell-derived xenograft mouse model, and patient-derived xenograft mouse model was used to identify the biological function of EPRS. Immunoprecipitation was applied to elucidate the interaction between EPRS and SCYL2. Computer docking model and multiple in vitro and in vivo experiments were conducted to discover EPRS inhibitors. RESULTS: Here, we report that EPRS is frequently overexpressed in GC tissues compared to that adjacent controls and its overexpression predicts poor prognosis in GC patients. Functionally, high expression of EPRS positively co-relates with GC development both in vitro and in vivo. Mechanistically, EPRS directly binds with SCYL2 to enhance the activation of WNT/GSK-3ß/ß-catenin signaling pathway and the accumulation of ß-catenin in the nuclear, leading to GC cell proliferation and tumor growth. Moreover, we identified that xanthoangelol (XA) and 4-hydroxyderricin (4-HD) can directly bind to EPRS to block WNT/GSK-3ß/ß-catenin signaling pathway. More importantly, XA and 4-HD restrain gastric cancer patient-derived xenograft tumor growth and Helicobacter pylori combined with alcohol-induced atrophic gastritis and gastric tumorigenesis. CONCLUSION: These findings unveil a promising strategy for GC prevention and therapy by targeting EPRS-mediated WNT/GSK-3ß/ß-catenin cascades. Moreover, XA and 4-HD may be effective reagents used for GC prevention and therapy.

Tracking antibiotic resistance gene transfer at all seasons from swine waste to receiving environments.

Antibiotic resistance genes (ARGs) in livestock farms have attracted a growing attention with potential effects on human health. As one of the most important organic fertilizer, swine waste provided an ideal environment for understanding the dissemination and accumulation of ARGs in agricultural ecosystems. Here we conducted a year-round follow-up trace from swine waste to receiving environments, with the purpose of revealing the contamination profiles and ecological risks of ARGs at different seasons. Results indicated that a variety of common ARGs and even high-risk ARGs (i.e., blaampC, blaOXA-1, blaTEM-1 and mcr-1) were prevalent from swine waste to farmland soil, with changing in various degrees from season to season. Regarding the occurrence pattern of ARGs, tetracycline resistance genes (tet-ARGs) were predominant genes at four seasons in all fresh pig feces, swine manure, manured soil and wastewater. The levels of most ARGs in solid waste were reduced at a different degree via natural composting, and the removal effect was best in summer, while ARGs decreased poorly after wastewater treatment, especially in winter (up to 10-1 copies/16S copies in the residual level), which increased the possibility of propagation to receiving environment. This concern was also validated by the investigation on farmland environment with long-term application of manure, where causing an increase in ARG abundances in soils (approximately 0.9-32.7 times). To our knowledge, this study is the first to demonstrate the distribution pattern of ARGs from swine waste to its receiving farmland environment at all seasons on this integrity chain.

Tracking antibiotic resistance genes (ARGs) during earthworm conversion of cow dung in northern China.

Using cow dung to breed earthworms poses a risk of environmental transmission of antibiotic resistance genes (ARGs). The purpose of this study was to address the occurrence, persistence and environmental fate of ARGs during earthworm conversion of cow dung. The results showed that ARGs persisted through the whole process. Notably, earthworm conversion effectively reduced some ARGs in cow dung, but a definite concentration of ARGs still remained in earthworms and vermicompost (up to 10-1 and 10-2 copies/16S copies, respectively). We found that tet-ARGs were the most abundant in 15 earthworm farms (10-6~10-1 copies/16S copies) and some high-risk ARGs (i.e., blaampC, blaOXA-1 and blaTEM-1) were even prevalent in these farms. Interestingly, although ARGs differ widely in cow dung (10-10~10-1 copies/16S copies), the ARGs levels were comparable in vermicompost samples from different farms (10-8~10-2 copies/16S copies). Notably, earthworm conversion effectively reduced some ARGs in cow dung, but significant level of ARGs still remained in earthworms and vermicompost (up to 10-1 and 10-2 copies/16S copies, respectively). Nevertheless, the concentrations of some heavy metals (Cu, Zn and Ni), the abundance of mobile genetic elements (MGEs) and total nitrogen content were confirmed to be correlated to the enrichment of some ARGs. Overall, this study demonstrated the high prevalence of ARGs contamination in earthworm farms, and also highlighted the dissemination risk of ARGs during the earthworm conversion of cow dung.

Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation.

Pharmaceutical interest in targeting mitochondria is increasing because of their contribution in incurable diseases. However, the inner mitochondrial layer represents a major hurdle to overcome for most drugs. Penetrating peptides are a promising strategy for drug delivery, but the absence of standard principles and reliable prediction tools limits the design and discovery of sequences with improved organelle specificity. In our hypothesis, peptide local flexibility represents a valuable source to predict peptide performance. Here, a pool of short nonnatural peptides was designed with the same amino acid content but different positioning. Molecular dynamics and membrane-transfer simulations were used to generate the low-energy conformers in extra, intracellular, and membrane-inserted environments. The contributions of the hydrophobic and hydrophilic side chain-exposed surfaces revealed that the amino acid's relative position significantly affected the simulated peptide's dynamics. Based on the structural versatility, we predicted the peptides' behavior and the sequence with the most efficient membrane penetration and mitochondrial localization. The prediction and the improved performance of our peptides were experimentally confirmed and compared with a reported mitochondrial-targeting sequence. We demonstrated that an accurate understanding of the structural versatility is a valid aid for future works in designing sequences with improved mitochondrial targeting.-Pirisinu, M., Blasco, P., Tian, X., Sen, Y., Bode, A. M., Liu, K., Dong, Z. Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation.

A comparative study of 14-day dual therapy (esomeprazole and amoxicillin four times daily) and triple plus bismuth therapy for first-line Helicobacter pylori infection eradication: A randomized trial.

BACKGROUND: Favorable outcomes in treating H pylori infection using "dual therapy (proton pump inhibitor and amoxicillin four times daily)" have attracted widespread attention. However, there are few reports, and the study results lack agreement. This study aimed to compare the eradication rate, safety, and compliance of naïve-treatment patients with H pylori infection on "dual therapy" with those on "triple plus bismuth (TPB) therapy." METHODS: This is a non-inferior randomized controlled trial conducted on 760 patients with H pylori infection. The participants were randomly assigned to two eradication groups: dual therapy (esomeprazole 20 mg and amoxicillin 750 mg four times daily) and TPB therapy (esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg twice daily) for 14 days. Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed about 8 weeks after eradication to evaluate outcome. Antibiotic resistance and CYP2C19 polymorphism were determined. RESULTS: Compared with TPB therapy, dual therapy had significantly higher eradication rates in intention-to-treat (87.1% vs 80.5%, rate difference 6.6%), modified intention-to-treat (90.9% vs 85.5%, 5.5%) and per-protocol (92.4% vs 87.8%, 4.7%) analyses, respectively. Adverse reactions in dual therapy group were significantly lower than TPB therapy group (17.6% vs 25.5%, P = .008), and dual therapy group had better compliance (96.3% vs 92.3%, P = .019). Antibiotic resistance and poor compliance were also associated with treatment failure. CONCLUSIONS: Dual therapy (esomeprazole and amoxicillin four times daily) was non-inferior to, and even superior to TPB therapy as first-line H pylori eradication.

Family livestock waste: An ignored pollutant resource of antibiotic resistance genes.

The random discharge of livestock waste from family farms without utilization and treatment has caused great pressure on the rural ecological environment and gravely increased the environmental pollution. In this study, we targeted 26 family livestock farms to assess the occurrence characteristics of antibiotic resistance genes (ARGs) in livestock waste and its receiving farmland environment in Erhai Lake basin of China by real-time fluorescence quantitative PCR. The results showed that various common ARGs and some high-risk ARGs (i.e., blaampC, blaOXA-1 and blaTEM-1) were prevalent in family livestock waste, and the pollution of tetracycline resistance genes was the most serious in these family livestock farms. Meanwhile, we also found that the ARG levels were higher in family chicken farms than that in pig and cattle farms, and ARGs pollution in layer waste and sow waste was more severe than that in broiler waste and piglet/fattening pig waste, respectively. Troublesomely, significant ARGs levels could be discharged via manure application, further causing the increase of ARGs abundance in soil environment (approximately 11-36 times). This study demonstrated the high prevalence and severity of ARGs contamination in family livestock farms, also emphasizing that family livestock waste was a non-ignored important pollutant resource of ARGs in the environment.

Randomized Clinical Trial: Esomeprazole, Bismuth, Levofloxacin, and Amoxicillin or Cefuroxime as First-Line Eradication Regimens for Helicobacter pylori Infection.

BACKGROUND: The eradication of Helicobacter pylori infection remains a challenge, especially in the patients unsuitable to take penicillin. Cephalosporin has the potential to replace amoxicillin for H. pylori eradication. AIMS: To compare the effectiveness, safety, and compliance of amoxicillin- and cefuroxime-containing quadruple regimens in treatment-naïve patients. METHODS: In this open-label randomized control study, 400 patients with H. pylori infection were divided into amoxicillin-containing (esomeprazole 20 mg twice/day, amoxicillin 1000 mg twice/day, levofloxacin 500 mg once/day, and bismuth 220 mg twice/day for 14 days) or cefuroxime-containing (esomeprazole 20 mg twice/day, cefuroxime 500 mg twice/day, levofloxacin 500 mg once/day, and bismuth 220 mg twice/day for 14 days) quadruple therapy groups. The safety and compliance were assessed 1-3 days after eradication. Urea breath test was performed 8-12 weeks after eradication to determine treatment outcome. RESULTS: The baseline data including antibiotic resistance were well matched between the two groups. The eradication rates between amoxicillin- and cefuroxime-containing quadruple therapy groups were not significantly different [intention-to-treat analysis: 83.5% (95% confidence interval 78.3-88.7%) vs. 81.0% (75.5-86.5%), P = 0.513; modified intention-to-treat analysis: 90.3% (86.0-94.6%) vs. 88.5% (83.9-93.2%), P = 0.586; per-protocol analysis: 91.6% (87.5-95.7%) vs. 89.8% (85.3-94.3%), P = 0.560]. The incidence of adverse effects (18.4 vs. 20.1%, P = 0.678) and compliance (94.7 vs. 94.2%, P = 0.813) were also similar. Variate analyses showed that antibiotic resistance and poor compliance were the independent risk factors for eradication failure. CONCLUSIONS: Esomeprazole, bismuth, levofloxacin, and amoxicillin or cefuroxime achieved similar and relatively satisfactory cure rates, safety, and compliance in first-line H. pylori eradication. Cefuroxime may be a good alternative medicine for eradication instead of amoxicillin for the patients unsuitable to take penicillin.

A functional DnaK dimer is essential for the efficient interaction with Hsp40 heat shock protein.

Highly conserved molecular chaperone Hsp70 heat shock proteins play a key role in maintaining protein homeostasis (proteostasis). DnaK, a major Hsp70 in Escherichia coli, has been widely used as a paradigm for studying Hsp70s. In the absence of ATP, purified DnaK forms low-ordered oligomer, whereas ATP binding shifts the equilibrium toward the monomer. Recently, we solved the crystal structure of DnaK in complex with ATP. There are two molecules of DnaK-ATP in the asymmetric unit. Interestingly, the interfaces between the two molecules of DnaK are large with good surface complementarity, suggesting functional importance of this crystallographic dimer. Biochemical analyses of DnaK protein supported the formation of dimer in solution. Furthermore, our cross-linking experiment based on the DnaK-ATP structure confirmed that DnaK forms specific dimer in an ATP-dependent manner. To understand the physiological function of the dimer, we mutated five residues on the dimer interface. Four mutations, R56A, T301A, N537A, and D540A, resulted in loss of chaperone activity and compromised the formation of dimer, indicating the functional importance of the dimer. Surprisingly, neither the intrinsic biochemical activities, the ATP-induced allosteric coupling, nor GrpE co-chaperone interaction is affected appreciably in all of the mutations except for R56A. Unexpectedly, the interaction with co-chaperone Hsp40 is significantly compromised. In summary, this study suggests that DnaK forms a transient dimer upon ATP binding, and this dimer is essential for the efficient interaction of DnaK with Hsp40.

Improving therapeutic outcomes in heart failure with reduced nonvalvular ejection fraction: A clinical study of heart failure education intervention.

OBJECTIVE: The current study delves into the impact of heart failure education intervention on improving therapeutic outcomes for heart failure (HF) patients with reduced nonvalvular ejection fraction. METHODS: There involved a total of 60 HF patients with non-valvular ejection fraction reduction who met the inclusion requirements. Patients enrolled were randomly distributed into an observation group and a control group. The observation group received heart failure education intervention, while the control group received conventional intervention. The therapeutic effect, changes in physical indicators, cardiac function indicators, coagulation function, self-management scale scores, and the incidence of adverse cardiovascular events were meticulously evaluated. RESULTS: The total effective proportion in the observation group was 96.67%, which was significantly higher than the control group's proportion of 76.67% (p < .05). After treatment, several parameters in the observation group showed significant improvements compared to the control group: hs-CRP, IL-6, LVEDV value, LVESV value, PT value, APTT value, and TT value were all evidently lower in the observation group. Additionally, the cardiac index, LVEF value, and heart failure self-management scale fraction were significantly higher in the observation group compared to the control group (p < .05). Furthermore, the incidence of adverse cardiovascular events in the observation group was only 6.67%, which was significantly lower than the control group's incidence of 20.00% (p < .05). CONCLUSION: Heart failure education intervention demonstrates effectiveness in improving the therapeutic outcomes for HF patients and reduced nonvalvular ejection fraction. Additionally, it enhances patients' self-management abilities. Given these positive results, it is highly recommended to promote and implement HF education intervention in clinical practice.

Minocycline in the eradication of Helicobacter pylori infection: A systematic review and meta-analysis.

BACKGROUND: Difficulty in obtaining tetracycline, increased adverse reactions, and relatively complicated medication methods have limited the clinical application of the classic bismuth quadruple therapy. Therefore, the search for new alternative drugs has become one of the research hotspots. In recent years, minocycline, as a semisynthetic tetracycline, has demonstrated good potential for eradicating Helicobacter pylori (H. pylori) infection, but the systematic evaluation of its role remains lacking. AIM: To explore the efficacy, safety, and compliance of minocycline in eradicating H. pylori infection. METHODS: We comprehensively retrieved the electronic databases of PubMed, Embase, Web of Science, China National Knowledge Infrastructure, SinoMed, and Wanfang database as of October 30, 2023, and finally included 22 research reports on H. pylori eradication with minocycline-containing regimens as per the inclusion and exclusion criteria. The eradication rates of H. pylori were calculated using a fixed or a random effect model, and the heterogeneity and publication bias of the studies were measured. RESULTS: The single-arm meta-analysis revealed that the minocycline-containing regimens achieved good overall H. pylori eradication rates, reaching 82.3% [95% confidence interval (CI): 79.7%-85.1%] in the intention-to-treat analysis and 90.0% (95%CI: 87.7%-92.4%) in the per-protocol analysis. The overall safety and compliance of the minocycline-containing regimens were good, demonstrating an overall incidence of adverse reactions of 36.5% (95%CI: 31.5%-42.2%). Further by traditional meta-analysis, the results showed that the minocycline-containing regimens were not statistically different from other commonly used eradication regimens in eradication rate and incidence of adverse effects. Most of the adverse reactions were mild to moderate and well-tolerated, and dizziness was relatively prominent in the minocycline-containing regimens (16%). CONCLUSION: The minocycline-containing regimens demonstrated good efficacy, safety, and compliance in H. pylori eradication. Minocycline has good potential to replace tetracycline for eradicating H. pylori infection.

Intratumoural delivery of TRAIL mRNA induces colon cancer cell apoptosis.

Novel strategies in intratumoral injection and emerging immunotherapies have heralded a new era of precise cancer treatments. The affinity of SARS-CoV-2 to ACE2 receptors, a feature which facilitates virulent human infection, is leveraged in this research. Colon cancer cells, with their high ACE2 expression, provide a potentially strategic target for using this SARS-CoV-2 feature. While the highly expression of ACE2 is observed in several cancer types, the idea of using the viral spike protein for targeting colon cancer cells offers a novel approach in cancer treatment. Intratumoral delivery of nucleic acid-based drugs is a promising alternative to overcoming the limitations of existing therapies. The increasing importance of nucleic acids in this realm, and the use of Lipid Nanoparticles (LNPs) for local delivery of nucleic acid therapeutics, are important breakthroughs. LNPs protect nucleic acid drugs from degradation and enhance cellular uptake, making them a rapidly evolving nano delivery system with high precision and adaptability. Our study leveraged a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combined with a receptor-binding domain from the SARS-CoV-2 spike protein, encapsulated in LNPs, to target colon cancer cells. Our results indicated that the TRAIL fusion-mRNA induced apoptosis in vitro and in vivo. Collectively, our findings highlight LNP-encapsulated TRAIL fusion-mRNA as a potential colon cancer therapy.

Cow manure simultaneously reshaped antibiotic and metal resistome in the earthworm gut tract by metagenomic analysis.

Earthworm conversion is an eco-friendly biological process that converts livestock waste into a benign nutrient-rich organic fertilizer. However, little is known about the impacts of earthworm-converted livestock manure on the antibiotic resistome in the earthworm gut microbiota. Herein, lab-scale vermicomposting was performed to comprehensively evaluate the shift of antibiotic resistance genes (ARGs) in the earthworm gut-feeding on cow manure (CM)-by metagenomic analysis. The effects of copper (Cu) as a food addictive were also evaluated. CM substantially enriched the antibiotic resistome in the foregut and midgut, while it decreased in the hindgut. A similar trend was observed for metal resistance genes (MRGs). Notably, Cu in the CM had little effect on composition of ARGs and MRGs in earthworm gut. The earthworm gut microbiome altered by CM was responsible for the shift of ARGs and MRGs. In wormcast, Cu (100 and 300 mg/kg) significantly increased the abundance of ARGs and MRGs. Our study provides valuable insight into the response of ARGs and MRGs to CM in earthworm gut, and underscores the need for the judicious use of heavy metals as feed additives in livestock and poultry farming.