Research progress in MCM family: Focus on the tumor treatment resistance.

Malignant tumors constitute a significant category of diseases posing a severe threat to human survival and health, thereby representing one of the most challenging and pressing issues in the field of biomedical research. Due to their malignant nature, which is characterized by a high potential for metastasis, rapid dissemination, and frequent recurrence, the prevailing approach in clinical oncology involves a comprehensive treatment strategy that combines surgery with radiotherapy, chemotherapy, targeted drug therapies, and other interventions. Treatment resistance remains a major obstacle in the comprehensive management of tumors, serving as a primary cause for the failure of integrated tumor therapies and a critical factor contributing to patient relapse and mortality. The Minichromosome Maintenance (MCM) protein family comprises functional proteins closely associated with the development of resistance in tumor therapy.The influence of MCMs manifests through various pathways, encompassing modulation of DNA replication, cell cycle regulation, and DNA damage repair mechanisms. Consequently, this leads to an enhanced tolerance of tumor cells to chemotherapy, targeted drugs, and radiation. Consequently, this review explores the specific roles of the MCM family in various cancer treatment strategies. Its objective is to enhance our comprehension of resistance mechanisms in tumor therapy, thereby presenting novel targets for clinical research aimed at overcoming resistance in cancer treatment. This bears substantial clinical relevance.

Advancing application of satellite remote sensing technologies for linking atmospheric and built environment to health.

Background: The intricate interplay between human well-being and the surrounding environment underscores contemporary discourse. Within this paradigm, comprehensive environmental monitoring holds the key to unraveling the intricate connections linking population health to environmental exposures. The advent of satellite remote sensing monitoring (SRSM) has revolutionized traditional monitoring constraints, particularly limited spatial coverage and resolution. This innovation finds profound utility in quantifying land covers and air pollution data, casting new light on epidemiological and geographical investigations. This dynamic application reveals the intricate web connecting public health, environmental pollution, and the built environment. Objective: This comprehensive review navigates the evolving trajectory of SRSM technology, casting light on its role in addressing environmental and geographic health issues. The discussion hones in on how SRSM has recently magnified our understanding of the relationship between air pollutant exposure and population health. Additionally, this discourse delves into public health challenges stemming from shifts in urban morphology. Methods: Utilizing the strategic keywords "SRSM," "air pollutant health risk," and "built environment," an exhaustive search unfolded across prestigious databases including the China National Knowledge Network (CNKI), PubMed and Web of Science. The Citespace tool further unveiled interconnections among resultant articles and research trends. Results: Synthesizing insights from a myriad of articles spanning 1988 to 2023, our findings unveil how SRMS bridges gaps in ground-based monitoring through continuous spatial observations, empowering global air quality surveillance. High-resolution SRSM advances data precision, capturing multiple built environment impact factors. Its application to epidemiological health exposure holds promise as a pioneering tool for contemporary health research. Conclusion: This review underscores SRSM's pivotal role in enriching geographic health studies, particularly in atmospheric pollution domains. The study illuminates how SRSM overcomes spatial resolution and data loss hurdles, enriching environmental monitoring tools and datasets. The path forward envisions the integration of cutting-edge remote sensing technologies, novel explorations of urban-public health associations, and an enriched assessment of built environment characteristics on public well-being.

Identification of specific and shared epitopes at the extreme N-terminal VP1 of Coxsackievirus A4, A2 and A5 by monoclonal antibodies.

Hand, foot and mouth disease (HFMD) is caused by a variety of serotypes in species A of the Enterovirus genus, including recently re-emerged Coxsackievirus A2 (CV-A2), CV-A4 and CV-A5. For development of diagnostic reagents, for surveillance, and the development of multivalent vaccines against HFMD, the antigenicity of HFMD-associated enteroviruses warrants investigation. The purified virions of CV-A4 were inoculated into Balb/c mice and hybridomas were obtained secreting monoclonal antibodies (mAbs) directed against CV-A4 and cross-reacting with other closely related species A enteroviruses. The mAbs were characterized by ELISA, Western blotting and in vitro neutralizing assays. The majority of mAbs was non-neutralizing, with only 2% of the mAbs neutralizing CV-A4 specifically. Most of mAbs bound to linear VP1 epitopes of CV-A4. Interestingly, four types of mAbs were obtained which bound specifically to CV-A4 or were broadly to CV-A4/-A2, CV-A4/-A5 and CV-A4/-A2/-A5, respectively. Mapping with overlapping or single-amino-acid mutant peptides revealed that the four types of mAbs all bound to the first 15 amino acids at the N-terminus of the VP1. This region of picornaviruses is functionally important as it is involved in uncoating and releasing of viral RNA into the cytosol. The binding footprints of four type mAbs are composed of conserved and variable residues and are different from each other. The newly discovered broadly cross-reactive mAbs reflect the high homology of CV-A4/ CV-A2/CV-A5. The results also demonstrate that it is possible and beneficial to develop the diagnostic reagents to detect rapidly the main pathogens of enteroviruses associated with HFMD cause by CV-A4/CV-A2/CV-A5.

Design, synthesis, and biological activity of 9-O-cinnamoylberberines as novel lipid-lowering agents.

Berberine possesses a wide spectrum of lipid regulation, and yet it has poor physicochemical property and cytotoxicity as a drug candidate. In order to alleviate the problems, a total of twenty-one 9-O-cinnamoylberberines and twenty 9-O-cinnamoyltetrahydroberberines were designed, synthesized, and evaluated by in vitro cell viability experiment and four classical lipid-lowering assays involving with total cholesterol, triglyceride, low density lipoprotein cholesterol, and high density lipoprotein cholesterol. A structure-activity relationship study of these compounds resulted in the discovery of two promising candidate molecules (5p and 7u). Compound 5p displayed the most potent inhibitory effect for TG formation, with the inhibitory rates of 40.5% and 76.8% in 3T3-L1 cells and HepG2 cells, respectively. Compound 7u exhibited the most promoting activity for the production of HDLC, with the increasing rates of 52.6% and 70.5% in both models, respectively. These two attractive compounds can be further investigated as new lipid-lowering agents in follow-up researches.

Compromised cerebrovascular reactivity in migraineurs with right-to-left shunts: a potential mechanism of white matter hyperintensities.

OBJECTIVE: Our study aims to explore the changes of cerebrovascular reactivity (CVR) in migraineurs with right-to-left shunts (RLS), and further evaluate the association between CVR and the occurrence of the white matter hyperintensities (WMHs). METHODS: RLS was diagnosed based on a contrast enhancement transcranial Doppler (c-TCD) examination. The breath holding index (BHI), which represents CVR, was measured from the middle cerebral artery (MCA) using a TCD with the breath-holding method. WMHs was defined as clearly hyperintense areas in 3 T magnetic resonance imaging (MRI). All migraineurs underwent a standardized questionnaire for family and personal history and detailed migraine features. RESULTS: Three hundred and ninety-seven migraineurs and 100 controls were included in our study. The BHI was significantly lower in migraineurs than controls (0.527 ± 0.709 vs. 0.674 ± 0.489, P = 0.016). Moreover, migraineurs with RLS had lower BHI than those without RLS (0.504 ± 0.671 vs. 0.674 ± 0.721, p = 0.024). Migraineurs with WMHs had lower BHI than those without (0.47 ± 0.71 vs. 0.75 ± 0.49, p = 0.035). The reduced BHI was an independent influencing factor for WMHs in our study (OR = 0.338; 95% CI = 0.142-0.806, p = 0.014). CONCLUSION: Our results indicated that BHI was reduced in migraineurs, and the reduced BHI was associated with RLS. Moreover, the reduced CVR in migraineurs with RLS might be related to the occurrence of WMHs.

Lower uric acid level may be associated with hemorrhagic transformation after intravenous thrombolysis.

BACKGROUND: Previous studies have shown that uric acid (UA) is a powerful water-soluble antioxidant and free radical scavenger for humans. However, the relationship between serum uric acid (SUA) and hemorrhagic transformation (HT) is still controversial. To address this challenge, we aimed to explore the association between serum UA and HT in patients with acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). METHODS: A retrospective analysis was conducted in patients with anterior circulation AIS who underwent IVT at Affiliated Hospital of Qingdao University from 2016 to 2021. HT was evaluated by CT or MRI within 7 days after admission. Baseline demographic, clinical, and laboratory data were compared between the HT and non-HT groups, and between different types of HT groups which were documented according to the European Cooperative Acute Stroke Study III Classification (ECASS III). RESULTS: A total of 727 AIS patients were enrolled, including 112 patients who experienced HT (HT group) and 615 patients who did not experience HT (non-HT group). Patients with HT had significantly lower UA levels compared to those without HT (253.65 ± 97.75 vs 315.97 ± 96.42, p < 0.001); however, there was no significant difference for UA levels in different types of HT (p = 0.907). After adjusting confounders, patients in the fourth UA quartile showed a significant decrease in HT compared with those in the first quartile (OR 0.266, 95% CI 0.107-0.661, p = 0.006). The best cutoff value was identified as 218.5 µmol/L after analysis. CONCLUSIONS: These findings suggest that low levels of UA may be associated with HT after IVT.

Overproduction of the Escherichia coli Chaperones GroEL-GroES in Rhodococcus ruber Improves the Activity and Stability of Cell Catalysts Harboring a Nitrile Hydratase.

Three combinations of molecular chaperones from Escherichia coli (i.e., DnaK-DnaJ-GrpEGroEL- GroES, GroEL-GroES, and DnaK-DnaJ-GrpE) were overproduced in E. coli BL21, and their in vitro stabilizing effects on a nitrile hydratase (NHase) were assessed. The optimal gene combination, E. coli groEL-groES (ecgroEL-ES), was introduced into Rhodococcus ruber TH3. A novel engineered strain, R. ruber TH3G was constructed with the native NHase gene on its chromosome and the heterologous ecgroEL-ES genes in a shuttle plasmid. In R. ruber TH3G, NHase activity was enhanced 37.3% compared with the control, TH3. The in vivo stabilizing effect of ecGroEL-ES on the NHase was assessed using both acrylamide immersion and heat shock experiments. The inactivation behavior of the in vivo NHase after immersion in a solution of dynamically increased concentrations of acrylamide was particularly evident. When the acrylamide concentration was increased to 500 g/l (50%), the remaining NHase activity in TH3G was 38%, but in TH3, activity was reduced to 10%. Reactivation of the in vivo NHases after varying degrees of inactivation was further assessed. The activity of the reactivated NHase was more than 2-fold greater in TH3G than in TH3. The hydration synthesis of acrylamide catalyzed by the in vivo NHase was performed with continuous acrylonitrile feeding. The final concentration of acrylamide was 640 g/l when catalyzed by TH3G, compared with 490 g/l acrylamide by TH3. This study is the first to show that the chaperones ecGroEL-ES work well in Rhodococcus and simultaneously possess protein-folding assistance functions and the ability to stabilize and reactivate the native NHases.