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European Journal of Pharmacology Jun 2024The link between type 2 diabetes mellitus (T2DM) and an increased risk of breast cancer has prompted the exploration of novel therapeutic strategies targeting shared... (Review)
Review
The link between type 2 diabetes mellitus (T2DM) and an increased risk of breast cancer has prompted the exploration of novel therapeutic strategies targeting shared metabolic pathways. This review focuses on the emerging evidence surrounding the potential anti-cancer effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the context of breast cancer. Preclinical studies have demonstrated that various SGLT2 inhibitors, such as canagliflozin, dapagliflozin, ipragliflozin, and empagliflozin, can inhibit the proliferation of breast cancer cells, induce apoptosis, and modulate key cellular signaling pathways. These mechanisms include the activation of AMP-activated protein kinase (AMPK), suppression of mammalian target of rapamycin (mTOR) signaling, and regulation of lipid metabolism and inflammatory mediators. The combination of SGLT2 inhibitors with conventional treatments, including chemotherapy and radiotherapy, as well as targeted therapies like phosphoinositide 3-kinases (PI3K) inhibitors, has shown promising results in enhancing the anti-cancer efficacy and potentially reducing treatment-related toxicities. The identification of specific biomarkers or genetic signatures that predict responsiveness to SGLT2 inhibitor therapy could enable more personalized treatment selection and optimization, particularly for challenging breast cancer subtypes [e, g., triple negative breast cancer (TNBC)]. Ongoing and future clinical trials investigating the use of SGLT2 inhibitors, both as monotherapy and in combination with other agents, will be crucial in elucidating their translational potential and guiding their integration into comprehensive breast cancer care. Overall, SGLT2 inhibitors represent a novel and promising therapeutic approach with the potential to improve clinical outcomes for patients with various subtypes of breast cancer, including the aggressive and chemo-resistant TNBC.
PubMed: 38950839
DOI: 10.1016/j.ejphar.2024.176803 -
Life Sciences Jun 2024To detect the therapeutic efficacy of CelTrac1000-labeled hair follicle epidermal neural crest stem cells (EPI-NCSCs) on repairing facial nerve defects by second...
Predicting in vivo therapeutic efficacy of CelTrac1000-labeled hair follicle epidermal neural crest stem cells in models of repairing rat facial nerve defects via second near-infrared fluorescence imaging.
AIMS
To detect the therapeutic efficacy of CelTrac1000-labeled hair follicle epidermal neural crest stem cells (EPI-NCSCs) on repairing facial nerve defects by second near-infrared (NIR-II) fluorescence imaging.
MATERIALS AND METHODS
Firstly, CelTrac1000-labeled EPI-NCSCs were microinjected into the acellular nerve allografts (ANAs) to bridge a 10-mm-long gap in the buccal branch of facial nerve in adult rats. Then, Celtrac1000-labeled EPI-NCSCs were detected by NIR-II fluorescence imaging system to visualize the behavior of the transplanted cells in vivo. Additionally, the effect of the transplanted EPI-NCSCs on repairing facial nerve defect was examined.
KEY FINDINGS
Through 14 weeks of dynamic observation, the transplanted EPI-NCSCs survived in the ANAs in vivo after surgery. Meanwhile, the region of the NIR-II fluorescence signals was gradually limited to be consistent with the direction of the regenerative nerve segment. Furthermore, the results of functional and morphological analysis showed that the transplanted EPI-NCSCs could promote the recovery of facial paralysis and neural regeneration after injury.
SIGNIFICANCE
Our research provides a novel way to track the transplanted cells in preclinical studies of cell therapy for facial paralysis, and demonstrates the therapeutic potential of EPI-NCSCs combined with ANAs in bridging rat facial nerve defects.
PubMed: 38950644
DOI: 10.1016/j.lfs.2024.122869 -
Life Sciences Jun 2024Sepsis-induced acute kidney injury (S-AKI) is one of the most serious life-threatening complications of sepsis. The pathogenesis of S-AKI is complex and there is no... (Review)
Review
Sepsis-induced acute kidney injury (S-AKI) is one of the most serious life-threatening complications of sepsis. The pathogenesis of S-AKI is complex and there is no effective specific treatment. Therefore, it is crucial to choose suitable preclinical models that are highly similar to human S-AKI to study the pathogenesis and drug treatment. In this review, we summarized recent advances in the development models of S-AKI, providing reference for the reasonable selection of experimental models as basic research and drug development of S-AKI.
PubMed: 38950643
DOI: 10.1016/j.lfs.2024.122873 -
Nutrition and Cancer Jul 2024The resistance of colorectal cancer (CRC) to conventional therapeutic modalities, such as radiation therapy and chemotherapy, along with the associated side effects,... (Review)
Review
The resistance of colorectal cancer (CRC) to conventional therapeutic modalities, such as radiation therapy and chemotherapy, along with the associated side effects, significantly limits effective anticancer strategies. Numerous epigenetic investigations have unveiled that naturally occurring stilbenes can modify or reverse abnormal epigenetic alterations, particularly aberrant DNA methylation status, offering potential avenues for preventing or treating CRC. By modulating the activity of the DNA methylation machinery components, phytochemicals may influence the various stages of CRC carcinogenesis through multiple molecular mechanisms. Several epigenetic studies, especially preclinical research, have highlighted the effective DNA methylation modulatory effects of stilbenes with minimal adverse effects on organisms, particularly in combination therapies for CRC. However, the available preclinical and clinical data regarding the effects of commonly encountered stilbenes against CRC are currently limited. Therefore, additional epigenetic research is warranted to explore the preventive potential of these phytochemicals in CRC development and to validate their therapeutic application in the prevention and treatment of CRC. This review aims to provide an overview of selected bioactive stilbenes as potential chemopreventive agents for CRC with a focus on their modulatory mechanisms of action, especially in targeting alterations in DNA methylation machinery in CRC.
PubMed: 38950568
DOI: 10.1080/01635581.2024.2364391 -
PLoS Medicine Jul 2024Preclinical animal studies have suggested that myeloid cell-synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa...
BACKGROUND
Preclinical animal studies have suggested that myeloid cell-synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa inhibitor, can be used to promote tumor immunity. This study was aimed at assessing whether patients with atrial fibrillation taking direct factor Xa inhibitors have lower risk of cancer and cancer-related mortality than patients taking the direct thrombin inhibitor dabigatran.
METHODS AND FINDINGS
This nationwide population-based cohort study in Denmark included adult patients with atrial fibrillation and without a history of cancer, who started taking a factor Xa inhibitor or dabigatran between 2011 and 2015. Data on medical history, outcomes, and drug use were acquired through Danish healthcare registries. The primary outcome was any cancer. Secondary outcomes were cancer-related mortality and all-cause mortality. Outcome events were assessed during 5 years of follow-up in an intention-to-treat analysis. The propensity score-based inverse probability of treatment weighting was used to compute cumulative incidence and subdistribution hazard ratios (SHRs) and corresponding 95% confidence intervals (CIs), with death as a competing event. Propensity scores were estimated using logistic regression and including in the model sex, age group at index date, comorbidities, and use of comedications. A total of 11,742 patients with atrial fibrillation starting a factor Xa inhibitor and 11,970 patients starting dabigatran were included. Mean age was 75.2 years (standard deviation [SD] 11.2) in the factor Xa cohort and 71.7 years (SD 11.1) in the dabigatran cohort. On the basis of the propensity score-weighted models, after 5 years of follow-up, no substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (2,157/23,711; 9.11%, 95% CI [8.61%,9.63%]) and dabigatran (2,294/23,715; 9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00], P value 0.0357). We observed no difference in cancer-related mortality (factor Xa inhibitors cohort 1,028/23,711; 4.33%, 95% CI [4.02%,4.68%]. Dabigatran cohort 1,001/23,715; 4.22%, 95% CI [3.83%,4.66%]; SHR 1.03, 95% CI [0.94,1.12]), but all-cause mortality was higher in the factor Xa inhibitor cohort (factor Xa inhibitors cohort 7,416/23,711; 31.31%, 95% CI [30.37%,32.29%]. Dabigatran cohort 6,531/23,715; 27.56%, 95% CI [26.69%,28.45%]; HR 1.17, 95% CI [1.13,1.21]). The main limitations of the study were the possibility of residual confounding and the short follow-up period.
CONCLUSIONS
In this population based cohort study, factor Xa inhibitor use was not associated with an overall lower incidence of cancer or cancer-related mortality when compared to dabigatran. We did observe an increase in all-cause mortality in the factor Xa inhibitor cohort.
PubMed: 38950074
DOI: 10.1371/journal.pmed.1004400 -
Journal of Medicinal Chemistry Jul 2024Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88...
Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88 allosteric agonists all have pharmacokinetic properties that preclude their progression to the clinic, including high lipophilicity and poor brain penetration. Here, we describe our attempts to improve GPR88 agonists' drug-like properties and our analysis of the trade-offs required to successfully target GPR88's allosteric pocket. We discovered two new GPR88 agonists: One that reduced morphine-induced locomotor activity in a murine proof-of-concept study, and the atropoisomeric BI-9508, which is a brain penetrant and has improved pharmacokinetic properties and dosing that recommend it for future studies in rodents. BI-9508 still suffers from high lipophilicity, and research on this series was halted. Because of its utility as a tool compound, we now offer researchers access to BI-9508 and a negative control free of charge via Boehringer Ingelheim's open innovation portal opnMe.com.
PubMed: 38949964
DOI: 10.1021/acs.jmedchem.4c00665 -
Critical Reviews in Analytical Chemistry Jul 2024Automation in sample preparation improves accuracy, productivity, and precision in bioanalysis. Moreover, it reduces resource consumption for repetitive procedures.... (Review)
Review
Automation in sample preparation improves accuracy, productivity, and precision in bioanalysis. Moreover, it reduces resource consumption for repetitive procedures. Automated sample analysis allows uninterrupted handling of large volumes of biological samples originating from preclinical and clinical studies. Automation significantly helps in management of complex testing methods where generation of large volumes of data is required for process monitoring. Compared to traditional sample preparation processes, automated procedures reduce associated expenses and manual error, facilitate laboratory transfers, enhance data quality, and better protect the health of analysts. Automated sample preparation techniques based on robotics potentially increase the throughput of bioanalytical laboratories. Robotic liquid handler, an automated sample preparation system built on a robotic technique ensures optimal laboratory output while saving expensive solvents, manpower, and time. Nowadays, most of the traditional extraction processes are being automated using several formats of online techniques. This review covered most of the automated sample preparation techniques reported till date, which accelerated and simplified the sample preparation procedure for bioanalytical sample analysis. This article critically analyzed different developmental aspects of automated sample preparation techniques based on robotics as well as conventional sample preparation methods that are accelerated using automated technologies.
PubMed: 38949910
DOI: 10.1080/10408347.2024.2362707 -
Hematological Oncology Mar 2024Chronic lymphocytic leukemia (CLL) is the most common leukemia in western societies, recognized by clinical and molecular heterogeneity. Despite the success of targeted... (Review)
Review
Chronic lymphocytic leukemia (CLL) is the most common leukemia in western societies, recognized by clinical and molecular heterogeneity. Despite the success of targeted therapies, acquired resistance remains a challenge for relapsed and refractory CLL, as a consequence of mutations in the target or the upregulation of other survival pathways leading to the progression of the disease. Research on proteins that can trigger such pathways may define novel therapies for a successful outcome in CLL such as the receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 is a signaling receptor for Wnt5a, with an important role during embryogenesis. The aberrant expression on CLL cells and several types of tumors, is involved in cell proliferation, survival, migration as well as drug resistance. Antibody-based immunotherapies and small-molecule compounds emerged to target ROR1 in preclinical and clinical studies. Efforts have been made to identify new prognostic markers having predictive value to refine and increase the detection and management of CLL. ROR1 can be considered as an attractive target for CLL diagnosis, prognosis, and treatment. It can be clinically effective alone and/or in combination with current approved agents. In this review, we summarize the scientific achievements in targeting ROR1 for CLL diagnosis, prognosis, and treatment.
Topics: Leukemia, Lymphocytic, Chronic, B-Cell; Humans; Receptor Tyrosine Kinase-like Orphan Receptors; Prognosis; Molecular Targeted Therapy; Animals; Biomarkers, Tumor
PubMed: 38949887
DOI: 10.1002/hon.3250 -
Expert Review of Respiratory Medicine Jul 2024Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The lung damage in COPD is associated with an enhanced...
INTRODUCTION
Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The lung damage in COPD is associated with an enhanced chronic inflammatory response in the airways and lung tissue to harmful particles or gases. Early detection and treatment of COPD can help manage symptoms and slow the progression of the disease.
AREAS COVERED
Status of knowledge regarding early diagnosis, definition of pre-COPD, possible new tools for an early diagnosis, possibilities of an early treatment and the results of studies in this population is discussed. Literature search (2014-2024) was done in PubMed, EMBASE and WoS databases using the keywords COPD, early diagnosis, treatment, smoking, prevention; with additional search of literature in found articles.
EXPERT OPINION
No early case-finding programs have been proposed or validated, so we still have many patients diagnosed in the late stage of the disease. Clinically manifest COPD is characterized as typically progressive and irreversible with current therapeutic options. If we aim to reduce the mortality and morbidity from COPD we should target these steps: Prevention; Early diagnosis; Form registries of persons at risk for COPD development; Diagnose preclinical COPD; and discover new preventive therapeutic interventions.
PubMed: 38949832
DOI: 10.1080/17476348.2024.2375418 -
Clinical Oral Implants Research Jul 2024To investigate the early impact of plaque accumulation in a buccal dehiscence defect on peri-implant marginal bone resorption.
OBJECTIVE
To investigate the early impact of plaque accumulation in a buccal dehiscence defect on peri-implant marginal bone resorption.
MATERIALS AND METHODS
In six male Mongrel dogs, four dental implants were placed in the posterior maxilla on both sides (two implants per side). Based on the group allocation, each implant was randomly assigned to one of the following four groups to decide whether buccal dehiscence defect was prepared and whether silk ligation was applied at 8 weeks post-implant placement for peri-implantitis induction: UC (no defect without ligation); UD (defect without ligation); LC (no defect with ligation); and LD (defect with ligation) groups. Eight weeks after disease induction, the outcomes from radiographic and histologic analyses were statistically analyzed (p < .05).
RESULTS
Based on radiographs, the exposed area of implant threads was smallest in group UC (p < .0083). Based on histology, both the distances from the implant platform to the first bone-to-implant contact point and to the bone crest were significantly longer in the LD group (p < .0083). In the UD group, some spontaneous bone fill occurred from the base of the defect at 8 weeks after implant placement. The apical extension of inflammatory cell infiltrate was significantly more prominent in the LD and LC groups compared to the UC group (p < .0083).
CONCLUSION
Plaque accumulated on the exposed implant surface had a negative impact on maintaining the peri-implant marginal bone level, especially when there was a dehiscence defect around the implant.
PubMed: 38949573
DOI: 10.1111/clr.14324