Search Results (109)

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, treats type 2 diabetes by blocking renal glucose reabsorption and promoting urinary glucose excretion. This mechanism lowers blood glucose concentrations independently of insulin. The resulting caloric loss also contributes to weight reduction. Although these effects are well documented in patients with diabetes, their magnitude and underlying mechanisms in healthy individuals remain poorly understood. Background/Objectives: We investigated metabolic alterations after a single 10 mg dose of dapagliflozin in healthy adults with normal body-mass indices (BMIs) using untargeted metabolomics. Methods: Thirteen healthy volunteers completed this study. Plasma was collected before and 24 h after dosing. Untargeted metabolic profiling was performed with ultra-high-performance liquid chromatography–quadrupole time-of-flight/mass spectrometry. Results: Twenty-five endogenous metabolites were annotated; ten were putatively identified. Eight metabolites increased significantly, whereas two decreased. Up-regulated metabolites included phosphatidylcholine (PC) species (PC O-36:5, PC 36:3), phosphatidylserine (PS) species (PS 40:2, PS 40:3, PS 36:1, PS 40:4), lysophosphatidylserine 22:1, and uridine. Dehydroepiandrosterone sulfate and bilirubin were down-regulated. According to the Human Metabolome Database, these metabolites participate in glycerophospholipid, branched-chain amino acid, pyrimidine, and steroid-hormone metabolism. Conclusions: Dapagliflozin may affect pathways related to energy metabolism and homeostasis beyond glucose regulation. These data provide a reference for future investigations into energy balance and metabolic flexibility in metabolic disorders. Full article

Background/Objectives: Vitamin D (VD) is metabolized in the body and plays a crucial role in regulating the antioxidant system. While exposure to heavy metals (HMs) inhibits VD activity, HMs can also be absorbed following VD stimulation. Despite differing views on the interaction between HM and VD activity, the effects of HM exposure on VD-related pathways have not been examined using metabolomics. This study aimed to investigate the impact of HM exposure on VD-related antioxidant activity under VD deficiency conditions using untargeted metabolic profiling. Methods: In this retrospective cohort study, 46 plasma samples were analyzed using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Metabolic profiling was performed on two groups: individuals with severe VD deficiency and low HM exposure (SVDD–LHM) and those with VD deficiency and high HM exposure (VDD–HHM). Results: As a compensatory response to oxidative stress induced by HMs, VD-related antioxidant pathways may be associated with elevated levels of antioxidants, including bilirubin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In-creases in EPA and DHA were also linked to alterations in lipid metabolism, including diacylglycerol and phosphatidylcholine levels. DHA showed an area under the curve (AUC) of 0.850 (95% CI: 0.651–0.990), suggesting that DHA could serve as a potential biomarker for VD activity in response to HM exposure. Conclusions: The identified metabolites and metabolic pathways suggest that HM exposure may stimulate VD-related antioxidant activity, even under VD-deficient conditions. Full article

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. While timely reperfusion therapies such as percutaneous coronary intervention (PCI) and thrombolysis are essential for salvaging ischemic myocardium, they can paradoxically exacerbate tissue injury through a process known as myocardial infarction reperfusion injury (MIRI). MIRI can contribute to up to 50% of the final infarct size, significantly diminishing the benefits of revascularization and leading to worsened cardiac outcomes. The pathophysiology of MIRI involves complex, interrelated mechanisms including oxidative stress, calcium overload, mitochondrial dysfunction, inflammatory responses, apoptosis, and dysregulated autophagy. Post-reperfusion recovery is further complicated by structural and functional abnormalities such as microvascular obstruction, endothelial dysfunction, and myocardial stunning. Clinically, distinguishing reperfusion injury from ischemic damage is challenging and often requires the use of sensitive biomarkers, such as cardiac troponins, alongside advanced imaging modalities. Although a range of pharmacological (e.g., antioxidants, calcium channel blockers, mitochondrial stabilizers, anti-inflammatory agents) and non-pharmacological (e.g., hypothermia, gene therapy, stem cell-based therapies) interventions have shown promise in preclinical studies, their clinical translation remains limited. This is largely due to the multifactorial and dynamic nature of MIRI. In this context, network pharmacology offers a systems-level approach to understanding the complex biological interactions involved in MIRI, facilitating the identification of multi-target therapeutic strategies. Integrating network pharmacology with omics technologies and precision medicine holds potential for advancing cardioprotective therapies. This review provides a comprehensive analysis of the molecular mechanisms underlying MIRI, examines the current clinical challenges, and explores emerging therapeutic strategies. Emphasis is placed on bridging the translational gap through validated, multi-target approaches and large-scale, multicenter clinical trials. Ultimately, this work aims to support the development of innovative and effective interventions for improving outcomes in patients with myocardial infarction. Full article

Ginnalin A (GA), a polyphenolic compound derived from amur maple trees, has been identified as a powerful scavenger of reactive oxygen species (ROS). Recognizing the pivotal role of ROS in exacerbating secondary damage during myocardial ischemia-reperfusion injury (MIRI), we fractionated GA-enriched extracts from the leaves of the amur maple tree, Acer tataricum L. subsp. ginnala (Maxim.) Wesm., using common solvents of dichloromethane (DCM) and ethyl acetate (EA). When co-administered for 30 min, the DCM- and EA-fractioned extracts effectively protected cardiomyocytes from H₂O₂-induced damage. ROS-sensitive probes indicated that treatment with ginnala extracts significantly reduced both intracellular and mitochondrial ROS levels. Instead of enhancing the activity of antioxidative enzymes, the ginnala extracts acted as natural antioxidases, directly scavenging various ROS such as superoxide, H₂O₂, hydroxyl radical, and Fe²⁺ within just 20 min. In a MIRI rat model, the in vivo administration of ginnala extracts provided significant cardioprotection by preserving viable myocardia and enhancing cardiac functions. Additionally, treatment with ginnala extracts significantly reduced cardiac fibrosis and denatured collagen. Our study suggests that the ultrafast ROS scavenging capability of ginnala extracts offers substantial heart protection during MIRI. Incorporating ginnala extracts as a pharmacological intervention during reperfusion could effectively mitigate ROS-induced cardiac injury. Full article

Service quality research has traditionally focused either on identifying Kano two-dimensional quality categories or detecting service quality deficiencies. However, integrating these perspectives remains a challenge due to the Kano model’s nonlinear characteristics and the importance-performance and gap analysis (IPGA) model’s linear approach. This study proposes the Kano-IPGA (KIPGA) model, incorporating mutual information (MI) to bridge the gap between these two models. The KIPGA model first employs moderated regression analysis to classify service attributes into Kano’s quality categories. MI is then used to calculate the relative importance (RI), while relative performance (RP) is determined using the original IPGA approach. The results are mapped into the KIPGA strategic matrix, categorizing service attributes into eight management strategies. An empirical analysis of Taiwan’s online insurance systems demonstrates the model’s effectiveness in simultaneously identifying Kano categories and prioritizing service quality improvements. The findings reveal that critical improvement and enhanced improvement regions require immediate attention. The proposed KIPGA model offers a systematic approach for service quality management, providing decision-makers with a structured framework to allocate resources effectively and enhance customer satisfaction. This study contributes to service quality research by offering an integrated model that accounts for both linear and nonlinear quality assessment perspectives. Full article

Background/Objectives: Cancer survivors require ongoing follow-up care, including regular health screening, to detect recurrence or secondary malignancies. Nonetheless, psychosocial factors may influence their participation in screening. This study aimed to investigate the associations among fear of cancer recurrence (FCR), unmet needs, and screening behavior in cancer survivors and to explore whether unmet needs mediated the relationship between FCR and health screening participation. Methods: Data from a cross-sectional pilot survey of 326 adult cancer survivors who completed primary cancer treatment in Korea were analyzed. Screening participation was defined as having undergone either a general health check-up or cancer screening within the past 2 years. Factors associated with screening behavior were identified using logistic regression analysis. Additionally, mediation analysis was conducted to examine the indirect effects of FCR on screening through unmet needs. Results: Higher income, older age, longer time since diagnosis, and fewer unmet needs were significantly associated with screening participation. FCR was not directly associated with screening but was positively associated with higher unmet needs (OR: 4.59 [95% CI: 2.66, 7.94], p < 0.001), which were negatively associated with screening (OR: 0.41 [95% CI: 0.20, 0.84], p = 0.015). The indirect effect of FCR on screening for unmet needs was statistically significant (OR: 0.25 [95% CI: 0.08, 0.85], p = 0.027). Conclusions: Unmet needs may mediate the relationship between FCR and screening behavior in cancer survivors. Addressing these needs may represent a promising strategy for improving adherence to recommended follow-up screening. Full article

Background: More and more women are following a vegan and vegetarian diet. For some, the use of a vegan diet during lactation is controversial. Purpose: The aim of the study was to comparatively analyze the concentration of selected hormones, micro- and macronutrients, vitamins, and the basic composition and antioxidant status of the milk of vegan women, compared to the milk of omnivorous women. Methods: The study included 17 breastfeeding vegan women and 27 omnivorous women. The basic composition of human milk was analyzed using the MIRIS HMATM analyzer (Uppsala, Sweden) The levels of hormones and vitamins were determined by the enzyme-linked immunosorbent method. In order to determine the antioxidant activity and micro- and macroelements, spectrophotometric methods were used. Results: The vegan group was characterized by a lower average age, lower BMI, and lower WHR index compared to the control group. The milk of vegan women showed significantly higher cortisol concentrations and lower iron, vitamin B6, and antioxidant status than the milk of omnivorous women. Conclusions: A vegan diet helps maintain a healthy body weight and is more popular among younger women, under 30 years of age. Higher levels of milk cortisol in vegan women may indicate a high level of anxiety and stress experienced by breastfeeding women, which may have negative consequences not only for breastfeeding mothers but also for the development of their children. Lack of appropriate supplementation in women who do not consume meat and animal products may cause a deficiency of micro- and macroelements in breast milk. Full article

The progression of type 2 diabetes is associated with multiple complications, one of which is diabetic nephropathy (DN). This study aimed at investigating the nephroprotective potential of two doses 150 mg/kg and 300 mg/kg of Tanacetum balsamita leaf extract (ETB) on metabolic-induced renal injury (MIRI) in rats. Markers of renal oxidative stress and antioxidant defense, histopathology, serum biochemistry, and urinalysis were measured. Blood glucose level and arterial blood pressure were assessed weekly for the experimental period of eight weeks. ETB at a high dose significantly decreased the blood glucose levels and mildly lowered systolic pressure in diabetic rats. In the kidney, ETB restored the antioxidant marker malondialdehyde, reduced glutathione, and markedly increased enzymatic activity related to GSH turnover by 46% (GPx), 22% (GR), 32% (GST), and 96% (SOD). ETB reduced elevated urea and creatinine levels and alleviated the proteinuria along with other urinalysis parameters. Histopathological examination of the kidney supported the observed protective effects. Both doses of the ETB ameliorated most of the investigated parameters similarly to positive controls enalapril and acarbose. ETB benefits on MIRI-induced damages could be associated with high levels of mono- and dicaffeoylquinic acids together with a series of methoxylated flavones and flavonols, which may hold significance for its antidiabetic and nephroprotective activity. Full article

Alzheimer’s disease (AD) is the most common form of dementia, characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to neuronal loss and cognitive impairments. Recent studies have reported the dysregulation of RNA splicing in AD pathogenesis. Our previous transcriptomic study demonstrated the neuroprotective effect of the phytocannabinoid cannabinerol (CBNR) against the cell viability loss induced by Aβ in differentiated SH-SY5Y cells. This study also highlighted the deregulation of genes involved in mRNA splicing after Aβ exposure or CBNR pre-treatment. Here, we investigated whether CBNR could restore the splicing defects induced by Aβ in an AD in vitro model. Using the rMATS computational tool for detecting differential alternative splicing events (DASEs) from RNA-Seq data, we obtained 96 DASEs regulated in both conditions and, remarkably, they were all restored by CBNR pre-treatment. The pathway analysis indicated an over-representation of the “Alzheimer’s disease–amyloid secretase pathway”. Additionally, we observed that Aβ exposure increased the frequency of retained introns (RIs) among the shared DASEs, and that this frequency returned to normality by CBNR pre-treatment. Interestingly, most of these RIs contain a premature in-frame stop codon within the RNA sequence. Finally, analyzing the DASE regions for miRNA hybridization, we found 33 potential DASE/miRNA interactions that were relevant in AD pathogenesis. These findings revealed a novel trans-gene regulation by CBNR, potentially explaining part of its neuroprotective role. This is the first study demonstrating the involvement of a cannabinoid in the regulation of mRNA splicing in an AD model. Full article

Mitochondrial homeostasis is crucial for maintaining cellular energy production and preventing oxidative stress, which is essential for overall cellular function and longevity. Mitochondrial damage and dysfunction often occur concomitantly in myocardial ischemia–reperfusion injury (MIRI). Notoginsenoside R1 (NGR1), a unique saponin from the traditional Chinese medicine Panax notoginseng, has been shown to alleviate MIRI in previous studies, though its precise mechanism remains unclear. This study aimed to elucidate the mechanisms of NGR1 in maintaining mitochondrial homeostasis in hypoxia/reoxygenation (H/R) H9c2 cells. The results showed that NGR1 pretreatment effectively increased cell survival rates post-H/R, reduced lactate dehydrogenase (LDH) leakage, and mitigated cell damage. Further investigation into mitochondria revealed that NGR1 alleviated mitochondrial structural damage, improved mitochondrial membrane permeability transition pore (mPTP) persistence, and prevented mitochondrial membrane potential (Δψm) depolarization. Additionally, NGR1 pretreatment enhanced ATP levels, increased the activity of mitochondrial respiratory chain complexes I–V after H/R, and reduced excessive mitochondrial reactive oxygen species (mitoROS) production, thereby protecting mitochondrial function. Further analysis indicated that NGR1 upregulated the expression of mitochondrial biogenesis-related proteins (PGC-1α, Nrf1, Nrf2) and mitochondrial fusion proteins (Opa1, Mfn1, Mfn2), while downregulating mitochondrial fission proteins (Fis1, Drp1) and reducing mitochondrial autophagy (mitophagy) levels, as well as the expression of mitophagy-related proteins (Pink1, Parkin, BNIP3) post-H/R. Therefore, this study showed that NGR1 can maintain mitochondrial homeostasis by regulating mitophagy, mitochondrial fission–fusion dynamics, and mitochondrial biogenesis, thereby alleviating H9c2 cell H/R injury and protecting cardiomyocytes. Full article

Programmed cell death, especially programmed necrosis such as necroptosis, ferroptosis, and pyroptosis, has attracted significant attention recently. Traditionally, necrosis was thought to occur accidentally without signaling pathways, but recent discoveries have revealed that molecular pathways regulate certain forms of necrosis, similar to apoptosis. Accumulating evidence indicates that programmed necrosis is involved in the development of various diseases, including myocardial ischemia–reperfusion injury (MIRI). MIRI occurs when blood flow and oxygen return to an ischemic area, causing excessive production of reactive oxygen species. While this reperfusion is critical for treating myocardial infarction, it inevitably causes cellular damage via oxidative stress. Furthermore, this cellular damage triggers multiple forms of cardiomyocyte death, which is the primary cause of inflammation, cardiac tissue remodeling, and ensuing heart failure. Therefore, understanding the molecular mechanisms of various forms of cell death in MIRI is crucial for therapeutic target discovery. Developing therapeutic strategies to inhibit multiple cell death pathways simultaneously could provide effective protection against MIRI. In this paper, we review the fundamental molecular pathways and MIRI-specific mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis. Additionally, we suggest that the simultaneous suppression of multiple cell death pathways could be an effective therapy and identify potential therapeutic targets for implementing this strategy. Full article

Background: Influenza remains a significant public health challenge, with vaccination being a substantial way to prevent it. Cell-cultured influenza vaccines have emerged to improve on the drawbacks of egg-based vaccines, but there are few studies focusing on T cell immunity with both types of vaccines. Therefore, we studied the following 2022–2023 seasonal influenza vaccines with a standard dose and high dose: cell-based (C_sd and C_hd) and egg-based (E_sd and E_hd) vaccines. Methods: Along with a saline control group, C_sd, C_hd, E_sd, and E_hd vaccines were administered to BALB/c mice, followed by a challenge with the A/Victoria/2570/2019 (H1N1) strain. Results: After the challenge, four out of five mice in the saline group died by day 7 post-infection (P.I.). None of the vaccinated groups experienced over 20% weight loss or any deaths. On day 7 P.I., the lung viral load in the saline group (mean log value of 4.17) was higher than that in the vaccinated groups, with the C_sd group showing the lowest viral load (mean log value of 3.47). The C_sd group showed a significantly high response in macrophage 1 (M1), IFN-γ+ T cells, and tissue-resident memory (T_RM) T cells compared with the E_sd group on day 2 P.I. These M1, IFN-γ+ T cells, and T_RM cells showed similar trends (p < 0.01). In terms of humoral immunity, only the E_hd group showed HAI titers above 40 for all four strains before and after the challenge. Conclusions: The high levels of T cells in the cell-cultured vaccines suggest, pending further real-world research, that these vaccines may offer advantages. Full article

Background: Varicella can lead to severe complications in immunocompromised children, including those undergoing hematopoietic stem cell transplantation (HSCT) or chemotherapy. Preventing primary varicella zoster virus (VZV) infection is crucial in these populations to mitigate morbidity and mortality. This study aimed to evaluate the immunogenicity and safety of the live attenuated MAV/06 varicella vaccine in pediatric patients post-HSCT and post-chemotherapy. Additionally, it sought to compare fluorescent-antibody-to-membrane-antigen (FAMA) and enzyme-linked immunosorbent assay (ELISA) titers to establish effective cut-off levels for protection against varicella. Methods: The FAMA assay was conducted at the Vaccine Bio Research Institute, and a VARICELLA-ZOSTER ELISA (Vircell, Granada, Spain) kit, which relies on lysate from whole cells infected with VZV, was used to determine VZV IgG. A prospective cohort study was conducted with 76 pediatric patients under 18 years old who tested negative for VZV IgG via ELISA. Patients post-HSCT and post-chemotherapy were included. Participants received the MAV/06 varicella vaccine, and serologic responses were evaluated using ELISA and FAMA. Results: The median age of participants was 9.8 years, with acute lymphoid leukemia and acute myeloid leukemia being the most common underlying disease. Post-dose 1, the seropositive rate was 56.1% by ELISA and 97.2% by FAMA. Based on the FAMA seropositive cut-off ≥1:4, post-dose 1 geometric mean titers (GMTs) of seropositive patients in the post-HSCT group were 14.7 (95% CI, 11.3–19.1) versus 20.2 (95% CI, 13.0–31.3) in the post-chemotherapy group (p = 0.690). Based on a FAMA seropositive cut-off ≥1:16, the post-dose 1 GMT of patients considered seropositive in the post-HSCT group was 19.3 (95% CI, 15.6–24.0) versus 34.1 (95% CI, 21.0–55.4) in the post-chemotherapy group (p = 0.116), and post-dose 2 FAMA titers of 76.1 (95% CI, 14.6–398.1) in the post-HSCT group and 64.0 (95% CI, 11.4–358.1) in the post-HSCT group (p = 0.853) were observed. In patients with lower baseline FAMA titers (1:4 to 1:8), 66.7% in the post-HSCT group and 71.5% in the post-chemotherapy group achieved a greater than four-fold increase in FAMA titers post-dose 1, while those with higher baseline titers (≥1:16) did not. There were no serious adverse events or vaccine-related rashes occurring in any of the patients. Conclusion: The MAV/06 varicella vaccine is immunogenic in pediatric patients post-HSCT and post-chemotherapy, particularly when administered in a two-dose schedule using a cut-off FAMA titer of <1:16. Full article

Pediatric patients who have undergone hematopoietic stem cell transplantation (HSCT) or chemotherapy are at increased risk for severe influenza complications, necessitating annual vaccination. This study evaluated the immunogenicity and antibody persistence of the 2021–2022 seasonal quadrivalent influenza vaccine in pediatric patients post-HSCT or chemotherapy, compared to healthy controls. A prospective cohort study included 80 pediatric participants divided into three groups: chemotherapy (n = 33), HSCT (n = 27), and healthy controls (n = 20). All participants were vaccinated with the 2021–2022 GC FLU Quadrivalent vaccine. Hemagglutination inhibition (HI) assays measured seroprotection rates (SPR), geometric mean titers (GMT), and seroconversion rates (SCR) for the four vaccine antigens (A/H1N1, A/H3N2, B/Victoria, B/Yamagata) at one, three, and six months post-vaccination. At one month post-vaccination, all groups met the 70% SPR threshold for A/H1N1 and A/H3N2, but not for B/Victoria. For B/Yamagata, the SPR was low in the chemotherapy and HSCT groups (18.18% and 33.33%, respectively), compared to 80.00% in controls (p < 0.0001 and p = 0.0015). While A/H1N1 and A/H3N2 GMTs were protective in all groups, only controls achieved protective levels for B/Yamagata. Over time, the control group maintained >70% SPR for A/H1N1 up to six months, but the chemotherapy and HSCT groups declined by three and six months, respectively. For A/H3N2, the SPR in controls dropped below 70% at three months, while it remained above 70% in the chemotherapy and HSCT groups until three months. None of the groups achieved protective GMTs for B strains at three or six months. Pediatric patients post-HSCT or chemotherapy demonstrated a comparable immune response to healthy controls for A/H1N1 and A/H3N2, but the rapid decline in A/H1N1 antibody levels suggests the need for ongoing monitoring and adjusted vaccination schedules. The poor response to B antigens, particularly B/Yamagata, underscores the need for improved vaccination strategies in these vulnerable populations. Full article

(1) Background: Does the variation in sequential development times of embryos, observed through time-lapse monitoring, between the two study groups play a role in predicting pregnancy success? (2) Methods: The prospective double-arm study was to identify the morphokinetic parameters specific to embryos that were capable of implanting and were conducted on 89 embryos cultured in the Esco Miri time-lapse incubator, divided into two groups: Lot A, consisting of 57 embryos that successfully implanted and resulted in life birth rate (LBR), and Lot B (NLB), comprising 32 embryos that did not implant, leading to a negative beta-hCG outcome. (3) Results: Baseline characteristics, including female age, were not found to be statistically significant (p > 0.01). In contrast, there is a highly statistically significant difference concerning oocytes (p = 0.0029). Morphokinetic variables represented by sequential culture times were not statistically significant (p > 0.01) when comparing the two groups. However, the negative mean differences between these parameters suggest that the times for Lot A are better (shorter) than those for Lot B. While not statistically significant, these differences may still have practical significance. In the case of grading, the difference is considered to be extremely statistically significant (p < 0.01). (4) Conclusions: Although there are no statistically significant differences in sequential timings (p > 0.01) between the two groups, there are parameters indicating predictive potential for exploring pregnancy in embryo morphokinetics. Full article