Search Results (30)

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

Emerging evidence links ferroptosis–mitochondrial dysregulation to depression pathogenesis through an oxidative stress–energy deficit–neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal–hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a “ferroptosis–mitochondrial fragmentation–metabolic maladaptation” triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shifts therapeutic paradigms from monoaminergic targets toward multimodal strategies addressing iron homeostasis, organelle dynamics, and metabolic vulnerability—a framework with significant implications for developing neuroprotective antidepressants. Full article

A typical county for traditional village conservation in China is Songyang County. It is renowned for its ancient rammed earth dwellings, which exhibit a unique microclimate and possess significant historical value. However, high precipitation and acid rain under the subtropical monsoon climate have caused severe surface erosion, including cracking and spalling. This study focuses on traditional rammed earth dwellings in Chenjiapeng Village, Songyang County, combining field surveys, experimental analysis, and microscopic characterization to systematically investigate erosion mechanisms and protection strategies. Techniques, such as drone aerial photography, X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), and microbial diversity detection, were employed to elucidate the anti-erosion mechanisms of gray–green biological crusts on rammed earth surfaces. The results indicate that algal crusts enhance surface compressive strength and shear resistance through macroscopic coverage (reducing raindrop kinetic energy and moisture retention) and microscopic extracellular polysaccharide-cemented soil particles forming a three-dimensional network. However, acidic environments induce metabolic acid release from algae, dissolving cementing materials and creating a “surface protection-internal damage” paradox. To address this, a “transparent film-biofiber-acid inhibition layer” composite biofilm design is proposed, integrating a biodegradable polylactic acid (PLA) mesh, algal attachment substrates, and calcium carbonate microparticles to dynamically neutralize acidic substances, achieving synergistic ecological protection and cultural heritage authenticity. This study provides innovative solutions for the anti-erosion protection of traditional rammed earth structures, emphasizing environmental compatibility and sustainability. Full article

Coronary artery disease remains a leading cause of morbidity and mortality worldwide. Acute myocardial infarction results in ischemia-induced cellular dysfunction and death. While timely reperfusion limits myocardial damage, it paradoxically triggers ischemia–reperfusion injury (IRI), exacerbating tissue damage. IRI, first observed in the 1960s, is mediated by complex molecular pathways, including oxidative stress, calcium dysregulation, endothelial dysfunction, and inflammation. This review examines emerging therapeutic strategies targeting IRI, including ischemic preconditioning, postconditioning, pharmacological agents, and anti-inflammatory therapies. Preconditioning serves as an endogenous protection mechanism, while pharmacological postconditioning has become a more clinically feasible approach to target oxidative stress, inflammation, and apoptosis during reperfusion. Pharmacological agents, such as GSK-3β inhibitors, JNK inhibitors, and mesenchymal stem cell-derived exosomes, have shown promise in modulating molecular pathways, including Wnt/β-catenin and NF-κB, to reduce myocardial injury and enhance recovery. Combination therapies, integrating pharmacological agents with mechanical postconditioning, provide a synergistic approach to further protect tissue and mitigate damage. However, translating preclinical findings to clinical practice remains challenging due to discrepancies between animal models and human conditions, particularly with comorbidities such as diabetes and hypertension. Continued research is essential to refine these therapies, optimize clinical application, and address translational challenges to improve outcomes in IRI. Full article

Background/Objectives: Vitamin and/or mineral supplements are designed to correct micronutrient deficiencies or maintain adequate intake. However, evidence suggests the indiscriminate use of these products, particularly among populations that already meet their micronutrient requirements through diet. This study aims to estimate the prevalence of vitamin and/or mineral supplement use and assess the dietary intake of micronutrients among users and non-users in the Brazilian adult and elderly populations. Methods: The prevalence of vitamin and/or mineral supplement use was estimated from a sample of 37,364 individuals who participated in the Brazilian National Food Survey, a module of the 2017–2018 Household Budget Survey. The average dietary intake of micronutrients—including calcium, magnesium, phosphorus, iron, copper, zinc, vitamin A, thiamine, riboflavin, niacin, cobalamin, pyridoxine, vitamin D, vitamin E, vitamin C, and folate—was calculated for both users and non-users of these supplements, based on 24 h dietary recalls collected during the survey. Analyses of dietary intake were stratified by sex and age group. Results: The estimated overall prevalence of supplement use was 16.0% (95% CI: 15.4–16.6), with a higher prevalence among women (19.5% [95% CI: 18.7–20.5]) and the elderly (27.9% [95% CI: 26.4–29.4]). Women who used vitamin and/or mineral supplements showed higher average intakes for a greater number of dietary micronutrients compared to non-users. Conclusions: The findings from the analysis of average micronutrient intake from food sources, particularly among women and elderly women who used supplements, support the paradox of the “inverse supplement hypothesis”, which suggests that individuals who use dietary supplements are often those with the least need for them. Full article

Transient receptor potential (TRP) channels are broadly implicated in the developmental programs of most tissues. Amongst these tissues, skeletal muscle and adipose are noteworthy for being essential in establishing systemic metabolic balance. TRP channels respond to environmental stimuli by supplying intracellular calcium that instigates enzymatic cascades of developmental consequence and often impinge on mitochondrial function and biogenesis. Critically, aminoglycoside antibiotics (AGAs) have been shown to block the capacity of TRP channels to conduct calcium entry into the cell in response to a wide range of developmental stimuli of a biophysical nature, including mechanical, electromagnetic, thermal, and chemical. Paradoxically, in vitro paradigms commonly used to understand organismal muscle and adipose development may have been led astray by the conventional use of streptomycin, an AGA, to help prevent bacterial contamination. Accordingly, streptomycin has been shown to disrupt both in vitro and in vivo myogenesis, as well as the phenotypic switch of white adipose into beige thermogenic status. In vivo, streptomycin has been shown to disrupt TRP-mediated calcium-dependent exercise adaptations of importance to systemic metabolism. Alternatively, streptomycin has also been used to curb detrimental levels of calcium leakage into dystrophic skeletal muscle through aberrantly gated TRPC1 channels that have been shown to be involved in the etiology of X-linked muscular dystrophies. TRP channels susceptible to AGA antagonism are critically involved in modulating the development of muscle and adipose tissues that, if administered to behaving animals, may translate to systemwide metabolic disruption. Regenerative medicine and clinical communities need to be made aware of this caveat of AGA usage and seek viable alternatives, to prevent contamination or infection in in vitro and in vivo paradigms, respectively. Full article

Ischemia/reperfusion injury (IRI) represents a significant contributor to morbidity and mortality associated with various clinical conditions, including acute coronary syndrome, stroke, and organ transplantation. During ischemia, a profound hypoxic insult develops, resulting in cellular dysfunction and tissue damage. Paradoxically, reperfusion can exacerbate this injury through the generation of reactive oxygen species and the induction of inflammatory cascades. The extensive clinical sequelae of IRI necessitate the development of therapeutic strategies to mitigate its deleterious effects. This has become a cornerstone of ongoing research efforts in both basic and translational science. This review examines the use of molecular hydrogen for IRI in different organs and explores the underlying mechanisms of its action. Molecular hydrogen is a selective antioxidant with anti-inflammatory, cytoprotective, and signal-modulatory properties. It has been shown to be effective at mitigating IRI in different models, including heart failure, cerebral stroke, transplantation, and surgical interventions. Hydrogen reduces IRI via different mechanisms, like the suppression of oxidative stress and inflammation, the enhancement of ATP production, decreasing calcium overload, regulating cell death, etc. Further research is still needed to integrate the use of molecular hydrogen into clinical practice. Full article

Following ischemia/reperfusion, AMPA receptors (AMPARs) mediate pathologic delayed neuronal death through sustained expression of calcium-permeable AMPARs, leading to excitotoxicity. Preventing the surface removal of GluA2-containing AMPARs may yield new therapeutic targets for the treatment of ischemia/reperfusion. This study utilized acute organotypic hippocampal slices from aged male and female Sprague Dawley rats and subjected them to oxygen-glucose deprivation/reperfusion (OGD/R) to examine the mechanisms underlying the internalization and degradation of GluA2-containing AMPARs. We determined the effect of OGD/R on AMPAR subunits at the protein and mRNA transcript levels utilizing Western blot and RT-qPCR, respectively. Hippocampal slices from male and female rats responded to OGD/R in a paradoxical manner with respect to AMPARs. GluA1 and GluA2 AMPAR subunits were degraded following OGD/R in male rats but were increased in female rats. There was a rapid decrease in GRIA1 (GluA1) and GRIA2 (GluA2) mRNA levels in the male hippocampus following ischemic insult, but this was not observed in females. These data indicate a sex-dependent difference in how AMPARs in the hippocampus respond to ischemic insult, and may help explain, in part, why premenopausal women have a lower incidence/severity of ischemic stroke compared with men of the same age. Full article

Vitamin D is known to have a positive effect on bone health. Despite the greater frequency of vitamin D deficiency in African Americans (AA), they have a higher bone mineral density (BMD) compared to whites, demonstrating a disconnect between BMD and vitamin D levels in AA. Another intriguing relationship seen in AA is the triglyceride (TG) paradox, an unusual phenomenon in which a normal TG status is observed even when patients house conditions known to be characterized by high TG levels, such as Type II diabetes. To the best of our knowledge, no study has examined whether these two paradoxical relationships exist simultaneously in AA subjects with Type II diabetes. In this study, we compared levels of blood markers, including HbA1c, TG, and vitamin D, measured as serum 25-hydroxyvitamin D [25(OH)VD] µM/mL, [25(OH)VD]/TG, calcium, and BMD in AA (n = 56) and white (n = 26) subjects with Type II diabetes to see whether these relationships exist concurrently. We found that AA subjects had significantly lower TG and [25(OH)VD] levels and a significantly higher BMD status compared to white subjects, even when the ages, BMI, duration of diabetes, HbA1c, and calcium levels were similar between the two groups. This demonstrates that these two paradoxical relationships exist simultaneously in Type II diabetic AA subjects. In addition to these findings, we discuss the current hypotheses in the literature that attempt to explain why these two intriguing relationships exist. This review also discusses four novel hypotheses, such as altered circulating levels and the potential role of estrogen and hydrogen sulfide on BMD and HMG-CoA reductase as a possible contributor to the TG paradox in AA subjects. This manuscript demonstrates that there are still many unanswered questions regarding these two paradoxical relationships and further research is needed to determine why they exist and how they can be implemented to improve healthcare. Full article

Mesembryanthemum crystallinum L. is an obligatory halophyte species showing optimum growth at elevated soil salinity levels, but the ionic requirements for growth stimulation are not known. The aim of the present study was to compare the effects of sodium, potassium and calcium in the form of chloride and nitrate salts on the growth, physiological performance, ion accumulation and mineral nutrition of M. crystallinum plants in controlled conditions. In a paradoxical way, while sodium and potassium had comparable stimulative effect on plant growth, the effect of calcium was strongly negative even at a relatively low concentration, eventually leading to plant death. Moreover, the effect of Ca nitrate was less negative in comparison to that of Ca chloride, but K in the form of nitrate had some negative effects. There were three components of the stimulation of biomass accumulation by NaCl and KCl salinity in M. crsytallinum: the increase in tissue water content, increase in ion accumulation, and growth activation. As optimum growth was in a salinity range from 20 to 100 mM, the increase in the dry biomass of plants at a moderate (200 mM) and high (400 mM) salinity in comparison to control plants was mostly due to ion accumulation. Among physiological indicators, changes in leaf chlorophyll concentration appeared relatively late, but the chlorophyll a fluorescence parameter, Performance Index Total, was the most sensitive to the effect of salts. In conclusion, both sodium and potassium in the form of chloride salts are efficient in promoting the optimum growth of M. crystallinum plants. However, mechanisms leading to the negative effect of calcium on plants need to be assessed further. Full article

Aortic valve stenosis (AS) is increasing in prevalence due to the aging population, and severe AS is associated with significant morbidity and mortality. Echocardiography remains the mainstay for the initial detection and diagnosis of AS, as well as for grading of severity. However, there are important subgroups of patients, for example, patients with low-flow low-gradient or paradoxical low-gradient AS, where quantification of severity of AS is challenging by echocardiography and underestimation of severity may delay appropriate management and impart a worse prognosis. Aortic valve calcium score by computed tomography has emerged as a useful clinical diagnostic test that is complimentary to echocardiography, particularly in cases where there may be conflicting data or clinical uncertainty about the degree of AS. In these situations, aortic valve calcium scoring may help re-stratify grading of severity and, therefore, further direct clinical management. This review presents the evolution of aortic valve calcium score by computed tomography, its diagnostic and prognostic value, as well as its utility in clinical care. Full article

Obesity is a health condition that represents a risk factor for numerous diseases and complications. However, obesity might also have—to some extent—some “benefits” in certain situations. This includes potential bone protection in patients suffering from chronic kidney disease. In an attempt to explain such a paradox, we highlight secreted protein acidic and rich in cysteine (SPARC) as a hypothetical mediator of this protection. Indeed, SPARC properties provide a logical rationale to describe such bone protection via its overexpression combined with its calcium-binding and collagen-binding properties. We believe that exploring such hypotheses could open new doors to elucidate unknown pathways towards developing a new generation of molecular therapies. Full article

The apical dendrite of a cortical projection neuron (CPN) is generated from the leading process of the migrating neuron as the neuron completes migration. This transformation occurs in the cortical marginal zone (MZ), a layer that contains the Cajal-Retzius neurons and their axonal projections. Cajal-Retzius neurons (CRNs) are well known for their critical role in secreting Reelin, a glycoprotein that controls dendritogenesis and cell positioning in many regions of the developing brain. In this study, we examine the possibility that CRNs in the MZ may provide additional signals to arriving CPNs, that may promote the maturation of CPNs and thus shape the development of the cortex. We use whole embryonic hemisphere explants and multiphoton microscopy to confirm that CRNs display intracellular calcium transients of <1-min duration and high amplitude during early corticogenesis. In contrast, developing CPNs do not show high-amplitude calcium transients, but instead show a steady increase in intracellular calcium that begins at the time of dendritic initiation, when the leading process of the migrating CPN is encountering the MZ. The possible existence of CRN to CPN communication was revealed by the application of veratridine, a sodium channel activator, which has been shown to preferentially stimulate more mature cells in the MZ at an early developmental time. Surprisingly, veratridine application also triggers large calcium transients in CPNs, which can be partially blocked by a cocktail of antagonists that block glutamate and glycine receptor activation. These findings outline a model in which CRN spontaneous activity triggers the release of glutamate and glycine, neurotransmitters that can trigger intracellular calcium elevations in CPNs. These elevations begin as CPNs initiate dendritogenesis and continue as waves in the post-migratory cells. Moreover, we show that the pharmacological blockade of glutamatergic signaling disrupts migration, while forced expression of a bacterial voltage-gated calcium channel (CavMr) in the migrating neurons promotes dendritic growth and migration arrest. The identification of CRN to CPN signaling during early development provides insight into the observation that many autism-linked genes encode synaptic proteins that, paradoxically, are expressed in the developing cortex well before the appearance of synapses and the establishment of functional circuits. Full article

Hyperacusis, i.e., an increased sensitivity to sounds, is described in several neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). The mechanisms underlying hyperacusis in FXS are still largely unknown and effective therapies are lacking. Big conductance calcium-activated potassium (BKCa) channels were proposed as a therapeutic target to treat several behavioral disturbances in FXS preclinical models, but their role in mediating their auditory alterations was not specifically addressed. Furthermore, studies on the acoustic phenotypes of FXS animal models mostly focused on central rather than peripheral auditory pathways. Here, we provided an extensive characterization of the peripheral auditory phenotype of the Fmr1-knockout (KO) mouse model of FXS at adulthood. We also assessed whether the acute administration of Chlorzoxazone, a BKCa agonist, could rescue the auditory abnormalities of adult mutant mice. Fmr1-KO mice both at 3 and 6 months showed a hyperacusis-like startle phenotype with paradoxically reduced auditory brainstem responses associated with a loss of ribbon synapses in the inner hair cells (IHCs) compared to their wild-type (WT) littermates. BKCa expression was markedly reduced in the IHCs of KOs compared to WT mice, but only at 6 months, when Chlorzoxazone rescued mutant auditory dysfunction. Our findings highlight the age-dependent and progressive contribution of peripheral mechanisms and BKCa channels to adult hyperacusis in FXS, suggesting a novel therapeutic target to treat auditory dysfunction in NDDs. Full article

Deposits of calcium sulfate scale on the surfaces of industrial equipment in distillation facilities, reverse osmosis desalination plants, in oil and gas industries lead to significant clogging of pipes and membranes and to a serious increase in production costs. For the mitigation of scale formation, the wide spectrum of antiscalants is applied. The present work is dedicated to the study of calcium sulfate deposition from supersaturated aqueous solutions in the presence of polyacrylic antiscalant with fluorescent marker (naphthalimide fragment) PAA-F1, which provides traceability of the scale inhibitor and a better understanding of its efficacy. A paradoxical phenomenon is being described here. Antiscalant causes a change in the crystal phase from bassanite to gypsum, significantly reduces the amount of deposit, but does not reveal the presence of its molecules either at the kink, step, or at selected edge sites of deposited crystals. Contrary to the predictions of the theory, it either stays in the aqueous phase, or forms its own separate phase Ca-PAA-F1. It is demonstrated that the antiscalant does not block the surfaces of calcium sulfate nuclei or crystal surfaces, but rather the foreign particles of nanodust with particle sizes around 1 nm, naturally occurring in any aqueous solution. As a result, the number of calcium nucleation sites is reduced, and the rate of scale formation decreases without any apparent antiscalant–scale interaction. On the grounds of the current experiment, the substoichiometric effect of scale inhibition obtained an alternative, quite stoichiometric explanation. Full article