Comparative evaluation of single and multiple exposure to PM2.5 in respirable air on cardiac physiology, structure and function in a Wistar rat model.

Many studies have shown the negative relationship between long term exposure to PM2.5 and cardiac dysfunction. Recently, studies have shown that even a single exposure of PM2.5 from air sample in permissible range can induce very mild cardiac pathological changes. In the present study, we revisited the toxic effect of PM2.5 on rat heart by adopting single and multiple exposure durations. Female Wistar rats were exposed to PM2.5 at a concentration of 250 µg/m3 daily for 3 hr for single (1 day) and multiple (7, 14, 21 days) durations. The major pathological changes noted in 21 days exposed myocardium comprised of an elevated ST segment (the segment between the S wave and the T wave), development of cardiac fibrosis, hypertrophy, cardiac injury, tissue inflammation and declined cardiac function. With 14 days exposed heart, the electrocardiograms (ECG),data showed insignificantly declined heart rate and an increased QT (the time from the start of the Q wave to the end of the T wave) interval along with mild fibrosis, hypertrophy and lesser number of TUNEL positive cells. On the other hand, single- and 7-days exposure to PM2.5 did not impart any significant changes in the myocardium. To determine the reversibility potential of PM2.5 induced cardiotoxicity, a washout period of 24 hours was adopted and all observed changes in the myocardium were reversed till day 7, but not in 14- and 21-days exposed samples. Based on the above findings we concluded that PM2.5 associated cardiac dysfunction is the cumulative outcome of ineffective cardiac adaptive and repair process that accumulate additively over the time due to prolonged exposure durations.

The Worsening of Myocardial Ischemia-Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology.

Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250 µg/m3 for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.

Synthesis of a Palladium Dimer Supported by a C-Bound Trifluoroacetonate Bridge Formed by Cleavage of a Hexafluoroacetylacetonate Ligand.

Palladium(II) hexafluoroacetylacetonate (Pd(Hfacac)2) is known to form adducts of bases, such as lutidine (2,6-dimethylpyridine). When treated with approximately 3 equiv of lutidine, Pd(Hfacac)2 yields a 1:1 complex as reported in the literature, Pd(O,O-Hfacac)(C-Hfacac)(lutidine), 1. However, when the amount of excess lutidine is increased, a new complex, 2, is formed. A single-crystal X-ray structure of 2 proves it is a rare example of a dimeric palladium complex containing two Pd(Hfacac)(lutidine) fragments bridged by a dianionic trifluoroacetonate ligand, µ-CHC(O)CF3. The formation of 2 is accompanied by a white precipitate determined to be a mixture of trans-Pd(O2CCF3)2(lutidine)2 (3), confirming the fate of the missing trifluoroacetate fragment from the cleavage of the Hfacac ligand, and [lutidinium][Hfacac] (4). Subsequent experiments revealed the determinative role that water played in this reaction. The mechanism of cleavage of the Hfacac ligand was explored by DFT methods.

Non-Aufbau electronic structure in radical enzymes and control of the highly reactive intermediates.

Radicals are highly reactive, short-lived chemical species that normally react indiscriminately with biological materials, and yet, nature has evolved thousands of enzymes that employ radicals to catalyze thermodynamically challenging chemistry. How these enzymes harness highly reactive radical intermediates to steer the catalysis to the correct outcome is a topic of intense investigation. Here, the results of detailed QM/MM calculations on archetype radical B12-enzymes are presented that provide new insights into how these enzymes control the reactivity of radicals within their active sites. The catalytic cycle in B12-enzymes is initiated through the formation of the 5'-deoxyadenosyl (Ado˙) moiety, a primary carbon-centred radical, which must migrate up to 8 Što reach the target substrate to engage in the next step of the catalytic process, a hydrogen atom abstraction. Our calculations reveal that Ado˙ within the protein environment exhibits an unusual non-Aufbau electronic structure in which the singly occupied molecular orbital is lower in energy than the doubly occupied orbitals, an uncommon phenomenon known as SOMO-HOMO inversion (SHI). We find that the magnitude of SHI in the initially formed Ado˙ is larger compared to when the Ado˙ is near the intended substrate, leading to the former being relatively less reactive. The modulation of the SHI originates from Coulombic interactions of a quantum nature between a negative charge on a conserved glutamate residue and the spin on the Ado˙. Our findings support a novel hypothesis that these enzymes utilize this quantum Coulombic effect as a means of maintaining exquisite control over the chemistry of highly reactive radical intermediates in enzyme active sites.

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin.

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.

PM2.5 toxicity in blood impairs cardiac redox balance and promotes mitochondrial dysfunction in rat heart that further aggravates ischemia reperfusion injury by modulating PI3K/AKT/mTOR/NF-kB signaling axis.

According to the pathophysiological mechanisms linking particulate matter (PM2.5) exposure and cardiovascular diseases, PM2.5 may directly translocate into the blood stream and remote target organs and thereby induce cardiovascular effects. The toxicity of PM2.5 is known to induce oxidative stress in pulmonary tissue, but its impact on the redox state in heart (distant organ) is unknown and how it modulates the cardiac response to ischemia reperfusion (IR) remains unclear. In the present study, we evaluated the toxic effect of PM2.5 on cardiac physiology in the presence and absence of IR after introducing PM2.5 into the blood. Female Wistar rats were injected with diesel particulate matter (DPM) via i.p & i.v routes at a concentration of 10 µg/ml. The toxic impact of PM2.5 not only adversely affects the cardiac ultra-structure (leading to nuclear infiltration, edema, irregularities in heart muscle and nuclear infiltration), but also altered the cellular redox balance, elevated inflammation and promoted the upregulation of proapoptotic mediator genes at the basal level of myocardium. The results showed alterations in cardiac ultrastructure, elevated oxidative stress and significant redox imbalance, increased inflammation and proapoptotic mediators at the basal level of myocardium. Moreover, the cardioprotective pro survival signaling axis was declined along with an increased NF-kB activation at the basal level. IR inflicted further injury with deterioration of cardiac hemodynamic indices (Heart rate [HR], Left ventricular developed pressure [LVDP], Left ventricular end-diastolic pressure [LVEDP] and rate pressure product [RPP]) along with prominent inactivation of signaling pathways. Furthermore, the levels of GSH/GSSG, NADH/NAD, NADPH/NADP were significantly low along with increased lipid peroxidation in mitochondria of PM2.5 treated IR rat hearts. This observation was supported by downregulation of glutaredoxin and peroxiredoxin genes in the myocardium. Similarly the presence of oxidative stress inducing metals was found at a higher concentration in cardiac mitochondria. Thus, the toxic impact of PM2.5 in heart augment the IR associated pathological changes by altering the physiological response, initiating cellular metabolic alterations in mitochondria and modifying the signaling molecules.

Investigating the temporal link between PM2.5 exposure and acceleration of myocardial ischemia reperfusion injury: Emphasizing the hazardous presence of metals in inhaled air.

Exposure to PM2.5 is widely acknowledged to induce cardiotoxic effects, leading to decreased myocardial tolerance to revascularization procedures and subsequent ischemia reperfusion injury (IR). However, the temporal relationship between PM2.5 exposure and vulnerability to IR, along with the underlying mechanisms, remains unclear and is the focus of this study. Female Wistar rats were exposed to PM2.5 at a concentration of 250 µg/m³ for 3 h daily over varying durations (7, 14, and 21 days), followed by IR induction. Our results demonstrated a significant increase in cardiac injury, as evidenced by increased infarct size and elevated cardiac injury markers, starting from day 14 of PM2.5 exposure, accompanied by declined cardiac function. These adverse effects were associated with apoptosis and impaired mitochondrial function, including reduced bioenergetics, mitochondrial DNA copy number and quality control mechanisms, along with inactivation of the PI3K/AKT/AMPK signalling pathways. Furthermore, analysis of myocardial tissue revealed elevated metal accumulation, particularly within mitochondria. Chelation of PM2.5 -associated metals using EDTA significantly mitigated the toxic effects on cardiac IR pathology, as confirmed in both rat myocardium and H9c2 cells. These findings suggest that metals in PM2.5 play a crucial role in inducing cardiotoxicity, impairing myocardial resilience to stress through mitochondrial accumulation and dysfunction.

Does cardiac impairment develop in ischemic renal surgery in rats depending on the reperfusion time?

Background: Renal dysfunction is known to cause heart failure. However, renal dysfunction associated with kidney surgeries (mediated by reperfusion injury) that affects the cardiac physiological function, especially during the recovery and repair phase of renal surgery is unknown. Method: Male Wistar rats (238 ± 18 g) were subjected to renal sham and ischemia-reperfusion (IR-bilateral clamping for 15 min/45 min and reperfusion for 24 h/48 h/7 days) surgeries. At the end of the experiment, the heart was isolated from the animal (to exclude neurohormonal influence) and perfused for 60 min with Krebs-Hanseleit buffer to study the physiological changes. Result: Renal artery bilateral occlusion for 45 min that creates ischemia, followed by 24 h of reperfusion did not impart any significant cardiac physiological functional decline but 48 h of reperfusion exhibited a significant decline in cardiac hemodynamic indices (Rate pressure product in x104 mmHg*beats/min: Sham- 3.53 ± 0.19, I45_R48-2.82 ± 0.21) with mild tissue injury. However, 7 days of reperfusion inflict significant physiological decline (Rate pressure product in x104 mmHg*beats/min - 2.5 ± 0.14) and tissue injury (Injury score- 4 ± 1.5) in isolated rat hearts. Interestingly, when the renal artery bilateral occlusion time was reduced to 15 min the changes in the hearts were negligible after 7 days. Cellular level exploration reveals a positive relation between functional deterioration of mitochondria and elevated mitochondrial oxidative stress and inflammation with cardiac physiological decline and injury linked with renal ischemia-reperfusion surgery. Conclusion: Cardiac functional decline associated with renal surgery is manifested during renal repair or recovery. This decline depends on cardiac mitochondrial health, which is negatively influenced by the renal IR mediators and kidney function.

Ischemic preconditioning modulates the DNA methylation process of the rat heart to provide tolerance to withstand ischemia reperfusion injury and its associated mitochondrial dysfunction.

DNA methylation plays a crucial role in the pathogenesis of myocardial ischemia reperfusion injury(I/R) and the I/R injury can be combated effectively by ischemia preconditioning (IPC), but the role is DNA methylation in this process is unknown. In this study, we uncovered the role of ischemic preconditioning (IPC)- mediated cardioprotection of rat myocardium by using a Langendorff rat heart model with 30 min of ischemia followed by 60 min of reperfusion. Heart conditioned with short cycles of ischemia and reperfusion (IPC procedure) prior to I/R protocol significantly reduced the I/R-induced global DNA hypermethylation level by 32% and the DNMT activity by 33% while rendering cardioprotection. Blocking the PI3K pathway via wortmannin not only negates the cardio-protection by IPC, but also increases the methylation of DNA by 75%. Besides, the correlation analysis showed a negative relationship between PI3K gene expression and the global DNA methylation level (r = - 0.8690, p = 0.0419) in IPC-treated rat hearts. Moreover, the global level DNA hypomethylation induced by IPC exhibited a regulatory effect on the genes involved in I/R pathology mediators like apoptosis (Caspase3), mitochondrial function (PGC 1α, TFAM, ND1) and oxidative stress (CuZnSOD, SOD2), and their corresponding function. The present study results provide novel evidence for the involvement of DNA methylation in the IPC procedure, and suggest DNA methylation as one of the potential therapeutic targets regulated by ischemic preconditioning in rat hearts subjected to ischemia reperfusion. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03965-0.

The 2023 extreme coastal El Niño: Atmospheric and air-sea coupling mechanisms.

In the boreal spring of 2023, an extreme coastal El Niño struck the coastal regions of Peru and Ecuador, causing devastating rainfalls, flooding, and record dengue outbreaks. Observations and ocean model experiments reveal that northerly alongshore winds and westerly wind anomalies in the eastern equatorial Pacific, initially associated with a record-strong Madden-Julian Oscillation and cyclonic disturbance off Peru in March, drove the coastal warming through suppressed coastal upwelling and downwelling Kelvin waves. Atmospheric model simulations indicate that the coastal warming in turn favors the observed wind anomalies over the far eastern tropical Pacific by triggering atmospheric deep convection. This implies a positive feedback between the coastal warming and the winds, which further amplifies the coastal warming. In May, the seasonal background cooling precludes deep convection and the coastal Bjerknes feedback, leading to the weakening of the coastal El Niño. This coastal El Niño is rare but predictable at 1 month lead, which is useful to protect lives and properties.

Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes.

The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer's Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-ß (Aß) levels. KD's 'main actor' is thought to be Beta-Hydroxy-butyrate (BHB) whose levels rose significantly in KD vs. CD mice, and BHB itself significantly rescued LTP in APP/PS1 hippocampi. KD's 6 most significant pathways induced in brains by RNAseq all related to Synaptic Plasticity. KD induced significant increases in synaptic plasticity enzymes p-ERK and p-CREB in both sexes, and of brain-derived neurotrophic factor (BDNF) in APP/PS1 females. We suggest KD rescues LTP through BHB's enhancement of synaptic plasticity. LTP falls in Mild-Cognitive Impairment (MCI) of human AD. KD and BHB, because they are an approved diet and supplement respectively, may be most therapeutically and translationally relevant to the MCI phase of Alzheimer's Disease.

Mitochondria dysfunction induced by decyl-TPP mitochondriotropic antioxidant based on caffeic acid AntiOxCIN6 sensitizes cisplatin lung anticancer therapy due to a remodeling of energy metabolism.

The pharmacological interest in mitochondria is very relevant since these crucial organelles are involved in the pathogenesis of multiple diseases, such as cancer. In order to modulate cellular redox/oxidative balance and enhance mitochondrial function, numerous polyphenolic derivatives targeting mitochondria have been developed. Still, due to the drug resistance emergence in several cancer therapies, significant efforts are being made to develop drugs that combine the induction of mitochondrial metabolic reprogramming with the ability to generate reactive oxygen species, taking into consideration the varying metabolic profiles of different cell types. We previously developed a mitochondria-targeted antioxidant (AntiOxCIN6) by linking caffeic acid to lipophilic triphenylphosphonium cation through a 10-carbon aliphatic chain. The antioxidant activity of AntiOxCIN6 has been documented but how the mitochondriotropic compound impact energy metabolism of both normal and cancer cells remains unknown. We demonstrated that AntiOxCIN6 increased antioxidant defense system in HepG2 cells, although ROS clearance was ineffective. Consequently, AntiOxCIN6 significantly decreased mitochondrial function and morphology, culminating in a decreased capacity in complex I-driven ATP production without affecting cell viability. These alterations were accompanied by an increase in glycolytic fluxes. Additionally, we demonstrate that AntiOxCIN6 sensitized A549 adenocarcinoma cells for CIS-induced apoptotic cell death, while AntiOxCIN6 appears to cause metabolic changes or a redox pre-conditioning on lung MRC-5 fibroblasts, conferring protection against cisplatin. We propose that length and hydrophobicity of the C10-TPP+ alkyl linker play a significant role in inducing mitochondrial and cellular toxicity, while the presence of the antioxidant caffeic acid appears to be responsible for activating cytoprotective pathways.

Cardiac damage following renal ischemia reperfusion injury increased with excessive consumption of high fat diet but enhanced the cardiac resistance to reperfusion stress in rat.

Renal ischemia-reperfusion (IR) injury inflicts remote cardiac dysfunction. Studies on rats fed with a high-fat diet (HD) showed contradictory results: some demonstrated increased sensitivity of the heart and kidney to IR injury, while others reported resistance. In this study, we examined cardiac dysfunction and compromised cardiac tolerance associated with renal IR in HD and standard diet (SD) fed rats. Male Wistar rats fed with HD or SD diet for 16 weeks were subjected to either renal sham or IR protocol (bilateral clamping for 45 min and reperfusion for 24 h). The hearts isolated from these rats were further subjected to normal perfusion or IR procedure to study cardiac response. Renal IR surgery negatively affected cardiac function with substantial changes in the cardiac tissues, like mitochondrial dysfunction, elevated oxidative stress, and inflammation. HD-fed rat hearts exhibited hypertrophy at the end of 16 weeks, and the consequential impact on the heart was higher in the animals underwent renal IR surgery than with sham surgery. However, the IR induction in the isolated heart from renal sham or renal IR operation showed significant tissue injury resistance and better physiological recovery in HD-fed rats. However, in SD-fed rats, only hearts from renal IR-operated rats showed resistance to cardiac IR, whereas hearts from renal sham-operated rats were more susceptible to IR damage. The augmented IR resistance in the heart with prior renal surgery was due to preserved mitochondrial bioenergetics function, reduced oxidative stress, and activation of the PI3K/AKT signaling axis.

PM2.5 Exposure-Linked Mitochondrial Dysfunction Negates SB216763-Mediated Cardio-Protection against Myocardial Ischemia-Reperfusion Injury.

GSK3ß is a promising target for treating various disease conditions, including myocardial ischemia-reperfusion injury (IR). This study investigated the potential of GSK3ß as a novel drug for managing IR in rats exposed to PM2.5 for 1 day and up to 21 days. Female Wistar rats were exposed to PM2.5 at a concentration of 250 µg/m3 for 3 h daily for either a single day or 21 days. After exposure, the isolated rat hearts underwent 30 min of ischemia followed by 60 min of reperfusion. GSK3ß inhibition effectively reduced IR injury in rat hearts from animals exposed to PM2.5 for 1 day but not in those exposed for 21 days. PM2.5 exposure disrupted the redox balance in mitochondria and reduced the gene expression of antioxidants (glutaredoxin and peroxiredoxin) and NRF2, which protects against oxidative stress. PM2.5 also impaired mitochondrial bioenergetics, membrane potential, and quality control, leading to mitochondrial stress. Importantly, PM2.5 increased the translocation of GSK3ß into mitochondria and compromised the overall mitochondrial function, particularly in the 21-day-exposed rat myocardium. The results indicate that extended exposure to PM2.5 leads to oxidative stress that disrupts mitochondrial function and diminishes the effectiveness of GSK3ß inhibitors in offering cardio-protection through mitochondria.

DNA hypomethylation by fisetin preserves mitochondria functional genes and contributes to the protection of I/R rat heart.

Myocardial I/R can alter the expression of different sets of cardiac genes that negatively influence the I/R outcome via epigenetic modifications. Fisetin is known to be cardioprotective against I/R, but its underlying epigenetic mode of action is not known and is addressed in the present study. Male Wistar rats were subjected to I/R by using the Langendorff perfusion system. Fisetin (20 mg/kg; i.p.) was administered before I/R induction, followed by the measurement of cardiac injury, hemodynamics, physiological indices, the differential expression of genes that regulate DNA methylation, and the function of mitochondria were performed. Fisetin administered I/R rat heart significantly reduced the global DNA hypermethylation and infarct size with an improved physiological recovery, measured via RPP (81%) and LVDP (82%) from the I/R control. Additionally, we noted decreased expression of the DNMT1 gene by 35% and increased expression of the TET1, TET2, and TET3 genes in fisetin-treated I/R rat hearts. Molecular docking analysis data reveals that the fisetin inhibits DNMT1 at the substrate binding site with minimum binding energy (- 8.2 kcal/mol) compared to the DNMT1 inhibitor, 5-azacytidine. Moreover, fisetin-treated I/R heart reversed the expression of the I/R-linked declined expression of bioenergetics genes (MT-ND1, MT-ND2, MT-ND4, MT-Cyt B, MT-COX1, MT-COX2, MT-ATP6), mitochondrial fission gene (Fis1), replication control genes PGC-1α, POLG, and TFAM to near-normal level. Based on the above findings, we demonstrated that fisetin possesses the ability to modulate the expression of different mitochondrial genes via influencing the global DNA methylation in cardiac tissue, which contributes significantly to the improved contractile function and thereby renders cardioprotection against I/R.

Accurate Potential Energy Surfaces Using Atom-Centered Potentials and Minimal High-Level Data.

We demonstrate that a Δ-density functional theory (Δ-DFT) approach based on atom-centered potentials (ACPs) represents a computationally inexpensive and accurate method for representing potential energy surfaces (PESs) for the HONO and HFCO molecules and vibrational frequencies derived therefrom. Using as few as 100 CCSD(T)-F12a reference energies, ACPs developed for use with B3LYP/def2-TZVPP are shown to produce PESs for HONO and HFCO with mean absolute errors of 27.7 and 5.8 cm-1, respectively. Application of the multiconfigurational time-dependent Hartree (MCTDH) method with ACP-corrected B3LYP/def2-TZVPP PESs produces vibrational frequencies for cis- and trans-HONO with mean absolute percent errors (MAPEs) of 0.8 and 1.1, compared to 0.8 obtained for the two isomers with CCSD(T)-F12a/cc-pVTZ-F12/MCTDH. For HFCO, the vibrational frequencies obtained using the present (Δ-DFT)/MCTDH approach give a MAPE of 0.1, which is the error obtained with CCSD(T)-F12a/cc-pVTZ-F12/MCTDH. The ACP approach is therefore successful in representing a PES calculated at a high level of theory (CCSD(T)-F12a) and a promising method for the development of a general protocol for the representation of accurate molecular PESs and the calculation of molecular properties from them.

Exposure to real ambient particulate matter inflicts cardiac electrophysiological disturbances, vascular calcification, and mitochondrial bioenergetics decline more than diesel particulate matter: consequential impact on myocardial ischemia-reperfusion injury.

Particulate matter (PM) present in the air sample comprises different sizes and is derived from multiple sources, in particular from diesel engines. In the present study, we assessed the cardiotoxic effect of PM2.5 from real ambient air sample and diesel vehicular exhaust from a specific location and compared it with SRM-2975. Female Wistar rats were exposed to PM2.5 from real ambient PM (RA_PM), diesel particulate matter (DPM), and SRM-2975 for 3h daily for 21 days followed by cardiotoxicity assessment. Twenty-one days of daily PM2.5 exposure induced hypertrophy, vascular calcification, and alterations in cardiac electrophysiology, where the changes were more prominent in the animals exposed to RA_PM. The gross pathological changes were supported by altered mitochondrial function and increased oxidative stress in the myocardium. To evaluate the cardiac responsive ability, isolated rat hearts were subjected to ischemia-reperfusion injury (IR), and the results showed significantly low recovery in the RA_PM-exposed rat hearts. Chemical analysis of PM2.5 by ICPMS from different sources indicated the presence of additional metals like Cr, Ni, Ga, As, Rb, Cd, Ba, La, and Ce in the RA_PM sample. Additionally, the chelation of metals in the RA_PM enhanced the cell viability of H9c2 cells when compared to the non-chelated sample. Based on the above observations, we conclude that PM2.5 from the ambient air sample exhibited higher cardiovascular toxicity than DPM, emphasizing the contribution of non-diesel components of PM2.5 and the need for a comprehensive approach to tackle the PM2.5 in the air sample.

PM2.5-Induced Cardiac Structural Modifications and Declined Pro-Survival Signalling Pathways Are Responsible for the Inefficiency of GSK-3ß Inhibitor in Attenuating Myocardial Ischemia-Reperfusion Injury in Rats.

Circulatory GSK3ß is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM2.5 at a concentration of 250 µg/m3. The effects of GSK3ß inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3ß signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM2.5-exposed rats. Furthermore, the inhibitor stimulated autophagy in hearts exposed to PM2.5 for 21 days and subjected to IR, resulting in increased mTOR expression and decreased AMPK expression. In normal hearts and those exposed to a single dose of PM2.5, the inhibitor effectively activated the PI3K/Akt/AMPK axis. These findings suggest that GSK3ß may not be a reliable therapeutic target for IR in the presence of chronic PM2.5 exposure.

Deriving Convergent and Divergent Metabolomic Correlates of Pulmonary Arterial Hypertension.

High-dimensional metabolomics analyses may identify convergent and divergent markers, potentially representing aligned or orthogonal disease pathways that underly conditions such as pulmonary arterial hypertension (PAH). Using a comprehensive PAH metabolomics dataset, we applied six different conventional and statistical learning techniques to identify analytes associated with key outcomes and compared the results. We found that certain conventional techniques, such as Bonferroni/FDR correction, prioritized metabolites that tended to be highly intercorrelated. Statistical learning techniques generally agreed with conventional techniques on the top-ranked metabolites, but were also more inclusive of different metabolite groups. In particular, conventional methods prioritized sterol and oxylipin metabolites in relation to idiopathic versus non-idiopathic PAH, whereas statistical learning methods tended to prioritize eicosanoid, bile acid, fatty acid, and fatty acyl ester metabolites. Our findings demonstrate how conventional and statistical learning techniques can offer both concordant or discordant results. In the case of a rare yet morbid condition, such as PAH, convergent metabolites may reflect common pathways to shared disease outcomes whereas divergent metabolites could signal either distinct etiologic mechanisms, different sub-phenotypes, or varying stages of disease progression. Notwithstanding the need to investigate the mechanisms underlying the observed results, our main findings suggest that a multi-method approach to statistical analyses of high-dimensional human metabolomics datasets could effectively broaden the scientific yield from a given study design.