Myocardial dysfunction is a major cause of early mortality after successful cardiopulmonary resuscitation (CPR) following cardiac arrest (CA). Following the return of spontaneous circulation, myocardial ischemia-reperfusion injury can activate the NF-κB pathway, leading to the transcription of inflammatory genes that impair myocardial function. While clinical studies show hydrocortisone (HC) improves outcomes in CA patients during CPR, its specific role in modulating the NF-κB pathway is unclear. In this study, we established an in vitro model by inducing hypoxia/reoxygenation (H/R) injury in H9C2 cardiomyocytes using Na2S2O4, followed by HC treatment. The results showed that HC treatment of H/R-injured cardiomyocytes promoted proliferation, inhibited apoptosis, and suppressed the NF-κB pathway, thereby reducing IL-6, IL-8, and TNF-α levels. Moreover, inhibition of the NF-κB pathway enhanced the proliferative capacity of H/R cardiomyocytes, decreased apoptosis rates, and reduced IL-6, IL-8, and TNF-α expression levels, with these effects being further amplified by HC treatment. These findings were further supported by in vivo experiments. In conclusion, our study suggests that HC may promote H/R cardiomyocyte proliferation, inhibit apoptosis, and alleviate inflammatory responses by suppressing the NF-κB pathway, providing new evidence to support its potential clinical application in CA management.

This study mainly shows the role of endoplasmic reticulum transmembrane and coiled coil domains 1 (TMCO1) in the regulatory mechanism of hepatocellular carcinoma (HCC). Invasion and migration capacity were detected by Transwell and Wound healing after TMCO1 and TOMM20 overexpression and knockdown. And mitochondrial function was detected through reactive oxygen species (ROS), mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (MMP) and ATP production. A model of subcutaneous tumor formation in nude mice was established to detect the effect of TMCO1 on tumor formation. The results showed that overexpression of TMCO1 significantly promoted HCC cell metastasis, promoted cell proliferation and ATP production, inhibited cell apoptosis, mPTP opening and ROS production, mediated the increase of MMP level and cytoskeletal remodeling. However, knocking down TMCO1 can have the opposite effect. More importantly, knocking down TOMM20 can block the regulation effect of TMCO1, and TOMM20 overexpression can alleviate the inhibitory effect of knocking down TMCO1 on the development of liver cancer cells. In animal models, knockdown of TMCO1 expression significantly inhibited the growth of subcutaneous implant tumors. This suggests TMCO1 may be a potential and valuable therapeutic target for liver cancer.

Transcription factors (TFs) are specialized proteins that bind DNA in a sequence-specific manner and modulate RNA polymerase II (Pol II) in multiple steps of the transcription process. Phase separation is a spontaneous or driven process that can form membrane-less organelles called condensates. By creating different liquid phases at active transcription sites, the formation of transcription condensates can reduce the water content of the condensate and lower the dielectric constant in biological systems, which in turn alters the structure and function of proteins and nucleic acids in the condensate. In RNA Pol II transcription, phase separation formation shortens the time at which TFs bind to target DNA sites and promotes transcriptional bursting. RNA Pol II transcription is engaged in developing several diseases, such as cardiovascular disease, by regulating different TFs and mediating the occurrence of phase separation. This review aims to summarize the advances in the molecular mechanisms of RNA Pol II transcriptional regulation, in particular the effect of TFs and phase separation. The role of RNA Pol II transcriptional regulation in cardiovascular disease will be elucidated, providing potential therapeutic targets for the management and treatment of cardiovascular disease.

G protein-coupled receptor (GPCR) signaling regulates a wide range of pathophysiological cell functions via G protein α and βγ subunits. Small molecules targeting the subunits of Gα and Gβγ have been developed as cancer therapeutics. We have previously reported that transforming growth factor-α (TGF-α) induces the migration of human hepatocellular carcinoma (HCC) HuH7 cells through the activation of AKT, p38 mitogen-activated protein kinase (MAPK), Rho-kinase and c-Jun N-terminal kinase (JNK). This study aims to determine whether Gβγ subunits regulate the TGF-α-induced migration of HCC HuH7 cells using gallein, a Gβγ subunits inhibitor. The Janus family of tyrosine kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway was also involved in the regulation of the migration. Gallein significantly reduced the TGF-α-induced cell migration. In contrast, fluorescein, a gallein-related compound that has no effect on Gβγ subunits, failed to affect the cell migration. Gallein suppressed the TGF-α-stimulated phosphorylation of JNK without affecting the phosphorylation of epidermal growth factor receptor, AKT, p38 MAPK, target protein of Rho-kinase and STAT3. Conversely, fluorescein did not attenuate the phosphorylation of JNK. These results strongly suggest that Gβγ subunits act as positive regulators in TGF-α-induced migration of HCC cells via the JNK signalling pathway.

Chromatin is dynamically regulated during development, where structural changes affect the transcription of genes required to promote different cell types. One of the chromatin regulatory factors responsible for transcriptional regulation during development is the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, an ATP-dependent chromatin remodeling factor conserved throughout eukaryotes. The catalytic subunit of this complex, BRG1, is shared in all three SWI/SNF complexes subfamilies and is essential for developing most cell lineages. Interestingly, many human developmental diseases have correlative or causative mutations in different SWI/SNF subunits. Many polybromo-associated BAF (pBAF) complex-specific subunit genetic alterations result in developmental failures in tissue-specific ways. This observation suggests that the pBAF complex plays a vital role in development and differentiation, and studying the pBAF complex may provide an opportunity to better understand gene regulation during development. In this mini-view, we will focus on the functions of pBAF-specific subunits and their influence on the development of various cell and tissue types by regulating developmental gene expression.

This study aims to explore the role of 1-Deoxynojirimycin (DNJ) in high glucose-induced β-cells and to further explore the molecular mechanism of DNJ effect on β-cells through network pharmacology. In the study, high glucose treatment of mouse INS-1 cells inhibited cell proliferation and insulin secretion, decreased the expression of Bcl-2 protein and Ins1 and Ins2 genes, promoted apoptosis, and increased cleaved caspase-3 and cleaved caspase-9 expression levels as well as intracellular reactive oxygen species (ROS) production. DNJ treatment significantly restored the dysfunction of INS-1 cells induced by high glucose, and DNJ showed no toxicity to normal INS-1 cells. Silencing CEBPA promoted, while overexpression of CEBPA relieved the dysfunction of pancreatic β-cells induced by high glucose. DNJ treatment partially restored the pancreatic β-cell dysfunction caused by silencing CEBPA. In conclusion, DNJ can inhibit high glucose-induced pancreatic β-cell dysfunction by promoting the expression of CEBPA.

Enucleated cells, also known as cytoplasts, are valuable tools with a wide range of applications. However, their potential for bio-engineering is greatly restricted by the short lifespan. We postulated that the enucleation process damages the integrity of the plasma membrane and thus activates a cell death program(s). The results showed that a tiny hole was generated transiently on the plasma membrane when the nucleus was spun off, while force-gated ion channels were activated in response to the pulling by the nucleus. Influx of extracellular calcium stimulated the opening of calcium channels and the release of calcium from endoplasmic reticulum and mitochondria. Long lasting calcium transient increased protein phosphorylation and activated caspase 9 and calpain proteinase activities. Subsequently, mitochondria membrane permeability and Reactive Oxygen Species (ROS) levels were significantly elevated, which eventually led to eryptosis-like cell death. When extracellular calcium was maintained at optimal concentration, the lifespan of enucleated cells was extended; however, huge amounts of vacuoles appeared in the cytoplasm, possibly derived from enlarged autophagosomes. Inhibition of vacuolation by inhibitors of autophagy or in co-culture with primary muscle cells did not rescue cells dying from the paraptosis-like pathway. These results offer valuable insights for further investigation into the intricate mechanisms underlying enucleated cell death.

Prostate cancer (PCa) is a complex disease with diverse molecular alterations. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that exhibits pleiotropic roles in PCa, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR. While targeting ferroptosis is an innovative PCa therapeutic strategy, the impact of AhR on this process remains unclear. This study aimed to investigate the influence of AhR on lipid peroxidation and ferroptosis. Results showed that TCDD activated AhR, as evidenced by increased CYP1A1 expression, leading to reduced cell viability. TCDD caused mitochondria shrinkage, decreased the GSH/GSSG ratio, and elevated the MDA levels and lipid peroxidation. Interestingly, AhR knockdown reversed these effects, similar to the action of ferroptosis inhibitors. Mechanistically, TCDD suppressed nuclear receptor subfamily 4 group A member 1 (NR4A1) expression, in part due to AhR activation. This suppression subsequently led to a reduction in the expression of the NR4A1 downstream target stearoyl-CoA desaturase 1 (SCD1). NR4A1 overexpression counteracted the effects of TCDD. In vivo, TCDD activated AhR, downregulated NR4A1 and SCD1 expression, induced mitochondria shrinkage, and increased the MDA and 4-hydroxynonenal (4-HNE) levels. In summary, TCDD promotes ferroptosis in androgen-dependent PCa via inhibiting the NR4A1/SCD1 axis, in part dependent on AhR activation.

Antibiotics, specifically clindamycin (Clin), cause intestinal dysbiosis, reducing the microbiota with anti-inflammatory properties. Furthermore, Clin can induce alterations in the immune responses and oxidative stress. Lactoferrin, among other activities, participates in the maintenance of intestinal homeostasis and reduces dysbiosis induced by antibiotic treatment. The aim of this study was to analyze the effect of native and iron-saturated bovine LF in a murine model of dysbiosis induced by Clin. Six groups of male C57BL/6 mice were treated with saline (control), Clin, native lactoferrin (nLF), iron-saturated lactoferrin (sLF), nLF/Clin, or sLF/Clin. Oxidation caused in the intestinal cells of the ileum of animals subjected to different treatments was analyzed, focusing on lipid peroxidation and protein carbonyl content. The expression of inflammatory mediators was determined by qRT-PCR. Treatment with Clin did not modify lipid peroxidation, but significantly increased protein carbonyl levels up to almost 5-fold respect to the control, an effect that was reversed by orally administering sLF to mice. Furthermore, Clin increased the expression of interleukin-6 and TNF-α by 1- and 2-fold change, respectively. This effect was reversed by treatment with nLF and sLF, decreasing the expression to basal levels. In conclusion, this study indicates that lactoferrin can prevent some of the effects of Clin on intestinal cells and their associated immune system.

Enterotoxigenic (ETEC) is a major cause of diarrhea in humans and animals. The study aimed to evaluate the efficacy of bovine lactoferrin (bLf) as an adjuvant combined with AMP (N6) in the treatment of -induced bacterial enteritis. Firstly, 40 female ICR mice were randomly divided into four groups. The ETEC-A, ETEC-B, and ETEC-C groups were gavaged with 0.2 mL of ETEC K88 at 5 × 10, 5 × 10, and 5 × 10 CFU/mL for three consecutive days, respectively, the CK control group was given PBS. Based on the clinical symptoms and intestinal changes, the optimal model dose of ETEC K88 was determined to be 5 × 10 CFU/mL. Sixty female ICR mice were randomly divided into six groups: CK group (uninfected), NC group (infected and untreated), N6 treatment group (20 mg/kg), bLf treatment group (100 mg/kg), bLf + N6-A treatment group (10 mg/kg N6+100 mg/kg bLf), and bLf + N6-B group (20 mg/kg N6+100 mg/kg bLf). The clinical symptoms, intestinal morphology, inflammatory response and serum metabolites were monitored. The results showed that compared with the NC group, the bLf-N6-A and bLf-N6-B treatment groups had significant reductions in TNF-α and IL-6, significant increases in IL-10, and significant reductions in endotoxin and DAO in plasma ( < 0.05). Meanwhile, the bLf-N6-A and bLf-N6-B treatment groups significantly increased the expression of ZO-1, claudin-1 and occludin, increased the height of small intestinal mucosal villi and VH/CD after ETEC K88-induced intestinal injury ( < 0.05). The combination of bLf and N6 relieved enteritis by balancing intestinal mucosal immunity, improving intestinal morphology and barrier function. BLf combined with N6 can be used as an effective therapeutic strategy for the treatment of bacterial enteritis.

Fusarium graminearum FgSte2 and FgSte3 are G-protein coupled receptors (GPCRs) shown to play roles in hyphal chemotropism and fungal plant pathogenesis in response to activity arising from host-secreted peroxidases. Here, we follow up on the observation that chemotropism is dependent on both FgSte2 and FgSte3 being present; testing the possibility that this might be due to formation of an FgSte2-FgSte3 heterodimer. Bioluminescence resonance energy transfer (BRET) analyses were conducted in Saccharomyces cerevisiae, where the addition of horse radish peroxidase (HRP) was found to increase the transfer of energy from the inducibly-expressed FgSte3-Nano luciferase donor, to the constitutively-expressed FgSte2-yellow fluorescent protein (YFP) acceptor, compared to controls. A partial response was also detected when an HRP-derived ligand-containing extract was enriched from F. graminearum spores and applied instead of HRP. In contrast, substitution with pheromones or an unrelated bovine GPCR, rhodopsin-YFP used as acceptor, eliminated all BRET responses. Interaction results were validated by affinity pulldown and receptor expression was validated by confocal immunofluorescence microscopy. Taken together these findings demonstrate the formation of HRP and HRP-derived ligand stimulated heterodimers between FgSte2 and FgSte3. Outcomes are discussed from the context of the roles of ligands and reactive oxygen species in GPCR dimerization.

Dedifferentiated adipose tissue-derived (DFAT) cells represent an attractive source of stem cells for tissue engineering and the potential treatment of several clinical conditions. Our objective was to determine whether DFAT cells originate from mature adipocytes and address whether contamination from the stromal vascular fraction (SVF) could be as a source for these cells. A murine adiponectin-creERT; mT/mG model was used with the excision of the cassette induced by tamoxifen injection for the cells expressing adiponectin (adipoq). This model allows distinguishing mature adipocytes (green fluorescence) from other SVF cell types (red fluorescence) based on the fluorescent protein expressed. Mature adipocytes and SVF cells were isolated from adipose tissues by collagenase digestion. Ceiling cultures were imaged by time-lapse microscopy. Confocal microscopy was used to follow cells over 21 days. Time-lapse microscopy experiments showed liposecretion occurring in mature adipocytes displaying green fluorescence. Confocal imaging allowed the identification of a heterogeneous cell population expressing green but also red fluorescence after 21 days of culture. Asymmetrical division of mature adipocytes was not observed. In conclusion, liposecretion of mature adipocytes is a phenomenon that can be observed in vitro and DFAT cells do originate from mature adipocytes. However, the population of DFAT cells is heterogenous.

Inflammatory bowel disease is a gut-brain axis disorder that comprises chronic inflammatory conditions affecting the gastrointestinal tract, where alterations in the mood of patients are common. Gut-brain axis is a bidirectional communication that link gut and brain. The close association between inflammatory bowel disease and neuroinflammation has far-reaching implications, as is increasingly recognized as a contributing factor to neuropsychiatric and neurodegenerative diseases. The increasing prevalence and high economic cost, together with the loss of life quality of people suffering from these diseases, point to the need to find alternatives to alleviate them. Exploring new therapeutic avenues prompts us to consider the potential benefits of milk fractions, taking advantage of the use of dairy by-products, such as whey and buttermilk. This study examines the impact of cow's whey- and buttermilk-based formulas supplemented with bovine lactoferrin and milk fat globule membrane on the expression of cytokines, as well as on the components of immune and serotonergic system of the brain in a murine model of dextran sodium sulfate-induced colitis. Our results show the potential of these dairy by-products, especially whey, as functional foods in ameliorating neuroinflammation and safeguarding the central nervous system function amid the neurological complications induced or concomitant with intestinal inflammatory processes.

Recently, several antimicrobial peptides (AMPs) varying in length from 12 to 37 residues, have been shown to act as antibiofilm agents. Here we report a study of twenty-three hexapeptides modeled after four different Trp- and Arg-rich AMPs, including the RRWQWR-NH2 peptide, derived from bovine lactoferrin. They were tested against the pathogenic Gram-negative Pseudomonas aeruginosa PAO1 strain and a Gram-positive Staphylococcus aureus MRSA strain. Both strains were engineered to express the GFP protein, and fluorescence detection was used to measure the ability of the peptides to prevent biofilm formation (MBIC) or to cause the breakdown of established biofilms (MBEC). Similar antibiofilm activities were obtained with the standard crystal violet dye assay. Most Trp- and Arg-rich hexapeptides displayed a potent antibiofilm activity against the Gram-positive S. aureus MRSA strain. In particular, hexapeptides with 3 Arg and 3 Trp were very effective, especially when they contained the three Trp in sequence. Somewhat unexpectedly, the antimicrobial (MIC) values correlated with the MBIC and MBEC values, which has not been seen for some other AMP/antibiofilm peptides. Our results demonstrate that short Trp- and Arg-rich peptides merit further studies as antibiofilm agents, that could be deployed to address part of the antimicrobial resistance problem.

After 20 years of stagnation, federal scholarships have finally been increased within the new budget of the Canadian government. Tuition fees, inflation, and costs of living kept rising, which has resulted a rising number of graduate students in the life sciences living below poverty line, despite working far more than 40 h a week on science research in Canada. This does not only negatively affect the students research projects and thus science and innovation in Canada, but also their downstream decisions on whether to continue a research career in Canada and what jobs and economic endeavors to pursue. Graduate students are not just a line item in the budgets of universities, but integral for science and innovation, as well as the future high-quality personnel of the country. This importance should be reflected in all stipends and salaries of graduate students, not just the ones with a government scholarship.

Salmonellosis is a common foodborne disease caused by bacteria. The emergence of multidrug-resistant (MDR) Salmonella serotypes, such as Typhimurium, and Salmonella's ability to form biofilms contribute to their resistance and persistence in host and non-host environments. New strategies are needed to treat or prevent Salmonella infections. This work aimed to determine the effect of the bovine lactoferrin (bLF) and lactoferrin chimera (LFchimera) in preventing or disrupting biofilms formed on abiotic surfaces or Caco-2 cells by Typhimurium ATCC 14028 or an MDR strain. The inhibitory activity of planktonic bacteria, prevention of biofilm formation, and destruction of biofilms of Typhimurium (ATCC 14028 or MDR strain) on the abiotic surface and Caco-2 cells of bLF and LFchimera were quantified by CFU/mL and visualized by microscopy using Giemsa-stained samples. bLF (75-1000 µM) and LFchimera (1-20 µM) inhibited more than 95% of Typhimurium planktonic growth cultures (ATCC 14028 and MDR). In addition, bLF (600, 800, and 1000 µM) and LFchimera (10 and 20 µM) prevented more than 98% of . Typhimurium adherence and biofilm formation on Caco-2 cells. Finally, bLF (600 and 1000 µM) and LFchimera (10 and 20 µM) destroyed more than 80% of Typhimurium biofilms established on abiotic and Caco-2 cells. In conclusion, bLF and LFchimeras have the potential to inhibit and destroy Typhimurium biofilms.

The human lysine acetyltransferases KAT3A () and KAT3B () are essential enzymes in gene regulation in the nucleus. Their ubiquitous expression in metazoan cell types controls cell proliferation and differentiation during development. This comprehensive review delves into the biological roles of KAT3A and KAT3B in neurodevelopment, shedding light on how alterations in their regulation or activity can potentially contribute to a spectrum of neurodegenerative diseases (e.g., Huntington's and Alzheimer's). We explore the pathophysiological implications of KAT3 function loss in these disorders, considering their conserved protein domains and biochemical functions in chromatin regulation. The discussion also underscores the crucial role of KAT3 proteins and their substrates in supporting the integration of key cell signaling pathways. Furthermore, the narrative highlights the interdependence of KAT3-mediated lysine acetylation with lysine methylation and arginine methylation. From a cellular perspective, KAT3-dependent signal integration at subnuclear domains is mediated by liquid-liquid phase separation in response to KAT3-mediated lysine acetylation. The disruption of these finely tuned regulatory processes underscores their pathological roles in neurodegeneration. This review also points to the exciting potential for future research in this field, inspiring further investigation and discovery in the area of neurodevelopment and neurodegenerative diseases.

Bovine lactoferrin (bLf) confers significant functional benefits for human health, but low concentrations in milk and high cost of commercial production limit availability and thus product application. Precision fermentation offers a solution to increase availability of biosimilar recombinant bLf (rbLf) thereby opening new opportunities for this high-value ingredient. To comply with regulatory requirements, we aimed to establish that rbLf from is substantially similar to native bLf in structure and key functions. Intact mass analysis showed a molecular weight of 84 kDa for rbLf, comparable to 82-83 kDa of bLf. LC-MS -linked glycan profiling revealed predominantly high-mannose-based glycans on rbLf, similar to ~50% of bLf glycans. The isoelectric point and core amino acid sequence of rbLf and bLf are identical. rbLf retains the functional ability to bind and release iron, bind to intestinal Lf receptors, increase epithelial cell growth (>120% of control, P < 0.0001), reduce EPEC growth (>50% reduction, P < 0.0001), bind LPS (+4 fold, P < 0.001) and antagonize LPS-induced TLR4 activity (>40% reduction, P < 0.0001). These results demonstrate similarity of rbLf in structure and function to native bLf, supporting the effective application for expanded market opportunities for infant and adult health.

The field of RNA research has provided profound insights into the basic mechanisms modulating the function and adaption of biological systems. RNA has also been at the center stage in the development of transformative biotechnological and medical applications, perhaps most notably was the advent of mRNA vaccines that were critical in helping humanity through the Covid-19 pandemic. Unbeknownst to many, Canada boasts a diverse community of RNA scientists, spanning multiple disciplines and locations, whose cutting-edge research has established a rich track record of contributions across various aspects of RNA science over many decades. Through this position paper, we seek to highlight key contributions made by Canadian investigators to the RNA field, via both thematic and historical viewpoints. We also discuss initiatives underway to organize and enhance the impact of the Canadian RNA research community, particularly focusing on the creation of the not-for-profit organization RNA Canada ARN. Considering the strategic importance of RNA research in biology and medicine, and its considerable potential to help address major challenges facing humanity, sustained support of this sector will be critical to help Canadian scientists play key roles in the ongoing RNA revolution and the many benefits this could bring about to Canada.

Myelination is essential for the proper conduction of impulses across neuronal networks. Mature, myelinating glia differentiate from progenitor cells through distinct stages that correspond to oligodendrocyte-specific gene expression markers. Reverse transcription quantiatative PCR (RT-qPCR) is a common technique used to quantify gene expression across cell development; however, a lack of standardization and transparency in methodology may lead to irreproducible data. Here, we have designed and validated RT-qPCR assays for oligodendrocyte genes and reference genes in the developing C57BL6/J mouse brain that align with the MIQE guidelines, including quality controls for primer specificity, temperature dependence, and efficiency. A panel of eight commonly used reference genes was ranked using a series of reference gene stability methods that consistently identified , and as the top candidates for normalization across brain regions. In the cerebrum, myelin genes peaked in expression at postnatal day 21, which corresponds to the peak of developmental myelination. The gene expression patterns from the brain homogenate were in agreement with previously reported RNA-seq and microarray profiles from oligodendrocyte lineage cells. The validated RT-qPCR assays begin to build a framework for future investigation into the molecular mechanisms that regulate myelination in mouse models of brain development, aging, and disease.

Diabetic nephropathy (DN) is one of the most common complications of diabetes. Our previous study showed that CD38 knockout (CD38KO) mice had protective effects on many diseases. However, the roles and mechanisms of CD38 in DN remain unknown. Here, DN mice were generated by HFD feeding plus streptozotocin (STZ) injection in male CD38KO and CD38flox mice. Mesangial cells (SV40 MES 13 cells) were used to mimic the injury of DN with palmitic acid (PA) treatment in vitro. Our results showed that CD38 expression was significantly increased in kidney of diabetic CD38flox mice and SV40 MES 13 cells treated with PA. CD38KO mice were significantly resistant to diabetes-induced renal injury. Moreover, CD38 deficiency markedly decreased HFD/STZ-induced lipid accumulation, fibrosis and oxidative stress in kidney tissue. In contrast, overexpression of CD38 aggravated PA-induced lipid accumulation and oxidative stress. CD38 deficiency increased expression of SIRT3, while overexpression of CD38 decreased its expression. More importantly, 3-TYP, an inhibitor of SIRT3, significantly enhanced PA-induced lipid accumulation and oxidative stress in CD38 overexpressing cell lines. In conclusion, our results demonstrated that CD38 deficiency prevented DN by inhibiting lipid accumulation and oxidative stress through activation of the SIRT3 pathway.