SIRT1 Expression Research Articles

MicroRNA Profiling in Chronic Limb-Threatening Ischemia Their Role in Arteriogenesis

AbstractChronic limb-threatening ischemia (CLTI) represents poses a substantial threat with escalating mortality and amputation rates. Despite the existence of various clinical techniques for diagnosing CLTI, the role of microRNAs (miRNAs) in arteriogenesis remains ambiguous. Comprehensive knowledge on miRNAs may facilitate the advancement of targeted therapy pertaining to the enhancement of collateral blood flow in obstructed vessels. Therefore, this study aimed at analyzing arteriogenesis-associated plasma miRNA profiles in patients with CLTI using gene expression. Samples were acquired from the collateral arteries (CA group, n = 3) and the contralateral healthy limb (healthy artery; HA group, n = 3) of a single set of patients with CLTI. The RNA extracted from the samples was assessed for concentration and purity. A normalization factor was used to address variations in analyte abundance and/or quality across the samples. Subsequently, individual RNA molecules were directly quantified and subjected to comparative analysis between the CA and HA groups to identify the miRNAs involved in arteriogenesis. The five arteriogenesis-related miRNAs exhibiting maximum upregulation were miR-301b–3p, miR-221–5p, miR–639, miR-34a–5p, and let-7a–5p, while the five most downregulated miRNAs included miR-151a–5p, miR-371a–5p, miR-651–5p, miR-510–5p, and miR-660–5p. Summarily, this study documented marked upregulation and downregulation of miRNAs associated with arteriogenesis in the collateral arteries of patients with CLTI as compared with their contralateral healthy limbs. Possible mechanisms involved, including the regulation of YAP/TAZ pathway, TGFBR3 mRNA, SIRT1 expression, and other processes have shown to be modulated by miRNAs fluctuations.

Naringenin Inhibits Ferroptosis in Renal Tubular Epithelial Cells of Diabetic Nephropathy Through SIRT1/FOXO3a Signaling Pathway.

Naringenin has the potential to regulate ferroptosis and mitigate renal damage in diabetic nephropathy (DN). However, it remains unclear whether the naringenin's effects in DN are linked to its ability to regulate ferroptosis. This study investigated the potential anti-ferroptosis properties of naringenin in high glucose (HG)-induced renal tubular epithelial cell models. HK-2 cells were cultured in HG medium to establish the DN cell model. HK-2 cells were treated with different doses of naringenin to explore the effect of naringenin. The CCK-8 results show that 50 μM ~ 200 μM of naringenin do not affect the viability of HK-2 cells and the viability of HG-induced HK-2 cells increase in a dose-dependent manner with naringenin treatment. Additionally, naringenin increased the levels of IL-10 while decreasing the levels of IL-1β, TNF-α, IL-6, and ROS in HG-induced HK-2 cells. Naringenin also reduced the levels of Fe2+, oxidized lipid ROS, MDA, 4-HNE, ACSL4, and TFR1 in HG-induced HK-2 cells, while increasing the levels of non-oxidized lipid ROS, SOD, GSH-Px, SLC7A11, and GPX4. Meanwhile, naringenin restored the levels of MMP, ATP and MPTP opening, reduced OCR in HG-induced HK-2 cells. Furthermore, naringenin reversed the decreased expression of SIRT1, p-FOXO3a, Nrf2 and Nuclear Nrf2 caused by HG. SIRT1 inhibitor EX527 and Nrf2 inhibitor ML385 attenuated the effects of naringenin on ferroptosis in HG-induced HK-2 cells, with EX527 demonstrating a stronger reversal effect on ferroptosis than ML385. These results suggest that naringenin inhibits ferroptosis in HG-induced HK-2 cells mainly through SIRT1/FOXO3a signaling pathway. This finding further enhanced our understanding of the mechanism behind naringenin's protective effect on DN.

Compound K promotes thermogenic signature and mitochondrial biogenesis via the UCP1-SIRT3-PGC1α signaling pathway.

Compound K (CK), an active ingredient in ginseng, has anti-cancer, anti-inflammatory, and antioxidant properties. However, its effects on thermogenesis and mitochondrial dynamics in white adipose tissue (WAT) adipocytes are not well understood. This study explores CK's impact on thermogenesis and mitochondrial metabolism in cold-exposed mice and mouse stromal vascular fraction (SVF) cells. CK increased the expression of UCP1 and other brown/beige adipocyte markers (Cd137, Cytb, Letm1, Pgc1α, Prdm16, Tbp1, Tbx1, Uqcrc1) and mitochondrial biogenesis/dynamics factors (Cidea, Cox8b, Cycs, Dio2, Drp1, Fis1, Fgf21, Nrf1, Sirt3, Tfam) in 3T3-L1/iWAT SVF cells. CK enhanced mitochondrial respiration, reduced mitochondrial ROS levels, and restored MMP in iWAT SVF cells, leading to the differentiation of WAT into beige adipocytes, and that was also observed in cold-exposed subcutaneous tissue. CK administration to cold-exposed mice reduced fat droplet size and increased the number of mitochondria. Additionally, CK stimulated non-shivering thermogenesis, indicated by the upregulation of thermogenic and mitochondrial division proteins. The browning effect of CK was nullified by SIRT3 knockdown, suggesting that CK induces beige remodeling of WAT by regulating mitochondrial dynamics and SIRT3 expression. These findings suggest CK's potential as a therapeutic agent for obesity and metabolic disorders that promotes the transformation of WAT into a metabolically active beige phenotype.

Sirt1 Regulates Phenotypic Transformation of Diabetic Cardiac Fibroblasts through Akt/Α-SMA Pathway.

Cardiac fibrosis causes most pathological alterations of cardiomyopathy in diabetes and heart failure patients. The activation and transformation of cardiac fibroblasts (CFs) are the main pathological mechanisms of cardiac fibrosis. It has been established that Sirtuin1 (Sirt1) plays a protective role in the pathogenesis of cardiovascular disorders. This study aimed to ascertain the Sirt1 effect on the phenotypic transformation of CFs in diabetes and its possible mechanisms. Type 1 diabetes was induced in 6-week-old male mice by subcutaneously injecting 50 mg/kg streptozotocin (STZ, i.p.). Western blotting, collagen staining, and echocardiography were performed to detect protein expression and assess cardiac fibrosis and function in vivo. We used high glucose (HG) to culture CFs prior to protein expression measurement in vitro. Upregulation of Sirt1 expression effectively alleviated the degree of cardiac fibrosis by improving cardiac function in diabetic mice. In vitro experiments revealed that HG decreased the protein expression levels of Sirt1, but increased those of type I collagen and alpha-smooth muscle actin (α-SMA), as well as the transdifferentiation of fibroblasts into myofibroblasts. Further studies confirmed that downregulation of Sirt1 expression in the HG environment reduced the protein kinase-B (Akt) phosphorylation, thereby promoting the transdifferentiation of CFs into myofibroblasts coupled with the deterioration of cardiac function. Diabetes mellitus leads to downregulation of Sirt1 protein expression in CFs and decreased Akt phosphorylation, which promotes the transdifferentiation of CFs into myofibroblasts, the pathological process of cardiac fibrosis, and mediates the incidence and development of diabetic cardiomyopathy.

OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.

Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/ PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications.

Correlation between SIRT1 expression and overall survival across various cancers: A meta-analysis

Correlation between SIRT1 expression and overall survival across various cancers: A meta-analysis

Nitazoxanide alleviates experimental pulmonary fibrosis by inhibiting the development of cellular senescence.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by irreversible lung scarring with a poor prognosis. Emerging evidence has revealed that IPF is an aging-related disease, and the development of cellular senescence plays a pivotal role in persistent remodeling and fibrotic scarring, acting as a key mechanism in the pathophysiology of IPF. Exploring therapeutic strategies for modulating cellular senescence can provide crucial insights into unraveling IPF processes. Here, we have identified Nitazoxanide (NTZ), an FDA-approved antiprotozoal agent, has specific effects on inhibiting cellular senescence development. In the bleomycin and D-galactose-induced senescence model, NTZ effectively inhibits senescence associated-β-gal staining and preserves cell proliferation ability. We also found that NTZ effectively impedes senescence progression in the bleomycin-induced pulmonary fibrosis model, while mitigating the release of senescence-associated secretory phenotype and alleviating pulmonary fibrosis. The anti-senescence effect of NTZ is mechanistically dependent on the preservation of nuclear SIRT1 expression. We observed that PI3K induces a WIPI1-mediated nucleophagic degradation of SIRT1, while NTZ effectively inhibits PI3K and suppresses WIPI1 expression, thereby maintaining SIRT1 expression in the nucleus and exerting its anti-senescence function. Collectively, our research has shown that NTZ can inhibit PI3K in senescence progression, leading to the inhibition of WIPI1-mediated SIRT1 nucleophagic degradation. As a result, NTZ alleviates fibrosis by inhibiting senescence development.

SIRT6 knockdown alleviates keratinocyte hyperproliferation and inflammation in psoriasis via modulating acetylation of FOXO1.

The Sirtuins family (SIRT) has been implicated in numerous diseases, including psoriasis.However, the precise role of SIRT6 in psoriasis remains unclear. The analysis of publicly available RNA-seq data from GEO profiles showed that SIRT6 expression levels was significantly elevated in the lesional skins from patients with psoriasis, as compared to the non-lesional skins or the skins from normal healthy donors. It was also confirmed that SIRT6 and Ki67 expression was consistently upregulated inpsoriatic lesional skin,mouse models of psoriasis established by imiquimod treatment, and HaCat cells treated with M5. When SIRT6 was knocked down or inhibited in M5-treated HaCat cells, there was a significant suppression ofM5-induced increases in inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The upregulation of Ki67 expression and cell proliferation induced by M5 were also reduced. SIRT6 inhibitor also significantly reduced the epidermal thickness and Ki67 expression levels in mouse models of psoriasis. Mechanistically, SIRT6 knockdown or inhibition enhanced the nuclear translocation of forkhead box O 1 (FOXO1) by increasing its acetylation level. M5 treatment reduced the nuclear FOXO1 levels via enhancing the nuclear efflux of Foxo1. Knockdown or inhibition of SIRT6 resulted in an increase in nuclear FOXO1 levels, not through enhancing its nuclear influx, but possibly by impeding the nuclear efflux of Foxo1. In conclusion, the knockdown of the SIRT6 promoted the nuclear translocation of FOXO1 by upregulating its acetylation level, thereby inhibiting M5-induced hyperproliferation and inflammation of keratinocyte. Given the crucial role of SIRT6 in psoriasis, it may represent a promising target for the development of small-molecule inhibitors with therapeutic potential for psoriasis.

LncRNA HOXB3OS improves high glucose-mediated podocyte damage and progression of diabetic kidney disease through enhancing SIRT1 mRNA stability.

High glucose (HG)-mediated podocyte damage can be ameliorated by lncRNA HOXB3OS, and exosomes derived from adipose-derived mesenchymal stem cells (ADSCs-Exo) can ameliorate the progression of diabetic kidney disease (DKD) dependening on RNA. To investigate the mechanism by which HOXB3OS improves podocyte injury and the effects of engineered ADSCs-Exo with a high abundance of HOXB3OS on DKD progression, MPC5 cells stimulated with HG and db/db mice were used to develop a podocyte injury model and type II DKD mouse model, respectively. HOXB3OS expression and mRNA level of SIRT1 were detected by qRT-PCR. The protein content of SIRT1 and Ythdc2 was measured through WB, IHC, and IF assays. CCK-8 assay and flow cytometry assay were used to detect cell viability and apoptosis rate of MPC5 cells. RIP assay was used to investigate the binding capacity of Ythdc2 to HOXB3OS or SIRT1 mRNA. Albuminuria, renal function and glomerular structure were observed by kits and PAS, respectively. Consequently, we found that HOXB3OS combined with Ythdc2 and inhibited the binding of Ythdc2 to SIRT1 mRNA, hence inhibiting SIRT1 mRNA degradation. SIRT1 siRNA inhibited the effect of Ythdc2 siRNA on HOXB3OS knock-down or HG-induced podocyte injury. ADSCs-Exo with a high content of HOXB3OS ameliorated HG-mediated podocyte damage and DKD progression. This suggests that engineered ADSCs-Exo with HOXB3OS can suppress Ythdc2-mediated SIRT1 mRNA degradation by disturbing the binding of Ythdc2 to SIRT1 mRNA as well as reverse SIRT1 down-regulation induced by HG, thereby ameliorating podocyte injury and DKD progression.

Canagliflozin attenuates neurodegeneration and ameliorates dyskinesia through targeting the NLRP3/Nurr1/GSK-3β/SIRT3 pathway and autophagy modulation in rotenone-lesioned rats.

This study investigated for the first time the neuroprotective effect of canagliflozin against PD and LID in rotenone-intoxicated rats, emphasizing the crosstalk among the NLRP3/caspase-1 cascade, PGC-1α/SIRT3 pathway, mammalian target of rapamycin (mTOR)/beclin-1, and Nurr1/β-catenin/GSK-3β pathways as possible treatment strategies in PD and LID. Also, correlating NLRP3 expression with all evaluated parameters. The PD rat model was induced via eleven rotenone (1.5mg/kg) subcutaneous injections day after day. Canagliflozin (20mg/kg) and/or L-dopa/carbidopa (100/25mg/kg) were orally administered daily from the beginning until the end of the experiment. Canagliflozin significantly improved neurobehavioral and histological assessments, whereas dyskinesia scores declined. The improvement was confirmed through tyrosine hydroxylase and β-catenin upregulation in contrast to NLRP3 and caspase-1 in substantia nigra pars compacta, as revealed immunohistochemically. In addition, canagliflozin induced a prominent elevation in dopamine, Nurr1, PGC-1α, SIRT3, and beclin-1, whereas mTOR and GSK-3β expressions were downregulated. Our results revealed the aspiring canagliflozin neuroprotective properties against PD and LID in rotenone-lesioned rats via the assumed anti-inflammatory activity and implication of NLRP3/caspase-1, Nurr1/GSK-3β/β-catenin, PGC-1α/SIRT3, and beclin-1/mTOR pathways.

Resveratrol ameliorates postoperative cognitive dysfunction in aged mice by regulating microglial polarization through CX3CL1/CX3CR1 signaling axis.

Postoperative cognitive dysfunction (POCD) is a common cognitive challenge faced by older adults. One of the key contributors to the development of POCD is neuroinflammation induced by microglia. Resveratrol has emerged as a promising candidate for the prevention of cognitive decline. Previous studies have demonstrated its potential in alleviating cognitive deterioration, yielding encouraging results. Nonetheless, the mechanism of resveratrol improving cognitive function remains unclear. Therefore, we assessed the effect of resveratrol in both aged POCD model mice and BV2 cells on CX3CL1/CX3CR1 axis, a critical signaling pathway mediating microglial activity. Both in vitro and in vivo experiments have revealed that pre-administration of resveratrol not only mitigates cognitive deficits but also significantly reduces the levels of inflammatory cytokines. Additionally, it enhanced the expression of SIRT1 and CX3CR1 within the hippocampal region. We also evaluated the impact of resveratrol on CX3CR1 siRNA transfected BV2 cells. Delete of CX3CR1 reversed the preventive role of resveratrol. Our findings implied that resveratrol might inhibit microglial activation and improve cognition by mediating CX3CL1/CX3CR1 signaling.

ADSCs-derived exosomes suppress macrophage ferroptosis via the SIRT1/NRF2 signaling axis to alleviate acute lung injury in sepsis.

Acute lung injury being one of the earliest and most severe complications during sepsis and macrophages play a key role in this process. To investigate the regulatory effects and potential mechanisms of adipose mesenchymal stem cell derived-exosomes (ADSC-exo) on macrophages and septic mice, ADSCs-exo was administrated to both LPS-induced macrophage and cecal ligation and puncture (CLP) induced sepsis mice. ADSCs-exo was confirmed to inhibit M1 polarization of macrophages and to reduce excessive inflammation. The use of ADSCs-exo in CLP mice and in LPS-induced macrophages relieved oxidative stress, cellular damage, and acute lung injury. During this process, ADSCs-exo increased the nuclear translocation of Nrf2, significantly upregulating the activation of the antioxidant pathway Nrf2/HO-1. Concurrently, they enhanced the expression of SIRT1 in macrophages. Further SIRT1 interference experiments demonstrated that ADSCs-exo mitigated macrophage inflammatory responses and LPS-induced ferroptosis by upregulating SIRT1. In the LPS-induced macrophage model, after SIRT1 was interfered with, ADSCs-exo failed to upregulate the Nrf2/HO-1 signaling pathway, leading to enhanced ferroptosis. Finally, in a CLP sepsis mouse model with myeloid-specific SIRT1 knockout, ADSCs-exo was observed to reduce lung tissue injury, oxidative stress damage, and ferroptosis. Still, these beneficial effects were reversed due to the myeloid-specific knockout of SIRT1, while co-administration of a ferroptosis inhibitor rescued this situation, alleviating lung injury and significantly reducing tissue levels of oxidative stress. In conclusion, this study elucidated a novel potential therapeutic mechanism wherein ADSCs-exo upregulates the levels of SIRT1 in macrophages through a non-delivery approach.

Bioactive fraction of Musa balbisiana seed mitigates D-galactose-induced brain aging via SIRT1/PGC-1α/FoxO3a activation and intestinal barrier dysfunction by modulating gut microbiota and core metabolites

Aging is an inevitable biological process, and emerging research has highlighted the potential of dietary and pharmacological interventions to decelerate the trajectory of age-related diseases and prolong the health span. This study evaluates the protective effects of Musa balbisiana seed on healthy aging using D-galactose-induced accelerated aging rats. The results suggested that the bioactive ethyl acetate fraction of Musa balbisiana seed extract (BF) exhibited protective effects against aging-induced oxidative stress by reducing oxidative DNA damage, advanced glycation end-product formation, and malondialdehyde levels while restoring antioxidant and glyoxalase enzyme activities. BF also ameliorated neurodegeneration by decreasing acetylcholinesterase enzyme activity and amyloid beta plaque formation. Histopathological analysis demonstrated the protective effects of BF against brain aging, liver disruption, renal damage, and intestinal barrier dysfunction. BF further restored intestinal permeability by upregulating the tight junctions (zonula occludens 1 and 2, claudin 1,2,3 and 4, and occludin) and mucin (mucin 2 and mucin 5ac) gene expression while downregulating the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α). BF significantly induced the phosphorylation of FoxO3a proteins and upregulated the gene expression of SIRT1, PGC-1α, and TFAM in the hippocampus. Next-generation sequencing (NGS) of 16s rRNA amplicons of fecal metagenomics DNA and metabolites profiling showed that BF intervention restructured the gut microbiota and altered core metabolites related to cholesterol metabolism. Overall, our findings demonstrated the multifaceted protective effects of Musa balbisiana seed against D-galactose-induced aging.

Electroacupuncture inhibits neuronal pyroptosis in ischemic brain injury through modulating SIRT5-mediated NEK7 succinylation.

Ischemic stroke is a leading cause of global death. The treatment of this disease can inevitably result in reperfusion, thereby triggering cerebral ischemia-reperfusion injury (IRI) and neuronal pyroptosis. Electroacupuncture derived from traditional acupuncture has been proven to have favorable effects on ameliorating brain IRI and pyroptosis. Hence, the goal of the current research was to elucidate the mechanism governing electroacupuncture in cerebral IRI. We employed middle cerebral artery occlusion (MCAO) model to induce brain IRI. Our results revealed that electroacupuncture attenuated IRI in MCAO mice by minishing brain damage and hindering neuronal pyroptosis. Strikingly, it was discovered that electroacupuncture provoked the decrease of succinylation level and enhanced expression of SIRT5. Then, we demonstrated that knockdown of SIRT5 reversed the role of electroacupuncture in cerebral infarct injury and pyroptosis. In terms of mechanism, SIRT5 impeded the succinylation modification of NEK7 at K81 site to downregulate its expression level. Eventually, overexpression of NEK7 abrogated the impacts of electroacupuncture on MCAO mice. In conclusion, this study provided the compelling evidence that electroacupuncture restrained neuronal pyroptosis to mitigate ischemic brain damage via desuccinylating NEK7 in a SIRT5-dependent manner.

Research development of Salacca zalacca skin against metabolic syndrome: A Review

Metabolic syndrome (MetS) is a group of metabolic disorders involving obesity, insulin resistance, dyslipidaemia and hypertension. The pathogenesis of MetS includes contributing factors such as genetics and epigenetics, physical inactivity, pollutant exposure, and high fat-high sugar intake that develop into a variety of interrelated pathomechanisms. There are various approaches to managing the MetS, including development of herbal medicine which is currently trending. One of the potential herbal products is Salacca zalacca (SZ) skin. Salak is a native Indonesian fruit that is also grown in the Asia Pacific region, such as Malaysia, Thailand, the Philippines, and others. However, the management of SZ skin is still limited. Thus, we reviewed studies on SZ skin related to MetS. In this review, we found that SZ skin of various cultivars contain saponins, flavonoids, triterpenoids, steroids, and phenols, which are sources of antioxidants. Moreover, an in vitro study found that SZ skin extract inhibits the activity of α-glucosidase enzyme, a key glucose breakdown enzyme that plays a role in the development of hyperglycaemia. In vivo studies also observed that SZ skin extract at a dose of 0.4 mg/mL can increase the expression of SIRT-1, BDNF, and SOD in zebrafish exposed to 3% glucose. In alloxan-induced diabetic rat model showed that the administration of SZ skin extract can reduce blood glucose levels. However, studies on SZ skin as anti-hypertensive and anti-hypercholesterol are very limited. Further studies are needed to consider SZ skin as a potential herbal medicine candidate, especially in managing MetS.

Neospora caninum infection specifically suppresses the expression of a host lncRNA XR_001919077.1 to facilitate parasite propagation by modulating host cell mitochondrial function and autophagy.

Neospora caninum is one of the most common pathogens causing reproductive failure in ruminants (e.g., cattle and goats) worldwide. However, due to a poor understanding of the pathogenic mechanisms of N. caninum infection, no effective drugs and vaccines are currently available. Long non-coding RNAs (lncRNAs) have been reported to be important regulators involved in a great number of physiological and pathological processes. Our previous study found that N. caninum infection induced significantly aberrant expression of lncRNA profiles in caprine endometrial epithelial cells (EECs). In the present study, we found that N. caninum infection specifically suppressed the expression of a novel lncRNA, XR_001919077.1, and knockdown of XR_001919077.1 with small interfering RNA significantly promoted the propagation of N. caninum in caprine EECs. Rapid amplification of cDNA ends analysis generated six splice variants of XR_001919077.1, with lengths ranging from 592 to 694 nt. Transfection of the full length of each variant markedly inhibited the propagation of N. caninum in caprine EECs. Further study suggested that XR_001919077.1 acted as a sponge of Chi-miR-93-5p to promote the expression of sirt1, and the XR_001919077.1/Chi-miR-93-5p/sirt1 axis significantly delayed the in vitro growth of N. caninum in caprine EECs by regulating host cell mitochondrial function and autophagy. Our findings provide a novel insight to understand the interactions between N. caninum and host cells.IMPORTANCEThe uterus is an indispensable reproductive organ for embryo implantation and fetal growth. The endometrium is more vulnerable to infection by pathogenic microorganisms resulting in an increased risk of miscarriage. Neospora caninum is one of the most common pathogens causing miscarriage in ruminants and is able to naturally inhabit the uterus, with N. caninum tissue cysts found in the endometrium. Recent advances in N. caninum research have revealed aberrant expression of long non-coding RNA (lncRNA) profiles in infected caprine endometrial epithelial cells. In the present study, N. caninum, but not Toxoplasma gondii, which has similar morphological and biological features to N. caninum, specifically suppresses the expression of a host lncRNA, XR_ 001919077.1, to impair host's defense through the competitive endogenous RNA mechanism to modulate the host cell mitochondrial function and autophagy to facilitate parasite propagation. The findings suggest a novel immune evasion strategy of N. caninum to facilitate intracellular propagation and provide an alternative path to develop control strategies against neosporosis.

Targeting the SIRT3/MnSOD and JNK/HMGB1/Beclin 1 Axes: Role of Apigenin in Multifaceted Metabolic Intervention in Colorectal Cancer.

Colorectal cancer (CRC) is the third most prevalent cancer worldwide. While chemotherapy remains the standard treatment approach, natural products have emerged as a promising alternative. Among these, apigenin, a natural flavonoid, has garnered significant attention due to its pro-oxidant and antioxidant properties in various types of cancer. This study aimed to assess the potential impact of apigenin in CRC treatment by targeting mitochondrial SIRT3, HMGB1, and beclin 1-mediated autophagy in a mouse model of CRC. We administered 20 mg/kg of dimethyl hydrazine (DMH) intraperitoneally once weekly for 20 weeks to induce CRC in C57BL/6 mice. After 6 weeks of initiating the study, apigenin was intragastrically co-administered by oral gavage at 25 and 50 mg/kg until the end of week 20. The results revealed significant weight loss, shortening of the colon, and diarrhea in DMH-induced CRC, which are considered the marks of CRC. In addition, histopathological examination revealed dysplastic changes in the DMH-treated group, while no dysplasia was found in the apigenin-treated CRC groups. Importantly, the administration of apigenin to DMH-treated animals has led to a significant reduction of SIRT3 and MnSOD expression levels with a significant increase in LC3-II at either dose and a significant dose-dependent increase in the levels of MDA, c-JNK, HMGB1, and beclin 1 compared to the DMH-treated group. In conclusion, apigenin may have a promising role in suppressing DMH-induced CRC. It elicits a pro-oxidant activity by suppressing the gene expression of SIRT3 and subsequently, its target MnSOD, resulting in increased reactive oxygen species (ROS) and lipid peroxidation. The released ROS, in turn, activates JNK-mediated autophagy by enhancing HMGB1, beclin 1, and LC3-II protein levels.

Influence of thermal stress during in vitro maturation on the developmental competence of oocytes and embryos and the expression of Sirtuins in cumulus oocyte complexes in cattle

Sirtuins are of central importance in many cellular functions and promote cell survival under stress. However, little information is available regarding the relationship between sirtuins and female reproductive biology, especially in response to thermal stress. This study investigated the influence of moderately high (40°C) and low (37°C) thermal stress during in vitro maturation on the development competence of bovine oocytes and embryos. The expression and abundance of sirtuins and other proteins involved in stress response were also studied. The cumulus-oocyte complexes (COCs) of Simmental (Bos taurus) cows underwent in vitro maturation (IVM) at different temperatures (37°C, 38.5°C and 40°C). Before maturation, the oocytes were stained with Brilliant Cresyl Blue (BCB) and categorized as labeled (BCB+) or unlabeled (BCB-). Embryo production was analyzed at the different IVM temperatures. Polar body extrusion was evaluated following IVM, and the mRNA and protein abundance of sirtuins and P53 in oocytes and cumulus cells were analyzed. The differing temperatures during IVM did not significantly alter polar body extrusion and cleavage rates; however, significant differences in blastocyst production were observed. COCs matured at 38.5°C (control, 37.3%) had the highest blastocyst rate, in contrast to those matured at 37°C (33.2%) and 40°C (21.5%). In all groups, the blastocyst rates were higher for BCB+ oocytes than for BCB- oocytes. In BCB+ oocytes, the expression of SIRT1, SIRT2, SIRT3, and SIRT5 genes was higher after maturation than that before maturation and in most of the cases, the expression was higher when IVM was performed at 38.5°C. In the cumulus cells of BCB+ COCs, only SIRT2 remained unaffected by the maturation temperature. In summary, the temperature change of ±1.5°C for 24 h during bovine oocyte maturation impaired in vitro embryo development. This lead to several cellular biochemical alterations in oocytes and granulosa cells from COCs with higher developmental competence (BCB+). Thus, SIRT1 is important for in vitro embryonic development and may protect against cold and heat stress.

Selenium Nanoparticles Suppressed Oxidative Stress and Promoted Tenocyte Marker Expression in Tendon-Derived Stem/Progenitor Cells.

Traumatic tendon injuries generate reactive oxygen species and inflammation, which may account for slow or poor healing outcomes. Selenium is an essential trace element presented in selenoproteins, many of which are strong antioxidant enzymes. Selenium nanoparticles (SeNPs) have been reported to promote tissue repair due to their anti-oxidative, anti-inflammatory, anti-apoptotic, and differentiation-modulating properties. However, its effects on the functions of tendon-derived stem/progenitor cells (TDSCs) and tendon healing have not been reported. This study examined the effects of SeNPs on the functions of hydroperoxide (H2O2)-stimulated TDSCs. Rat patellar TDSCs were treated with H2O2 with or without SeNPs. The viability, marker of proliferation, oxidative stress, inflammation, apoptosis, and tenocyte marker expressions of H2O2-stimulated TDSCs after SeNPs treatment were assessed. Our results showed that SeNPs increased the viability and expression of the marker of proliferation of TDSCs exposed to H2O2, while concurrently reducing oxidative stress, inflammation, and apoptosis. Additionally, the expressions of tenocyte markers were significantly elevated in H2O2-treated TDSCs after treatment with SeNPs. Furthermore, the expressions of Sirt1 and Nrf2 also increased after SeNPs treatment in H2O2-stimulated TDSCs. In conclusion, SeNPs mitigated oxidative stress, inflammation, and apoptosis while enhancing the survival and expression of the marker of proliferation of TDSCs in an oxidative stress environment. Additionally, it promoted the fate of TDSCs towards the tenocyte lineage in the presence of such oxidative stress. The increased expressions of Sirt1 and Nrf2 likely mediated the anti-oxidative and anti-inflammatory effects of SeNPs. SeNPs hold promise as a novel intervention for promoting tendon healing.

Cross-Sectional Analysis of Hypoxia-Regulated miRNA-181a, miRNA-199a, HIF-1α, and SIRT1 in the Development of Type 2 Diabetes in Patients with Obstructive Sleep Apnea-Preliminary Study.

Introduction: Obstructive sleep apnea (OSA) is recognized as an independent risk factor for diabetes mellitus type 2 (T2DM) development, which is twice as common in patients with OSA compared to non-OSA patients. Objectives: This study aimed to investigate changes in oxygen metabolism and their role in T2DM development among OSA patients through epigenetic processes via miRNA-181a, miRNA-199a, and enzymatic processes via SIRT1 and HIF-1α. Methods: Based on polysomnography, apnea-hypopnea index and the presence of T2DM patients were divided into three groups: control group (n = 17), OSA group (n = 11), OSA&T2DM (n = 20) group. Total RNA was extracted from the buffy coat. Moreover, HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) was counted. Results: Morning miRNA-181a expression was significantly higher in the OSA&T2DM group than in the control group: 67.618 vs. 32.685 (p = 0.036). Evening miRNA-199a expression was significantly higher in the OSA group than in the control group: 5.043 vs. 2.081 (p = 0.042), while its morning expression was significantly higher in the OSA&T2DM group when compared to the control: 4.065 vs. 1.605 (p = 0.036). MiRNA-181a evening expression revealed a negative correlation with the SIRT1 evening and morning expressions (R = -0.367, p = 0.010 and R = -0.405, p = 0.004, respectively). Moreover, morning miRNA-181a was positively correlated with HOMA-IR (R = 0.321, p = 0.034). MiRNA-199a evening expression presented a moderate positive correlation with the SIRT1 morning expressions (R = 0.48, p < 0.001) and HOMA-IR (R = 0.35, p = 0.02). Conclusions: Patients suffering from OSA and T2DM had an increased expression of miRNA-181a. Moreover, a negative correlation between miRNA-181a and SIRT1 expression was observed, while a correlation between miRNA-181a and insulin resistance was positive. This phenomenon might suggest a possible epigenetic pathway for an increased incidence of T2DM in OSA patients however further research is needed.