Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.

Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/ß-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/ß-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.

Age-induced accumulation of methylmalonic acid promotes tumour progression.

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards1-6. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy2,3,7,8. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing9-12. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.

mTORC1 Promotes Metabolic Reprogramming by the Suppression of GSK3-Dependent Foxk1 Phosphorylation.

The mammalian Target of Rapamycin Complex 1 (mTORC1)-signaling system plays a critical role in the maintenance of cellular homeostasis by sensing and integrating multiple extracellular and intracellular cues. Therefore, uncovering the effectors of mTORC1 signaling is pivotal to understanding its pathophysiological effects. Here we report that the transcription factor forkhead/winged helix family k1 (Foxk1) is a mediator of mTORC1-regulated gene expression. Surprisingly, Foxk1 phosphorylation is increased upon mTORC1 suppression, which elicits a 14-3-3 interaction, a reduction of DNA binding, and nuclear exclusion. Mechanistically, this occurs by mTORC1-dependent suppression of nuclear signaling by the Foxk1 kinase, Gsk3. This pathway then regulates the expression of multiple genes associated with glycolysis and downstream anabolic pathways directly modulated by Foxk1 and/or by Foxk1-regulated expression of Hif-1α. Thus, Foxk1 mediates mTORC1-driven metabolic rewiring, and it is likely to be critical for metabolic diseases where improper mTORC1 signaling plays an important role.

Aging-accumulated methylmalonic acid serum levels at breast cancer diagnosis are not associated with distant metastases.

PURPOSE: Recent evidence suggests that age-accumulated methylmalonic acid (MMA) promotes breast cancer progression in mice. This study aims to investigate the association between baseline serum MMA concentrations in patients with breast cancer and the development of subsequent distant metastases. METHODS: We included 32 patients with early Luminal B-like breast cancer (LumB, median age 62.4y) and 52 patients with early triple-negative breast cancer (TNBC, median age 50.5y) who developed distant metastases within 5 years. They were matched to an equal number of early breast cancer patients (median age 62.2y for LumB and 50.5y for TNBC) who did not develop distant metastases with at least 5 years of follow-up. RESULTS: Baseline serum MMA levels at breast cancer diagnosis showed a positive correlation with age (P < 0.001) and a negative correlation with renal function and vitamin B12 (all P < 0.02), but no statistical association was found with BMI or tumor stage (P > 0.6). Between matched pairs, no significant difference was observed in MMA levels, after adjusting for kidney function and age (P = 0.19). Additionally, in a mouse model, a significant decline in MMA levels was observed in the tumor-bearing group compared to the group without tumors before and after tumor establishment or at identical times for the control group (P = 0.03). CONCLUSION: Baseline serum MMA levels in patients with breast cancer are not correlated with secondary distant metastasis. Evidence in the mouse model suggests that the presence of a tumor perturbates MMA levels.

Nanoemulsions and Solid Microparticles Containing Pentyl Cinnamate to Control Aedes aegypti.

The Aedes aegypti mosquito is a vector of severe diseases with high morbidity and mortality rates. The most commonly used industrial larvicides have considerable toxicity for non-target organisms. This study aimed to develop and evaluate liquid and solid carrier systems to use pentyl cinnamate (PC), derived from natural sources, to control Ae. aegypti larvae. The liquid systems consisting of nanoemulsions with different lecithins systems were obtained and evaluated for stability over 30 days. Microparticles (MPs) were obtained by the spray drying of the nanoemulsions using maltodextrin as an adjuvant. Thermal, NMR and FTIR analysis indicated the presence of PC in microparticles. Indeed, the best nanoemulsion system was also the most stable and generated the highest MP yield. The PC larvicidal activity was increased in the PC nanoemulsion system. Therefore, it was possible to develop, characterize and obtain PC carrier systems active against Ae. aegypti larvae.

Clinical influence of calcium hydroxide intracanal medications on matrix metalloproteinases and tissue inhibitors of metalloproteinases in apical periodontitis.

OBJECTIVES: This study investigated the influence of calcium hydroxide intracanal medications on the levels of metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in apical periodontitis (AP). MATERIALS AND METHODS: Twenty primarily infected root canals with AP were randomly divided into two groups: Ca(OH)2 + sterile saline solution (SSL) group and Ca(OH)2 + 2% chlorhexidine gel (CHX gel) group. We collected samples from the periradicular tissue fluid (PTF) before (s1) and after 14 days of intracanal medication (s2). MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured by ELISA assay. RESULTS: MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were detected in all PTF samples at s1 and s2 (20/20). At s1, MMP-2 and MMP-9 were detected at higher levels than MMP-1 (p < .05). Higher levels of TIMP-1 than TIMP-2 were found in AP (p < .05). Additionally, we detected higher MMP-1, MMP-2, and MMP-9 over TIMP-1 and TIMP-2 levels in AP (p < .05). At s2, Ca(OH)2 + SSL was as effective as Ca(OH)2 + 2% CHX gel in lowering the levels of MMP-1, MMP-2, and MMP-9 after 14 days of intracanal medication, with no significant difference between them (p > .05). Both Ca(OH) 2 intracanal medications had no significant impact on the levels of TIMP-1 and TIMP-2 (both p > .05). At s2, TIMP-1 levels were higher than TIMP-2 (p < .05). Moreover, there were positive correlations between the levels of MMP-1 and TIMP-1 and MMP-1 and TIMP-2 (p < .05). CONCLUSIONS: Calcium hydroxide medications effectively lowered the levels of MMP-1, MMP-2, and MMP-9 in periapical tissues after 14 days of treatment, with no difference between them. Moreover, the calcium hydroxide intracanal medications tested here had no impact in TIMP-1 and TIMP-2 in periapical tissues. CLINICAL RELEVANCE: MMPs and TIMPs play an essential role in the degradation of the extracellular matrix. The imbalance MMPs and TIMPs can cause periapical tissue destruction. Therefore, the reestablishment of the balance between activated MMPs and TIMPs with root canal therapy is essential to restore tissue homeostasis.

Assessment of the efficacy of the utilisation of conventional and electric toothbrushes by the older adults.

OBJECTIVE: To evaluate the efficacy of electric and conventional toothbrushes for a group of elderly individuals. BACKGROUND: Although the electric toothbrush has been recommended for elderly individuals, there had previously never been a study regarding its efficacy. MATERIAL AND METHODS: Sixty independent elders of both genders with different oral conditions from the Center Adult Day Vitória, Espírito Santo, Brazil, were randomly divided into two groups of 30 individuals. One group received the Oral B CrossAction Power electric toothbrush, whereas the other received a conventional Bitufo Class 32 soft toothbrush to perform oral hygiene. The bacterial plaque index (O'Leary Plaque Index) and DMFT index were assessed as a measure of oral hygiene and oral health. The data were analysed using the Shapiro-Wilk, Mann-Whitney and Wilcoxon tests. RESULTS: The results of the efficacy of the Oral B Cross Action Power electric toothbrush demonstrated that on the 7th and 15th days, the bacterial plaque indexes were 24.91 ± 12.81 and 22.11 ± 14.46, respectively, which corresponds to a 50.24% removal of bacterial plaque on the 7th and 55.83% on the 15th days. Although the electric toothbrush removed more bacterial plaque than the conventional toothbrush, the difference was not statistically significant. CONCLUSION: Both the conventional and the electric toothbrushes were effective in removing bacterial plaque within the elderly group. More studies are necessary to test the efficacy of electric toothbrushes in relation to conventional toothbrushes for elderly patients.

Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers.

Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing to the importance of the amino acid serine in tumorigenesis is striking. The gene encoding the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of serine biosynthesis, is overexpressed in tumors and cancer cell lines via focal amplification and nuclear factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing cells are exquisitely sensitive to genetic ablation of the pathway. Here, we report the discovery of a selective small molecule inhibitor of PHGDH, CBR-5884, identified by screening a library of 800,000 drug-like compounds. CBR-5884 inhibited de novo serine synthesis in cancer cells and was selectively toxic to cancer cell lines with high serine biosynthetic activity. Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH. The identification of a small molecule inhibitor of PHGDH not only enables thorough preclinical evaluation of PHGDH as a target in cancers, but also provides a tool with which to study serine metabolism.

Clinical comparison of the effectiveness of 7- and 14-day intracanal medications in root canal disinfection and inflammatory cytokines.

OBJECTIVE: This clinical study compared the effectiveness of 7- and 14-day intracanal medications in the reduction of bacteria/endotoxins from primarily infected root canals and determined their antigenicity against macrophages through the levels of cytokines. METHODS: Seventy-two primarily infected teeth were randomly divided into six groups according to medication and time of application: 7-day groups = G1, Ca(OH)2 + saline solution (SSL); G2, Ca(OH)2 + 2% chlorhexidine (CHX) gel; and G3, 2% CHX gel and 14-day groups = G4, Ca(OH)2 + SSL; G5, Ca(OH)2 + 2% CHX gel; and G6, 2% CHX gel (all groups, n = 12). Bacterial and endotoxin samples were collected from root canals and inflammatory cytokines of macrophages supernatants. Culture techniques were used to determine bacterial counts and limulus amebocyte lysate (LAL) assay to quantify endotoxins. IL-1ß, TNF-α, and PGE2 were measured by ELISA-assay. RESULTS: With regard to the bacterial reduction, no differences were found between all protocols tested (p > 0.05). The CHX protocols (G3 and G6) exhibited the lowest effectiveness against endotoxins (p < 0.05). All protocols were effective in lowering the levels of IL-1ß, TNF-α, and PGE2 (p < 0.05), with no difference between the medications tested on days 7 or 14 (p > 0.05). Particularly, the 7-day CHX-protocol (G3) exhibited the lowest effectiveness in lowering the levels of most cytokines compared to the 14-day protocols (G6) (p < 0.05). CONCLUSIONS: All the 7- and 14-day intracanal medications were effective in reducing bacteria and endotoxins as well as in lowering the levels of inflammatory cytokines, with CHX showing limited effectiveness against endotoxins. Moreover, 7-day CHX-protocol exhibited the lowest effectiveness in lowering the levels of most cytokines compared to the 14-day protocols. CLINICAL SIGNIFICANCE: Seven-day CHX protocol is the less effective protocol and should be carefully applied by the clinician.

Effects of Resistance Training on Cardiovascular Function in Patients With Peripheral Artery Disease: A Randomized Controlled Trial.

Gomes, APF, Correia, MA, Soares, AHG, Cucato, GG, Lima, AHRA, Cavalcante, BR, Sobral-Filho, DC, and Ritti-Dias, RM. Effects of resistance training on cardiovascular function in patients with peripheral artery disease: A randomized controlled trial. J Strength Cond Res 32(4): 1072-1080, 2018-The aim of this study was to analyze the effects of resistance training on cardiovascular function of patients with peripheral artery disease (PAD). In total, 30 patients with PAD were invited to participate in this randomized controlled trial, randomly allocated to a control (n = 15, 66 ± 2 years; stretching and relaxation exercises) or resistance training group (n = 15, 60 ± 3 years; 3 sets of 10 repetitions of 8 whole-body exercises, with a 2-minute interval between sets). Resting and 24-hour blood pressure (BP), cardiac output, systemic vascular resistance, and autonomic variables were obtained before and after 12 weeks of intervention. A blinded investigator performed all analyses. After 12 weeks of intervention there was maintenance of resting systolic, diastolic, and mean BP (p > 0.18), cardiac output (p = 0.46), and systemic vascular resistance (p = 0.55) in both groups. There was a time effect reduction in heart rate (p = 0.02), accompanied by changes in cardiac autonomic modulation (p = 0.03). There were no changes in 24-hour systolic, diastolic, and mean BP, heart rate, or rate pressure product (p > 0.05). The BP variability decreased in systolic (asleep, p = 0.003), diastolic (24 hours and awake, p = 0.001), and mean (24 hours and asleep, p < 0.02) only in the resistance training (RT) group. Twelve weeks of RT did not change resting and 24-hour BP, or their hemodynamic and autonomic determinants in patients with PAD; however, there were decreases in BP variability, indicating that it could be considered as an alternative to reducing cardiovascular risk in patients with PAD.

Adenosine receptors: regulatory players in the preservation of mitochondrial function induced by ischemic preconditioning of rat liver.

Although adenosine A1 receptors (A1R) have been associated to ischemic preconditioning (IPC), direct evidence for their ability to preserve mitochondrial function upon hepatic preconditioning is still missing and could represent a novel strategy to boost the quality of liver transplants. We tested if the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) prevented IPC in the liver and if the A1R agonist 2-chloro-N6-cyclopentyladenosine (CCPA) might afford a pharmacological preconditioning. Livers underwent a 120 min of 70% warm ischemia and 16 h of reperfusion (I/R), and the IPC group underwent a 5-min ischemic episode followed by a 10-min period of reperfusion before I/R. DPCPX or CCPA was administered intraperitoneally 2 h before IPC or I/R. The control of mitochondrial function emerged as the central element affected by IPC and controlled by endogenous A1R activation. Thus, livers from IPC- or CCPA-treated rats displayed an improved oxidative phosphorylation with higher state 3 respiratory rate, higher respiratory control ratio, increased ATP content, and decreased lag phase. IPC and CCPA also prevented the I/R-induced susceptibility to calcium-induced mitochondrial permeability transition, the rate of reactive oxygen species (ROS) generation, and the decreased mitochondrial content of phospho-Ser9 GSK-3ß. DPCPX abrogated these effects of IPC. These implicate the control of GSK-3ß activity by Akt-mediated Ser9-GSK-3ß phosphorylation preserving the efficiency of oxidative phosphorylation and ROS-mediated cell death in the ability of A1R activation to mimic IPC in the liver. In conclusion, the parallel between IPC and A1R-mediated preconditioning also paves the way to consider a putative therapeutic use of the later in liver transplants.

The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression.

AIMS: The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe(-/-)) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg(-1) diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr(-/-) mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis. CONCLUSION: We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis.

Endodontic retreatment: clinical comparison of reciprocating systems versus rotary system in disinfecting root canals.

INTRODUCTION: This clinical study was conducted to compare the effectiveness of single-file reciprocating systems and rotary systems in removing endotoxins and cultivable bacteria in endodontic retreatment. METHODS: Thirty endodontically treated teeth with post-treatment apical periodontitis were selected. The specimens were divided into three groups according to the system used: WaveOne (n = 10), Reciproc instrument (n = 10), and ProTaper Universal Retreatment system (n = 10). Samples were collected before and after chemomechanical preparation. The irrigation was performed by using 2.5% sodium hypochlorite. A chromogenic limulus amebocyte lysate assay test was used to quantify endotoxins. Culture techniques were used to determine bacterial colony-forming unit counts. RESULTS: At baseline, endotoxins and cultivable bacteria were recovered from 100% of the root canal samples in a median value of 5.84 EU/mL and 4.98 × 10(3) CFU/mL, respectively. After CMP, no differences were found in the median percentage values of endotoxin reduction achieved with reciprocating systems-WaveOne [94.11%] and Reciproc [93.29%] and with rotary systems-ProTaper [94.98%] (P > 0.05). Both single-file reciprocating systems [WaveOne (98.27%) and Reciproc (99.54%)] and rotary system [ProTaper (98.73%)] were effective in reducing bacterial load (P > 0.05). Moreover, no differences were found among the systems tested. CONCLUSIONS: The Reciproc and WaveOne reciprocating systems were as effective as the ProTaper system for removal of endotoxins and bacteria in endodontic retreatment. CLINICAL RELEVANCE: All systems tested were effective to remove cultivable bacteria and endotoxin in endodontic retreatment. As no differences among systems were observed, it is possible to suggest that clinicians should choose the preferred technique to perform endodontic.

Methylmalonic acid in aging and disease.

Metabolic byproducts have conventionally been disregarded as waste products without functions. In this opinion article, we bring to light the multifaceted role of methylmalonic acid (MMA), a byproduct of the propionate metabolism pathway mostly commonly known as a clinical biomarker of vitamin B12 deficiency. MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway, the gut microbiota, and aggressive cancers. Here, we describe the diverse metabolic and signaling functions of MMA and discuss the consequences of increased MMA levels, such as during the aging process, for several age-related human pathologies.

CD5L as a promising biological therapeutic for treating sepsis.

Sepsis results from systemic, dysregulated inflammatory responses to infection, culminating in multiple organ failure. Here, we demonstrate the utility of CD5L for treating experimental sepsis caused by cecal ligation and puncture (CLP). We show that CD5L's important features include its ability to enhance neutrophil recruitment and activation by increasing circulating levels of CXCL1, and to promote neutrophil phagocytosis. CD5L-deficient mice exhibit impaired neutrophil recruitment and compromised bacterial control, rendering them susceptible to attenuated CLP. CD5L-/- peritoneal cells from mice subjected to medium-grade CLP exhibit a heightened pro-inflammatory transcriptional profile, reflecting a loss of control of the immune response to the infection. Intravenous administration of recombinant CD5L (rCD5L) in immunocompetent C57BL/6 wild-type (WT) mice significantly ameliorates measures of disease in the setting of high-grade CLP-induced sepsis. Furthermore, rCD5L lowers endotoxin and damage-associated molecular pattern (DAMP) levels, and protects WT mice from LPS-induced endotoxic shock. These findings warrant the investigation of rCD5L as a possible treatment for sepsis in humans.

Serum methylmalonic acid concentrations at breast cancer diagnosis significantly correlate with clinical frailty.

Methylmalonic acid (MMA), a by-product of propionate metabolism, is known to increase with age. This study investigates the potential of serum MMA concentrations as a biomarker for age-related clinical frailty in older patients with breast cancer. One hundred nineteen patients ≥ 70 years old with early-stage breast cancer were included (median age 76 years). G8 screening, full geriatric assessment, clinical parameters (i.e., estimated glomerular filtration rate (eGFR) and body mass index (BMI)), and serum sample collection were collected at breast cancer diagnosis before any therapy was administered. MMA concentrations were measured via liquid chromatography with tandem mass spectrometry. MMA concentrations significantly increased with age and eGFR (all P < 0.001) in this older population. The group with an abnormal G8 (≤ 14, 51% of patients) had significantly higher MMA levels than the group with normal G8 (> 14, 49%): 260 nmol/L vs. 188 nmol/L, respectively (P = 0.0004), even after correcting for age and eGFR (P = 0.001). Furthermore, in the detailed assessment, MMA concentrations correlated most with mobility (Eastern Cooperative Oncology Group (ECOG) Performance Status and Activities of Daily Living (ADL) tools, all P ≤ 0.02), comorbidity (Charlson Comorbidity Index (CCI) tool, P = 0.005), and polypharmacy (P < 0.001), whereas no significant associations were noted for instrumental ADL (IADL), Mini-Mental State Examination (MMSE), Geriatric Depression Scale-15 (GDS15), Mini Nutritional Assessment-Short Form (MNA-SF), and pain (all P > 0.1). In addition, our results showed that higher MMA levels correlate with poor overall survival in breast cancer patients (P = 0.003). Elevated serum MMA concentrations at initial diagnosis are significantly associated, not only with age but also independently with clinical frailty, suggesting a possible influence of MMA on clinical frailty in older patients with early-stage breast cancer.

Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance.

Chromatin structure is regulated through posttranslational modifications of histone variants that modulate transcription. Although highly homologous, histone variants display unique amino acid sequences associated with specific functions. Abnormal incorporation of histone variants contributes to cancer initiation, therapy resistance, and metastasis. This study reports that, among its biologic functions, histone H3.1 serves as a chromatin redox sensor that is engaged by mitochondrial H2O2. In breast cancer cells, the oxidation of H3.1Cys96 promotes its eviction and replacement by H3.3 in specific promoters. We also report that this process facilitates the opening of silenced chromatin domains and transcriptional activation of epithelial-to-mesenchymal genes associated with cell plasticity. Scavenging nuclear H2O2 or amino acid substitution of H3.1(C96S) suppresses plasticity, restores sensitivity to chemotherapy, and induces remission of metastatic lesions. Hence, it appears that increased levels of H2O2 produced by mitochondria of breast cancer cells directly promote redox-regulated H3.1-dependent chromatin remodeling involved in chemoresistance and metastasis.

Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis.

Berberine (BBR) has recently been shown to improve insulin sensitivity in rodent models of insulin resistance. Although this effect was explained partly through an observed activation of AMP-activated protein kinase (AMPK), the upstream and downstream mediators of this phenotype were not explored. Here, we show that BBR supplementation reverts mitochondrial dysfunction induced by High Fat Diet (HFD) and hyperglycemia in skeletal muscle, in part due to an increase in mitochondrial biogenesis. Furthermore, we observe that the prevention of mitochondrial dysfunction by BBR, the increase in mitochondrial biogenesis, as well as BBR-induced AMPK activation, are blocked in cells in which SIRT1 has been knocked-down. Taken together, these data reveal an important role for SIRT1 and mitochondrial biogenesis in the preventive effects of BBR on diet-induced insulin resistance.

Emulsion Electrospinning of PLLA/PVA/Chitosan with Hypericum perforatum L. as an Antibacterial Nanofibrous Wound Dressing.

Chronic wounds are one of the most severe health problems that affect millions of people worldwide. These types of injuries impair healing and lead to life-threatening complications. Therefore, suitable wound dressing materials are essential to prevent the risk of infection and to provide an excellent healing environment. The present research reports the development of an electrospun Poly (L-lactic acid) (PLLA)/Poly (vinyl alcohol) (PVA)/Chitosan (CS) wound dressing material, produced via emulsion electrospinning in a single step using homogeneous gel-like suspensions of two different and incompatible polymer solutions. The electrospun PLLA/PVA/CS fiber mats were loaded with two different amounts of Hypericum perforatum L. (HP) (2.5% and 5.0% owf). The results revealed that the produced electrospun PLLA/PVA/CS fiber mats displayed ideal properties as a wound dressing due to a total porosity, wettability, water vapor transmission rate (WVTR), and swelling properties similar to those reported for the extracellular matrix (ECM) of the skin, mainly when 2.5% owf HP was incorporated. Moreover, the electrospun PLLA/PVA/CS fiber mats containing HP were able to prevent the growth of gram-positive bacterium Staphylococcus aureus (S. aureus) without causing cytotoxicity to normal human dermal fibroblasts (NHDF). These findings suggest that these electrospun dressing mats are helpful for preventing wound infections as well as an appropriate support and microenvironment for wound healing.