Association of leukocyte mitochondrial DNA copy number with longitudinal C-reactive protein levels and survival in older adults: a cohort study.

BACKGROUND: Systemic chronic inflammation occurs with age. The association of the leukocyte mitochondrial DNA copy number, a measure of mitochondrial function in aging, with the temporal profile of serum high-sensitivity C-reactive protein and mortality risk remains uncertain. The objectives of this study were to examine the association of the leukocyte mitochondrial DNA copy number with longitudinal high-sensitivity C-reactive protein levels and the association of the longitudinal high-sensitivity C-reactive protein levels with mortality risk. METHODS: This prospective cohort study included 3928 adults aged ≥ 55 years without systemic inflammation in the baseline examination of the Healthy Aging Longitudinal Study in Taiwan, which started in 2009. Each participant received leukocyte mitochondrial DNA copy number measurement using a fluorescence-based quantitative polymerase chain reaction at baseline, serum high-sensitivity C-reactive protein measurements at baseline and the follow-up examination five years later, and the ascertainment of all-cause death (until November 30, 2021). The relationships among the leukocyte mitochondrial DNA copy number, longitudinal serum high-sensitivity C-reactive protein levels, and time to all-cause mortality were examined using the joint longitudinal and survival modeling analysis. RESULTS: Of the 3928 participants (mean age: 69 years; 2060 [52%] were women), 837 (21%) died during follow-up. In the adjusted analysis, one standard deviation lower natural log-transformed baseline leukocyte mitochondrial DNA copy number was associated with an increase of 0.05 (95% confidence interval [CI], 0.02 to 0.08) standard deviation in serum high-sensitivity C-reactive protein in subsequent years. An increase of 1 standard deviation in instantaneous high-sensitivity C-reactive protein levels was associated with a hazard ratio (HR) for all-cause mortality of 1.22 (95% CI, 1.14 to 1.30). Similar results were obtained after further adjusting for baseline high-sensitivity C-reactive protein levels (HR [95% CI], 1.27 [1.16 to 1.38]) and after excluding those with serum high-sensitivity C-reactive protein above 10 mg/L (HR [95% CI], 1.21[1.11 to 1.31]) or 3 mg/L (HR [95% CI], 1.19 [1.06 to 1.31]) during follow-up. CONCLUSIONS: A lower leukocyte mitochondrial DNA copy number was associated with persistently higher high-sensitivity C-reactive protein levels. Moreover, these higher time-varying high-sensitivity C-reactive protein levels were instantaneously associated with a higher risk of death.

Transcriptomic and Metabolic Network Analysis of Metabolic Reprogramming and IGF-1 Modulation in SCA3 Transgenic Mice.

Spinocerebellar ataxia type 3 (SCA3) is a genetic neurodegenerative disease for which a cure is still needed. Growth hormone (GH) therapy has shown positive effects on the exercise behavior of mice with cerebellar atrophy, retains more Purkinje cells, and exhibits less DNA damage after GH intervention. Insulin-like growth factor 1 (IGF-1) is the downstream mediator of GH that participates in signaling and metabolic regulation for cell growth and modulation pathways, including SCA3-affected pathways. However, the underlying therapeutic mechanisms of GH or IGF-1 in SCA3 are not fully understood. In the present study, tissue-specific genome-scale metabolic network models for SCA3 transgenic mice were proposed based on RNA-seq. An integrative transcriptomic and metabolic network analysis of a SCA3 transgenic mouse model revealed that metabolic signaling pathways were activated to compensate for the metabolic remodeling caused by SCA3 genetic modifications. The effect of IGF-1 intervention on the pathology and balance of SCA3 disease was also explored. IGF-1 has been shown to invoke signaling pathways and improve mitochondrial function and glycolysis pathways to restore cellular functions. As one of the downregulated factors in SCA3 transgenic mice, IGF-1 could be a potential biomarker and therapeutic target.

Growth hormone rescue cerebellar degeneration in SCA3 transgenic mice.

Spinocerebellar ataxia type 3 (SCA3) is a fatal neurodegenerative disease for which no identified effective treatment or prevention methods exist. However, low-dose growth hormone (GH) therapy, as a potential off-label use, may deter the progress of SCA3. SCA3 15Q and SCA3 84Q transgenic mice harboring a YAC transgene that expresses the human ATXN3 gene with a pathogenic expanded 15 CAG repeat and 84 CAG repeat motif, respectively, were recruited. SCA3 15Q transgenic mice were considered as the healthy control group, whereas low-dose GH- and PBS-treated SCA3 84Q transgenic mice were considered as the study and sham groups, respectively. The SCA3 84Q transgenic mice were administered intraperitoneal injections of GH or PBS weekly from the postnatal age of 9 months-18 months. After 9 months of GH treatment in the SCA3 84Q transgenic mice, all locomotor functions including rotarod test, behavior box analysis were restored. The GH-treated SCA3 84Q transgenic mice revealed more preserved Purkinje cells/cerebellar cortex and less ataxin-3 aggregation, DNA oxidative, cell apoptosis compared with the PBS-treated SCA3 84Q transgenic mice. GH therapy may be one of the potential off-labeled using in the alleviation of SCA3 progression.

Far-infrared Radiation Improves Motor Dysfunction and Neuropathology in Spinocerebellar Ataxia Type 3 Mice.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine neurodegenerative disease resulting from the misfolding and accumulation of a pathogenic protein, causing cerebellar dysfunction, and this disease currently has no effective treatments. Far-infrared radiation (FIR) has been found to protect the viability of SCA3 cells by preventing mutant ataxin-3 protein aggregation and promoting autophagy. However, this possible treatment still lacks in vivo evidence. This study assessed the effect of FIR therapy on SCA3 in vivo by using a mouse model over 28 weeks. Control mice carried a healthy wild-type ATXN3 allele that had a polyglutamine tract with 15 CAG repeats (15Q), whereas SCA3 transgenic mice possessed an allele with a pathological polyglutamine tract with expanded 84 CAG (84Q) repeats. The results showed that the 84Q SCA3 mice displayed impaired motor coordination, balance abilities, and gait performance, along with the associated loss of Purkinje cells in the cerebellum, compared with the normal 15Q controls; nevertheless, FIR treatment was sufficient to prevent those defects. FIR significantly improved performance in terms of maximal contact area, stride length, and base support in the forepaws, hindpaws, or both. Moreover, FIR treatment supported the survival of Purkinje cells in the cerebellum and promoted the autophagy, as reflected by the induction of autophagic markers, LC3II and Beclin-1, concomitant with the reduction of p62 and ataxin-3 accumulation in cerebellar Purkinje cells, which might partially contribute to the rescue mechanism. In summary, our results reveal that FIR confers therapeutic effects in an SCA3 transgenic animal model and therefore has considerable potential for future clinical use.

Personal exposure to fine particulate matter and benzo[a]pyrene from indoor air pollution and leukocyte mitochondrial DNA copy number in rural China.

Households in Xuanwei and Fuyuan, China, possess hazardous levels of fine particulate matter with an aerodynamic diameter <2.5 microns (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) from coal combustion. Previous studies found that increased exposure to PM2.5 and benzo[a]pyrene (BaP; a PAH) were associated with decreased mitochondrial DNA copy number (mtDNAcn), a marker of oxidative stress. We further evaluated these associations in a cross-sectional study of 148 healthy non-smoking women from Xuanwei and Fuyuan. Personal exposure to PM2.5 and BaP was measured using portable devices. MtDNAcn was measured using qPCR amplification of leukocyte DNA that was collected after air measurements. Linear regression models were used to estimate the associations between personal exposure to PM2.5 and BaP, and mtDNAcn adjusted for age, body mass index (BMI) and fuel type. We found inverse associations between exposure to PM2.5 and BaP, and mtDNAcn. Each incremental log-µg/m3 increase in PM2.5 was associated with a significant decrease in mtDNAcn of -10.3 copies per cell [95% confidence interval (95% CI): -18.6, -2.0; P = 0.02]. Additionally, each log-ng/m3 increase in BaP was associated with a significant decrease in mtDNAcn of -5.4 copies per cell (95% CI: -9.9, -0.8, P = 0.02). Age, BMI, fuel type and coal mine type were not significantly associated with mtDNAcn. Exposure to PM2.5 and BaP may alter mitochondrial dynamics in non-smoking Chinese women. MtDNAcn may be a potential mediator of indoor air pollution on chronic disease development.

A prospective study of mitochondrial DNA copy number and the risk of prostate cancer.

PURPOSE: Evidence suggests that mitochondrial DNA (mtDNA) copy number increases in response to DNA damage. Increased mtDNA copy number has been observed in prostate cancer (PCa) cells, suggesting a role in PCa development, but this association has not yet been investigated prospectively. METHODS: We conducted a nested case-control study (793 cases and 790 controls) of men randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) to evaluate the association between pre-diagnosis mtDNA copy number, measured in peripheral blood leukocytes, and the risk of PCa. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) and polytomous logistic regression to analyze differences in associations by non-aggressive (Stage I/II AND Gleason grade < 8) or aggressive (Stage III/IV OR Gleason grade ≥ 8) PCa. RESULTS: Although mtDNA copy number was not significantly associated with PCa risk overall (OR 1.23, 95% CI 0.97-1.55, p = 0.089), increasing mtDNA copy number was associated with an increased risk of non-aggressive PCa (OR 1.29, 95% CI 1.01-1.65, p = 0.044) compared to controls. No association was observed with aggressive PCa (OR 1.02, 95% CI 0.64-1.63, p = 0.933). Higher mtDNA copy number was also associated with increased PSA levels among controls (p = 0.014). CONCLUSIONS: These results suggest that alterations in mtDNA copy number may reflect disruption of the normal prostate glandular architecture seen in early-stage disease, as opposed to reflecting the large number of tumor cells seen with advanced PCa.

Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort.

It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.

A nested case-control study of leukocyte mitochondrial DNA copy number and renal cell carcinoma in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Mitochondrial DNA (mtDNA) is vulnerable to mutations, and the number of copies of mtDNA per cell may increase to compensate for DNA damage. Case-control studies have reported associations between altered mtDNA copy number and risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively. We conducted a nested case-control study (252 cases and 504 controls) of RCC risk in relation to pre-diagnostic leukocyte mtDNA copy number in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. mtDNA copy number was measured in triplicate using a fluorescence-based quantitative PCR assay; samples from 22 cases and 36 controls could not be assayed, leaving 230 cases and 468 controls for analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. High mtDNA copy number was associated with an increased risk of RCC, both overall (highest quartile versus lowest: OR = 2.0, 95% CI = 1.2-3.2; P trend = 0.002) and among cases diagnosed ≥6 years after blood collection (OR = 2.6, 95% CI = 1.4-5.0; P trend = 0.003). These findings did not differ significantly by sex, body mass index, history of hypertension or smoking status (P interaction ≥ 0.3). Results of this study suggest that high pre-diagnostic leukocyte mtDNA copy number, a suspected marker of oxidative DNA damage and mitochondrial dysfunction, is associated with increased future RCC risk.

Presence of cytomegalovirus DNA in leucocytes is associated with increased oxidative stress and subclinical atherosclerosis in healthy adults.

OBJECTIVE: Investigate the latent cytomegalovirus (CMV) infection as a biomarker of oxidative stress and atherosclerosis. METHODS: Latent CMV infection was diagnosed in healthy individuals with PCR-evidence of CMV DNA in peripheral leucocytes. Oxidative stress and atherosclerosis were measured by mitochondrial DNA oxidative damage index (mtDNA(ΔCT)) and intima media thickness (IMT). RESULTS: The CMV DNA positive subjects had a higher mean mtDNA(ΔCT) and greater IMT than subjects in the control group. CONCLUSIONS: Presence of CMV DNA in leucocytes, as a marker of latent CMV infection, was associated with increased levels of oxidative stress and subclinical atherosclerosis in healthy adults.

Physicochemical properties and structural changes of chicken breast meat subjected to radio frequency tempering combined with conventional thawing treatments.

Being able to thaw frozen meat in a reasonable time without impairing quality is crucial for industry and households. Radio frequency (RF) techniques have been used to defrost frozen foods. The influences of RF (50 kW, 27.12 MHz) tempering combined with water immersion (WI, 20°C) thawing (RFWI) or air convection (AC, 20°C) thawing (RFAC) on the physicochemical and structural changes of chicken breast meat were investigated, and the results were compared with those of the fresh meat (FM) and the meat samples subjected to WI and AC only. The thawing processes were terminated when the core temperatures of the samples reached 4°C. The results indicated that AC was the most time-consuming technique, whereas RFWI required the least amount of time. The moisture losses, contents of the thiobarbituric acid-reactive substance, total volatile basic nitrogen, and total viable counts of the meat subjected to AC were higher. Relatively less changes in water-holding capacity, coloration, oxidation, microstructure, protein solubility, and high sensorial acceptance were observed for RFWI and RFAC. This study demonstrated that the meat thawed using RFWI and RFAC was of satisfactory quality. Therefore, the RF techniques can be effective alternatives to the time-consuming conventional thawing methods and benefit the meat industry.

A pilot study: handgrip as a predictor in the disease progression of SCA3.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is an inherited, autosomal, and rare neurodegenerative disease. Serum/plasma biomarkers or functional magnetic resonance imaging used to assess progression, except for neurological examinations, is either inconvenient or expensive. Handgrip strength (HGS) may be considered as a biomarker to predict the progress of SCA3 and align with the alteration of plasma neurofilament light chain (NfL) and Scale for the Assessment and Rating of Ataxia (SARA). METHODS: Patients with SCA3 and healthy subjects were recruited from Changhua Christian Hospital. SARA, body mass index (BMI), and NfL were obtained for both groups. HGS was measured using a Jamar Plus + hand dynamometer. RESULTS: This study recruited 31 patients and 36 controls. HGS in the SCA3 group revealed a profound decrease (P < 0.001) compared with normal subjects. HGS also had a negative correlation with SARA (r = - 0.548, P = 0.001), NfL (r = - 0.359, P = 0.048), and a positive correlation with BMI (r = 0.680, P < 0.001). Moreover, HGS/BMI ratio correlated with SARA (r = - 0.441, P = 0.013). Controlling for gender and age, HGS still correlated with the above clinical items. The initial hypothesis was also proved in SCA3 84Q transgenic mice, showing grip strength weakness compared to normal mice. CONCLUSIONS: HGS can be an alternative tool to assess the clinical severity of SCA3. Further research is needed to investigate the underlying mechanisms.

Comparison of the disinfection effect of iodophor at two different temperatures on the skin of surgical field and its influence on blood pressure and heart rate of patients.

OBJECTIVE: To compare the disinfection effect of iodophor at two different temperatures on the skin of surgical field and its influence on blood pressure and heart rate of patients. METHODS: The clinical data of 150 patients who underwent surgery in the Seventh People's Hospital of Shanghai University of TCM were collected and divided into two groups based on different disinfection temperatures; the observation group (constant 36°C) and the control group ((24±2)°C), with 75 patients in each. The postoperative disinfection effects of the two groups were evaluated including the disinfection effect, blood pressure, heart rate, body temperature, cold sensation, gastrointestinal reactions, stress response, incidence of complications in the perioperative period, incision healing and satisfaction rate. RESULTS: The disinfection efficacy of the observation group was 96.00%, which was higher than that of the control group (81.33%, P<0.01); the blood pressure and heart rate of patients in the observation group after disinfection were lower than those in the control group (P<0.001); the body temperature was higher than that of the control group (P<0.001); the cold sensation was weaker and gastrointestinal adverse reactions were less than those of the control group (P<0.05); the MDA, GSH-PX and SOD levels after disinfection in the observation group were lower than those of the control group (P<0.001); the incidence rate of complications in the observation group was lower than that of the control group (P<0.05) and the incision healing rate was higher than that of the control group (P<0.05). Patients in observation group were more satisfied with disinfection method, disinfection effect, prevention of complications, postoperative recovery and disinfection times than patients in the control group (P<0.01). CONCLUSION: Iodophor at constant temperature is more effective in skin disinfection of the surgical field, with little influence on blood pressure, heart rate and body temperature. This helps to reduce the cold sensation of skin, the incidence rate of gastrointestinal adverse reactions and complications, promote incision healing and improve the satisfaction rate of the surgery. It is worthy of wide application and promotion.

IGF-1 as a Potential Therapy for Spinocerebellar Ataxia Type 3.

Although the effects of growth hormone (GH) therapy on spinocerebellar ataxia type 3 (SCA3) have been examined in transgenic SCA3 mice, it still poses a nonnegligible risk of cancer when used for a long term. This study investigated the efficacy of IGF-1, a downstream mediator of GH, in vivo for SCA3 treatment. IGF-1 (50 mg/kg) or saline, once a week, was intraperitoneally injected to SCA3 84Q transgenic mice harboring a human ATXN3 gene with a pathogenic expanded 84 cytosine-adenine-guanine (CAG) repeat motif at 9 months of age. Compared with the control mice harboring a 15 CAG repeat motif, the SCA3 84Q mice treated with IGF-1 for 9 months exhibited the improvement only in locomotor function and minimized degeneration of the cerebellar cortex as indicated by the survival of more Purkinje cells with a more favorable mitochondrial function along with a decrease in oxidative stress caused by DNA damage. These findings could be attributable to the inhibition of mitochondrial fission, resulting in mitochondrial fusion, and decreased immunofluorescence staining in aggresome formation and ataxin-3 mutant protein levels, possibly through the enhancement of autophagy. The findings of this study show the therapeutic potential effect of IGF-1 injection for SCA3 to prevent the exacerbation of disease progress.

Coenzyme Q10 Supplementation Increases Removal of the ATXN3 Polyglutamine Repeat, Reducing Cerebellar Degeneration and Improving Motor Dysfunction in Murine Spinocerebellar Ataxia Type 3.

Coenzyme Q10 (CoQ10), a well-known antioxidant, has been explored as a treatment in several neurodegenerative diseases, but its utility in spinocerebellar ataxia type 3 (SCA3) has not been explored. Herein, the protective effect of CoQ10 was examined using a transgenic mouse model of SCA3 onset. These results demonstrated that a diet supplemented with CoQ10 significantly improved murine locomotion, revealed by rotarod and open-field tests, compared with untreated controls. Additionally, a histological analysis showed the stratification of cerebellar layers indistinguishable from that of wild-type littermates. The increased survival of Purkinje cells was reflected by the reduced abundance of TUNEL-positive nuclei and apoptosis markers of activated p53, as well as lower levels of cleaved caspase 3 and cleaved poly-ADP-ribose polymerase. CoQ10 effects were related to the facilitation of the autophagy-mediated clearance of mutant ataxin-3 protein, as evidenced by the increased expression of heat shock protein 27 and autophagic markers p62, Beclin-1 and LC3II. The expression of antioxidant enzymes heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1) and 2 (SOD2), but not of glutathione peroxidase 2 (GPx2), were restored in 84Q SCA3 mice treated with CoQ10 to levels even higher than those measured in wild-type control mice. Furthermore, CoQ10 treatment also prevented skeletal muscle weight loss and muscle atrophy in diseased mice, revealed by significantly increased muscle fiber area and upregulated muscle protein synthesis pathways. In summary, our results demonstrated biochemical and pharmacological bases for the possible use of CoQ10 in SCA3 therapy.

Regulation of mitochondrial fusion and mitophagy by intra-tumoral delivery of membrane-fused mitochondria or Midiv-1 enhances sensitivity to doxorubicin in triple-negative breast cancer.

Increasing mitochondrial fusion by intra-tumoral grafting of membrane-fused mitochondria created with Pep-1 conjugation (P-Mito) contributes to breast cancer treatment, but it needs to be validated. Using mitochondrial division inhibitor-1 (Mdivi-1, Mdi) to disturb mitochondrial dynamics, we showed that the antitumor action of P-Mito in a mouse model of triple-negative breast cancer depends upon mitochondrial fusion and that Mdi treatment alone is ineffective. P-Mito significantly enhanced Doxorubicin (Dox) sensitivity by inducing mitochondrial fusion and mitophagy, and the same efficiency was also achieved with Mdi by inhibiting mitophagy. Cell death was induced via the p53 pathway and AIF nuclear translocation in the case of P-Mito, versus the caspase-dependent pathway for Mdi. Notably, both mitochondrial treatments reduced oxidative stress and blood vessel density of xenograft tumors, especially P-Mito, which was accompanied by inhibition of nuclear factor kappa-B activation. Furthermore, through enrichment analysis, four microRNAs in serum microvesicles induced by P-Mito caused expression of predicted targets via the PI3K-Akt pathway, and significantly impacted regulation of nuclear processes and myeloid cell differentiation. Clustering of gene-sets implicated a major steroid catabolic network. This study showed diverse roles of mitochondria in breast cancer and revealed effective adjuvant therapy targeting mitochondrial fusion and mitophagy.

Inhibitory effect of human breast cancer cell proliferation via p21-mediated G1 cell cycle arrest by araliadiol isolated from Aralia cordata Thunb.

A new polyacetylenic compound, araliadiol, was isolated from the leaves of Aralia cordata Thunb. (Araliaceae). The structure of araliadiol was determined to be 3( S),8( R)-pentadeca-1,9( Z)-diene-4,6-diyne-3,8-diol by MS, NMR, IR, and UV spectroscopic analysis as well as Mosher ester reaction. Araliadiol displayed a significant inhibitory effect on the growth of a human breast adenocarcinoma cell line (MCF-7), with an IC (50) value for cytotoxicity of 6.41 µg/mL. Cell cycle analysis revealed that the proportion of cells in the G (1) phase of the cell cycle increased in a dose-dependent manner (from 54.7 % to 72.0 %) after 48 h exposure to araliadiol at dosages ranging from 0 to 80 µM. The results suggest that araliadiol inhibits cell cycle progression of MCF-7 at the G (1)-S transition. After treatment with araliadiol, phosphorylation of retinoblastoma protein (Rb) in MCF-7 cells was inhibited, accompanied by a decrease in the levels of cyclin D (3) and cyclin-dependent kinase 4 (cdk4) and an increase in the expression of p21 (WAF-1/Cip1). However, the expression of phosphorylated p53 (Ser15) and Chk2 was not altered in MCF-7 cells. These findings indicate that araliadiol exhibits its growth-inhibitory effects on MCF-7 cells through downregulation of cdk4 and cyclin D (3), and upregulation of p21 (WAF-1/Cip1) by a p53-independent mechanism.

Intranasal delivery of mitochondria for treatment of Parkinson's Disease model rats lesioned with 6-hydroxydopamine.

The feasibility of delivering mitochondria intranasally so as to bypass the blood-brain barrier in treating Parkinson's disease (PD), was evaluated in unilaterally 6-OHDA-lesioned rats. Intranasal infusion of allogeneic mitochondria conjugated with Pep-1 (P-Mito) or unconjugated (Mito) was performed once a week on the ipsilateral sides of lesioned brains for three months. A significant improvement of rotational and locomotor behaviors in PD rats was observed in both mitochondrial groups, compared to sham or Pep-1-only groups. Dopaminergic (DA) neuron survival and recovery > 60% occurred in lesions of the substantia nigra (SN) and striatum in Mito and P-Mito rats. The treatment effect was stronger in the P-Mito group than the Mito group, but the difference was insignificant. This recovery was associated with restoration of mitochondrial function and attenuation of oxidative damage in lesioned SN. Notably, P-Mito suppressed plasma levels of inflammatory cytokines. Mitochondria penetrated the accessory olfactory bulb and doublecortin-positive neurons of the rostral migratory stream (RMS) on the ipsilateral sides of lesions and were expressed in striatal, but not SN DA neurons, of both cerebral hemispheres, evidently via commissural fibers. This study shows promise for intranasal delivery of mitochondria, confirming mitochondrial internalization and migration via RMS neurons in the olfactory bulb for PD therapy.

Mitochondrial DNA copy number and lung cancer risk in a prospective cohort study.

Mitochondria are eukaryotic organelles responsible for energy production. Mitochondrial DNA (mtDNA) lack introns and protective histones, have limited DNA repair capacity and compensate for damage by increasing the number of mtDNA copies. As a consequence, mitochondria are more susceptible to reactive oxygen species, an important determinant of cancer risk, and it is hypothesized that increased mtDNA copy number may be associated with carcinogenesis. We assessed the association of mtDNA copy number and lung cancer risk in 227 prospectively collected cases and 227 matched controls from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age at randomization, smoking years and number of cigarettes smoked per day. There was suggestion of a dose-dependent relationship between mtDNA copy number and subsequent risk of lung cancer, with a prominent effect observed in the highest mtDNA copy number quartile [ORs (95% CI) by quartile: 1.0 (reference), 1.3 (0.7-2.5), 1.1 (0.6-2.2) and 2.4 (1.1-5.1); P(trend) = 0.008]. This is the first report, to the best of our knowledge, to suggest that mtDNA copy number may be positively associated with subsequent risk of lung cancer in a prospective cohort study; however, replication is needed in other studies and populations.

Mitochondria DNA deletion and copy numbers of cumulus cells associated with in vitro fertilization outcomes.

OBJECTIVE: Mitochondria are important organelles in cell biology. We aimed to study the effects of mitochondrial DNA variations in cumulus cells (CCs) upon in vitro fertilization and embryo transfer (IVF-ET) outcomes. STUDY DESIGN: A total of 51 women undergoing IVF-ET were recruited for the study. The CCs were collected during oocyte retrievals. Mitochondria DNA 4977-bp deletion (dmtDNA-delta5Kb) and copy numbers (MCN) of CCs were analyzed by polymerase chain reaction. The relationships of dmtDNA-delta5Kb and MCN with patients' age, embryo qualities and pregnancy rates (PRs) were detected and compared. RESULTS: PRs were positively correlated with younger age, better transferred embryo qualities and lower dmtDNA-delta5Kb ratios in CCs. The dmtDNA-delta5Kb status was positively associated with older age and higher MCN but was not associated with embryo morphologic scoring. The dmtDNA-delta5Kb ratios of transferred embryos in pregnancy and nonpregnancy groups were 0% and 10.4%, respectively. The dmtDNA-delta5Kb in > or = 34-year-old and <34-year-old groups were 6.9% and 3.2%, respectively. CONCLUSION: The dmtDNA-delta5Kb and MCN statuses of CCs are negatively associated with PRs, which might be potential tools for oocyte evaluation and embryo selections during IVF-ET.

Gluten sensitivity: associated sporadic cerebellar ataxia in Taiwan.

PURPOSE: Gluten sensitivity (GS) is related to the pathogenesis of sporadic or hereditary ataxia. METHODS: Total of 194 healthy controls and patients with either hereditary ataxia (n=207) or sporadic ataxia (n=361) were tested for the circulating gluten-related autoantibodies which serve as biomarkers to interpret the existence of GS. RESULTS: The incidences of GS in each population were 1% in normal subjects, 2% in hereditary ataxia patients and 9% in sporadic ataxia patients. High serum level of anti-gliadin IgG/IgA and t-transglutaminase IgA were disclosed at the sporadic ataxia patients compared with normal subjects. However, the anti-gliadin IgG is more specific to the disease of sporadic ataxia. CONCLUSION: Relatively higher incidence of GS was found in the population of sporadic ataxia patients but not in either normal subjects or hereditary ataxia patients in Taiwan. Anti-gliadin IgG still is a very powerful indicator to implicate the immune-related sporadic ataxia and we conclude that GS-related sporadic ataxia exists in Taiwan with linkage to autoimmune events.