Iron status influences mitochondrial disease progression in Complex I-deficient mice.

Mitochondrial dysfunction caused by aberrant Complex I assembly and reduced activity of the electron transport chain is pathogenic in many genetic and age-related diseases. Mice missing the Complex I subunit NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) are a leading mammalian model of severe mitochondrial disease that exhibit many characteristic symptoms of Leigh Syndrome including oxidative stress, neuroinflammation, brain lesions, and premature death. NDUFS4 knockout mice have decreased expression of nearly every Complex I subunit. As Complex I normally contains at least 8 iron-sulfur clusters and more than 25 iron atoms, we asked whether a deficiency of Complex I may lead to iron perturbations, thereby accelerating disease progression. Consistent with this, iron supplementation accelerates symptoms of brain degeneration in these mice, while iron restriction delays the onset of these symptoms, reduces neuroinflammation, and increases survival. NDUFS4 knockout mice display signs of iron overload in the liver including increased expression of hepcidin and show changes in iron-responsive element-regulated proteins consistent with increased cellular iron that were prevented by iron restriction. These results suggest that perturbed iron homeostasis may contribute to pathology in Leigh Syndrome and possibly other mitochondrial disorders.

Iron is a mineral that contributes to many vital body functions. But as people age, it accumulates in many organs, including the liver and the brain. Excess iron accumulation is linked to age-related diseases like Parkinson's disease. Too much iron may contribute to harmful chemical reactions in the body. Usually, the body has systems in place to mitigate this harm, but these mechanisms may fail as people age. Uncontrolled iron accumulation may damage essential proteins, DNA and fats in the brain. These changes may kill brain cells causing neurodegenerative diseases like Parkinson's disease. Mitochondria, the cell's energy-producing factories, use and collect iron inside cells. As people age, mitochondria fail, which is also linked with age-related diseases. It has been unclear if mitochondrial failure may also contribute to iron accumulation and associated diseases like Parkinson's. Kelly et al. show that mitochondrial dysfunction causes iron accumulation and contributes to neurodegeneration in mice. In the experiments, Kelly et al. used mice with a mutation in a key-iron processing protein in mitochondria. These mice develop neurodegenerative symptoms and die early in life. Feeding the mice a high-iron diet accelerated the animals' symptoms. But providing them with an iron-restricted diet slowed their symptoms and extended their lives. Low-iron diets also slowed iron accumulation in the animal's liver and reduced brain inflammation. The experiments suggest that mitochondrial dysfunction contributes to both iron overload and brain degeneration. The next step for scientists is understanding the processes leading to mitochondrial dysfunction and iron accumulation. Then, scientists can determine if they can develop treatments targeting these processes. This research might lead to new treatments for Parkinson's disease or other age-related conditions caused by iron overload.

The effects of Baduanjin and yoga exercise programs on physical and mental health in patients with Multiple Sclerosis: A randomized controlled trial.

OBJECTIVE: To discuss whether Baduanjin and yoga exercise interventions improve motor function, posture control, and relieving fatigue and depression in MS patients. And to explore whether practicing Baduanjin benefits MS patients more than yoga. DESIGN: A prospective, randomized, controlled, three-arm trial comparing BDJ (n = 30), yoga (n = 30) and control group (n = 20). SETTING: Jiangsu Provincial Corps Hospital. INTERVENTION: Eligible participants were randomized to a 24-week Baduanjin or yoga intervention, or a usual activity control group. Balance, posture control and trunk movement were measured with the Berg Balance Scale (BBS) and Trunk Impairment Scale (TIS). Fatigue was measured using the Fatigue Severity Scale (FSS) and depressive symptoms via the Zung Self-Rating Depression Scale (SDS). RESULTS: For BBS and TIS, there were significant changes pre- to post- exercise in two exercise groups (P < 0.05), with greater increases in the Baduanjin exercise group (BDJ group). For the FSS, there were significant changes pre- to post- exercise in both the BDJ (P = 0.0292) and yoga groups (P = 0.0150). For the SDS, the pre- and post-exercise difference of the BDJ group was larger than the yoga group (P < 0.0001). On the other hand, we could not find any changes of the BBS, TIS, FSS, and SDS scores in the control group (p > 0.05). CONCLUSION: The results suggest that practicing Baduanjin was more effective than yoga and that it is suitable for the MS patients.

Structurally screening calixarenes as peptide transport activators.

Calixarenes are reportedly excellent activators that can remarkably improve the transport efficiencies of cell penetrating peptides. We employed eight calixarenes to systematically study the influence of structure on activation efficiency, which revealed that the scaffold, head group, and alkyl chain are all significant factors for activation efficiency by affecting affinities with the peptide and membrane.

Positive Regulatory Domain I-binding Factor 1 Mediates Peripheral Nerve Injury-induced Nociception in Mice by Repressing Kv4.3 Channel Expression.

BACKGROUND: The transcriptional repressor positive regulatory domain I-binding factor 1 (PRDM1) is expressed in adult mouse dorsal root ganglion and regulates the formation and function of peripheral sensory neurons. The authors hypothesized that PRDM1 in the dorsal root ganglion may contribute to peripheral nerve injury-induced nociception regulation and that its mechanism may involve Kv4.3 channel transcriptional repression. METHODS: Nociception was induced in C57BL/6 mice by applying chronic constriction injury, complete Freund's adjuvant, or capsaicin plantar injection. Nociceptive response was evaluated by mechanical allodynia, thermal hyperalgesia, cold hyperalgesia, or gait analysis. The role of PRDM1 was evaluated by injection of Prdm1 knockdown and overexpression adeno-associated viruses. The interaction of PRDM1 at the Kv4.3 (Kcnd3) promoter was evaluated by chromatin immunoprecipitation assay. Excitability of dorsal root ganglion neurons was evaluated by whole cell patch clamp recordings, and calcium signaling in spinal dorsal horn neurons was evaluated by in vivo two-photon imaging. RESULTS: Peripheral nerve injury increased PRDM1 expression in the dorsal root ganglion, which reduced the activity of the Kv4.3 promoter and repressed Kv4.3 channel expression (injured vs. uninjured; all P < 0.001). Knockdown of PRDM1 rescued Kv4.3 expression, reduced the high excitability of injured dorsal root ganglion neurons, and alleviated peripheral nerve injury-induced nociception (short hairpin RNA vs. Scram; all P < 0.05). In contrast, PRDM1 overexpression in naive mouse dorsal root ganglion neurons diminished Kv4.3 channel expression and induced hyperalgesia (PRDM1 overexpression vs. control, mean ± SD; n = 13; all P < 0.0001) as evaluated by mechanical allodynia (0.6 ± 0.3 vs. 1.2 ± 0.2 g), thermal hyperalgesia (5.2 ± 1.3 vs. 9.8 ± 1.7 s), and cold hyperalgesia (3.4 ± 0.5 vs. 5.3 ± 0.6 s). Finally, PRDM1 downregulation in naive mice reduced the calcium signaling response of spinal dorsal horn neurons to thermal stimulation. CONCLUSIONS: PRDM1 contributes to peripheral nerve injury-induced nociception by repressing Kv4.3 channel expression in injured dorsal root ganglion neurons.

Ferumoxytol Attenuates the Function of MDSCs to Ameliorate LPS-Induced Immunosuppression in Sepsis.

Sepsis-induced immunosuppression is recognized as one of the main features responsible for therapeutic failures. Myeloid-derived suppressor cells (MDSCs), which are mainly characterized by their suppressive properties, have been reported to be expanded in sepsis. Ferumoxytol (FMT), an FDA-approved iron supplement, has been shown to possess immune-modulatory properties in tumors. However, it is unclear whether FMT alters the functions of MDSCs to reduce late-sepsis immunosuppression. Here, we showed an immunomodulatory effect of FMT on MDSCs to ameliorate lipopolysaccharide (LPS)-induced immunosuppression in the late stage of sepsis. Separation of cells with internalized FMT and detection of the intracellular iron content showed that MDSCs could uptake FMT. Low doses of FMT had no effects on the cell viability of MDSCs, but FMT inhibited the expansion of MDSCs in vitro. Moreover, FMT significantly downregulated the expression levels of Arg-1, S100A8, S100A9, and p47phox as well as ROS production in MDSCs. FMT decreased the percentage of granulocytic MDSCs (G-MDSCs) and promoted the differentiation of MDSCs into macrophages. Furthermore, FMT reduced white blood cell recruitment and alveolar wall thickening in the lungs and areas of necrosis in the liver as well as some biochemical markers of liver dysfunction. FMT decreased the percentage of G-MDSCs and monocytic MDSCs (M-MDSCs) in the spleens of LPS-induced septic mice. Of note, FMT reduced the T cell immunosuppressive functions of both G-MDSCs and M-MDSCs. Expectedly, FMT also significantly reduced Arg-1 and p47phox gene expression in splenic CD11b+Gr-1+ cells isolated from LPS-challenged mice. These data indicate that FMT decreased the immunosuppressive functions of MDSCs by decreasing Arg-1 and ROS production, suggesting that FMT may reduce long-term immunosuppression in the late stage of sepsis.

Baicalein ameliorates pristane-induced lupus nephritis via activating Nrf2/HO-1 in myeloid-derived suppressor cells.

INTRODUCTION: Lupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of pristane-induced LN in mice. METHODS: The renoprotective effect of baicalein was detected in a pristane-induced lupus mice model. NLRP3 inflammasome activation and NF-κB phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-κB phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed. RESULTS: Baicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-κB phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome. CONCLUSION: The data show that baicalein alleviates the symptoms of pristane-induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.

[Determination of multi-pesticides in black tea by subcritical water extraction and gas chromatography-tandem mass spectrometry].

A gas chromatography-tandem mass spectrometry (GC-MS/MS) method with subcritical water extraction was developed for the determination of 21 organochlorine and pyrethroid pesticides in black tea. Under the extraction pressure of 5 MPa, the target compounds were extracted with subcritical water at the temperature of 150 degrees C for 15 min, transferred into acetone-n-hexane (1:1, v/v), and cleaned-up by an ENVI-Carb solid phase extraction (SPE) column. The GC separation was performed on a DB-5 capillary column. The pesticides were determined by MS/MS in multiple reaction monitoring (MRM) mode and quantified by matrix-matched internal standard method. The calibration curves showed good linearities in the range of 5.0-320.0 microg/L with the correlation coefficients greater than 0.99. The limit of quantification (S/N > 10) was 50 ng/g, and the limit of detection (S/N > 3) was 10 ng/g. The recoveries of pesticides spiked in the tea at three levels of 50, 100 and 200 ng/g were ranged from 70. 18% to 119.98% with the relative standard deviations (RSDs) of 5.01%-11.76%. The sensitivity, accuracy and precision of the method meet the technical standard of the pesticide determination. The method can be applied to the determination of organochlorine and pyrethroid pesticides in black tea.

Clinically controlled study on children's infectious mononucleosis treated by Chinese medicine.

OBJECTIVE: To evaluate the clinical efficacy and safety of Chinese drugs for the treatment of children's infectious mononucleosis (CIM). METHODS: Sixty CIM patients were assigned into the treated group and the control group, patients in the treated group were administered with Chinese herbal decoction, and those in the control group were treated with intravenous dripping of ganciclovir 10 mg/kg per day, for a treatment course of 14 days. RESULTS: The total effective rate was 96.0% in the treated group and 97.1% in the control group, showing insignificant difference between groups. The efficacy in the treated group was superior to that in the control group on the fever clearance time (3.0+/-1.5 days vs 4.9+/-3.9 days ) and the disappearance time of cervical lymph node swelling (0.8+/-1.0 score vs 1.5+/-1.2 score), showing statistical significance (all P<0.05). T-cell subsets were markedly improved in both groups after treatment. Adverse reaction occurred in four cases of the control group. CONCLUSION: Using Chinese herbs for clearing heat, removing toxin, activating blood circulation, and dissolving stasis is effective and safe for the treatment of CIM. It can effectively improve the clinical symptoms and shows a certain effect on immune regulation.

[Effect of berberin hydrochloride on blood concentration of cyclosporine A in cardiac transplanted recipients].

OBJECTIVE: To observe the clinic effect of combined use of berberin hydrochloride (Ber) with cyclosporine A (CsA) on the blood concentration of CsA in heart transplanted recipients. METHODS: The blood concentration of CsA, liver-renal function and blood lipids in 22 heart transplanted recipients, who received Ber-CsA combined therapy, were measured. RESULTS: The whole blood steady state concentration of CsA, C0 and C2, in recipients after being treated with Ber-CsA significantly increased than those before applying Ber-CsA (P < 0.01), with the mean increment of 26% and 18% respectively; the dosage of CsA used decreased in 21 patients by 25-100 mg/d; and the Ber-CsA showed no significant effect on liver-renal function or blood lipids (P > 0.05). CONCLUSION: Combined use of CsA with Ber could markedly increase the blood concentration of CsA in heart transplanted recipients and reduce the dosage of CsA required, save the fee for medical service, and shows no obvious adverse reaction.