HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy.

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.

Long-term vitamin A supplementation in a preclinical mouse model for RhoD190N-associated retinitis pigmentosa.

Retinitis pigmentosa (RP) is caused by one of many possible gene mutations. The National Institutes of Health recommends high daily doses of vitamin A palmitate for RP patients. There is a critical knowledge gap surrounding the therapeutic applicability of vitamin A to patients with the different subtypes of the disease. Here, we present a case report of a patient with RP caused by a p.D190N mutation in Rhodopsin (RHO) associated with abnormally high quantitative autofluorescence values after long-term vitamin A supplementation. We investigated the effects of vitamin A treatment strategy on RP caused by the p.D190N mutation in RHO by exposing Rhodopsin p.D190N (RhoD190N/+) and wild-type (WT) mice to experimental vitamin A-supplemented and standard control diets. The patient's case suggests that the vitamin A treatment strategy should be further studied to determine its effect on RP caused by p.D190N mutation in RHO and other mutations. Our mouse experiments revealed that RhoD190N/+ mice on the vitamin A diet exhibited higher levels of autofluorescence and lipofuscin metabolites compared to WT mice on the same diet and isogenic controls on the standard control diet. Vitamin A supplementation diminished photoreceptor function in RhoD190N/+ mice while preserving cone response in WT mice. Our findings highlight the importance of more investigations into the efficacy of clinical treatments like vitamin A for patients with certain genetic subtypes of disease and of genotyping in the precision care of inherited retinal degenerations.

Maternal dietary fatty acid composition and newborn epigenetic aging-a geometric framework approach.

BACKGROUND: Maternal nutrition is associated with epigenetic and cardiometabolic risk factors in offspring. Research in humans has primarily focused on assessing the impact of individual nutrients. OBJECTIVES: We sought to assess the collective impact of maternal dietary MUFAs, PUFAs, and SFAs on epigenetic aging and cardiometabolic risk markers in healthy newborn infants using a geometric framework approach. METHODS: Body fatness (n = 162), aortic intima-media thickness (aIMT; n = 131), heart rate variability (n = 118), and epigenetic age acceleration (n = 124) were assessed in newborn infants. Maternal dietary intake was cross-sectionally assessed in the immediate postpartum period via a validated 80-item self-administered FFQ. Generalized additive models were used to explore interactive associations of nutrient intake, with results visualized as response surfaces. RESULTS: After adjustment for total energy intake, maternal age, gestational age, and sex there was a 3-way interactive association of MUFAs, PUFAs, and SFAs (P = 0.001) with newborn epigenetic aging. This suggests that the nature of each fat class association depends upon one another. Response surfaces revealed MUFAs were positively associated with newborn epigenetic age acceleration only at proportionately lower intakes of SFAs or PUFAs. We also demonstrate a potential beneficial association of omega-3 (n-3) PUFAs with newborn epigenetic age acceleration (P = 0.008). There was no significant association of fat class with newborn aIMT, heart rate variability, or body fatness. CONCLUSIONS: In this study, we demonstrated an association between maternal dietary fat class composition and epigenetic aging in newborns. Future research should consider other characteristics such as the source of maternal dietary fatty acids.

Epigenetic aging in newborns: role of maternal diet.

BACKGROUND: Epigenetic aging is associated with higher risk of cardiovascular disease, cancer, and all-cause mortality and may be a mechanistic link between early-life exposures, such as maternal dietary characteristics during pregnancy, and risk of adult disease. OBJECTIVES: We sought to determine the early-life risk factors for newborn epigenetic aging, specifically maternal dietary macronutrient intake, and whether epigenetic aging is associated with cardiovascular health markers in the newborn. METHODS: Epigenetic age acceleration of 169 newborns was measured from saliva using the Horvath age calculator. Maternal diet during pregnancy was assessed using food-frequency questionnaires. RESULTS: Newborns with positive age acceleration were more likely to be female and have greater body fatness. Maternal intakes of saturated fat [6.2 wk epigenetic age acceleration (95% CI: 1.0, 11.3) per 5% of energy; P = 0.02] and monounsaturated fat [12.4 wk (95% CI: 4.2, 20.5) per 5% of energy; P = 0.003] were associated with higher epigenetic age acceleration in the newborn. The strongest association of individual fatty acids were for palmitoleic acid (25.3 wk; 95% CI: 11.4, 39.2; P = 0.0004), oleic acid (2.2 wk; 95% CI: 0.8, 3.6; P = 0.002), and palmitic acid (2.9 wk; 95% CI: 1.0, 4.9; P = 0.004) per 1% of energy intake. Vitamin D supplementation was associated with lower epigenetic age acceleration (-8.1 wk; 95% CI: -14.5, -1.7; P = 0.01). Epigenetic age acceleration was associated with aortic intima-media thickness in preterm infants [1.0 µm (95% CI: 0.2, 1.8) per week of epigenetic age acceleration; P = 0.01], but not among those born at term (P = 0.78). Epigenetic age acceleration was not associated with heart rate variability in either preterm or term born infants (both P > 0.2). CONCLUSIONS: This study provides evidence of maternal dietary characteristics that are associated with epigenetic aging in the offspring. Prospective intervention studies are required to determine whether such associations are causal.

A new p-hydroxybenzoic acid derivative from an endophytic fungus Penicillium sp. of Nerium indicum.

A new p-hydroxybenzoic acid derivative named 4-(2'R, 4'-dihydroxybutoxy) benzoic acid (1) was isolated from the fermentation of Penicillium sp. R22 in Nerium indicum. The structure was elucidated by means of spectroscopic (HR-ESI-MS, NMR, IR, UV) and X-ray crystallographic methods. The antibacterial and antifungal activity of compound 1 was tested, and the results showed that compound 1 revealed potent antifungal activity against Colletotrichum gloeosporioides, Alternaria alternata, and Alteranria brassicae with MIC value of 31.2 µg/ml.

A new isoquinolone alkaloid from an endophytic fungus R22 of Nerium indicum.

A new isoquinolone alkaloid named 5-hydroxy-8-methoxy-4-phenylisoquinolin-1(2H)-one (3), together with two known quinolinone alkaloids 3-O-methylviridicatin (1) and viridicatol (2) were isolated from the fermentation of an endophytic fungus Penicillium sp. R22 in Nerium indicum. Their structures were elucidated by NMR, IR and MS data, and were also confirmed by comparing with the reported data in the literature. Meanwhile, the antibacterial and antifungal activities of all compounds were tested, and the results showed that three compounds had strong antifungal activity. Among them, compound 2 revealed potent antibacterial activity against Staphylococcus aureus with MIC value of 15.6 µg/mL.

[Clinical observation of Alzheimer's disease treated with acupuncture].

OBJECTIVE: To compare the differences in the clinical efficacy on Alzheimer's disease between acupuncture and medicine. METHODS: One hundred and forty-one patients were randomized into an acupuncture group (72 cases) and a medicine group (69 cases). In the acupuncture group, the needling technique for benefiting qi, promoting blood circulation, regulating mind and improving intelligence was used at Shenting (GV 24), Baihui (GV 20), Fengchi (GB 20), Wangu (GB 12), Danzhong (CV 17), Zhangwan (CV 12), Qihai (CV 6), Xuehai (SP 10) and Zusanli (ST 36). The supplementary acupoints were selected according to the symptoms and physical signs. Acupuncture was given once a day and 6 treatments were required for a week. In the medicine group, the choline sterase inhibitor, donepezil (aricept) was prescribed for oral administration, 1 tablet (5 mg) each time, once every night. Four weeks later, the dose was increased to 2 tablets (10 mg) each time. In the two groups, the treatment of 4 weeks made one session and 4 sessions were required. The changes of scores before and after treatment in the minimum mental state examination (MMSE), the activity of daily living scale (ADL), Alzheimer's disease assessment scale-cognition (ADAS-cog) and the digit span (DS) were observed. RESULTS: After treatment, scores of MMSE and DS were increased as compared with those before treatment (both P < 0.05) and scores of ADL and ADAS-cog were reduced as compared with those before treatment. The score differences in MMSE, ADL, ADAS-cog and DS before and after treatment were significant in the two groups (all P < 0.01). CONCLUSION: The needling technique for benefiting qi, promoting blood circulation, regulating mind and improving intelligence significantly improves the overall function, cognition and activity of daily life in the patients of Alzheimer's disease and the efficacy is better than donepezil.

Nebrodeolysin, a novel hemolytic protein from mushroom Pleurotus nebrodensis with apoptosis-inducing and anti-HIV-1 effects.

A novel hemolysin was isolated from the edible mushroom Pleurotus nebrodensis by ion exchange and gel filtration chromatography on DEAE-Sepharose and Sephacryl S-100. The hemolysin from Pleurotus nebrodensis hemolysin (nebrodeolysin) is a monomeric protein with a molecular weight of approximately 27 kDa as determined by gel filtration and SDS-PAGE. Nebrodeolysin exhibited remarkable hemolytic activity towards rabbit erythrocytes and caused efflux of potassium ions from erythrocytes. Subsequently, this hemolysin showed strong cytotoxicity against Lu-04, Bre-04, HepG2, L929, and HeLa cells. It was also found that this hemolysin induced apoptosis in L929 and HeLa cells as evidenced by microscopic observations and DNA ladder, respectively. Moreover, this hemolysin was shown to possess anti-HIV-1 activity in CEM cell culture.

Electrochemotherapy and its mechanism for sarcoma of KM mice / 生物医学工程学杂志

In this paper are analyzed the effect of electrochemotherapy and its mechanism. The favorable parameter of electric pulses (EP) was studied in vitro using the S-180 cells exposed to various EP. After the tumor model was copied, the tumor-bearing mice were randomly divided into four groups: control, chemotherapy, electrotherapy, and electrochemotherapy. The tumor inhibitory ratio, the cure ratio and the level of oxygen free radicals (OFR) were determined. The inhibitory ratio and cure ratio of electrochemotherapy group were significantly higher than those in the chemotherapy, electrotherapy and control groups (P < 0.05). The injury of OFR was decreased while the immunological competence was increased. The mechanism of electrochemotherapy may be related with the enhancement of cell membranepermeability, the depression of drug resistance, the improvement of immunological competence, and so on.

Progress in electrochemotherapy / 生物医学工程学杂志

Electrochemotherapy (ECT) is a novel cancer treatment in which electric pulses (EPs) inducing cell membrane pored (electroporation) are used as a means of delivering antitumor drugs to the cytoplasm of cancer cells. The minimal thresholds of electric field strength of in vitro tumor cell line and tumor tissue are 450-650 V/cm and 400-600 V/cm, respectively. The typical electrical requirement is 600-1300 V/cm, pulse width of 100 micros, 8 pulses, 1 Hz. More than 10 kinds of antitumor drugs have been applied to ECT, in which the most efficacious drug is Bleomycin, and then Cisplatin. Some exciting inhibitory effects on cells in vitro and on solid tumors in clinical trials have been noticed. The factors influencing ECT effects include the electric parameters, diameter of electrode, distribution of electric field lines, size of tumor, model of drugs injection and kinds of drugs. Some questions of ECT are still open, such as the dosages and kinds of drugs for clinical trials, model of drug injection, influence on normal tissues, therapeutic mechanism.

Study of high-intensity electric pulse inhibited sarcoma for improving antitumor drug effect / 生物医学工程学杂志

This article reports the experiment studies on treating the S-180 sarcomas of KM mice with high-intensity electric pulse and antitumor drug (cyclophosphamide). The results showed that the experimental group of electric field combined with drug has the best effect on tumor, compared with the control group. In addition, electric field can inhibit the formation of vas Capillaries and decrease the supply of nutrition for tumor cell. In conclusion, electric field has inhibited the growth of tumor.