Extraction of pectins from renewable grapefruit (Citrus paradisi) peels using deep eutectic solvents and analysis of their structural and physicochemical properties.

This study presents an innovative attempt to extract high-quality pectins from grapefruit (Citrus paradisi) peels by using deep eutectic solvents (DESs) as extraction agents. The maximum yield of betaine-citric acid (BC)-extracted pectin (BC-P) reached 36.47 % under the optimum process conditions: an L/S ratio of 25 mL/g, a pH of 2.0, and a temperature of 85 °C for 120 min. The yield of BC-P was significantly higher than HCl-extracted pectin (HCl-P, 8.76 %) under a pH of 2.0. In addition, the structural, physicochemical, and emulsifying properties of the purified pectins (BC-P and HCl-P) and commercial pectin (CP) were comparatively analyzed. Results showed that BC-P exhibited higher RG-I value, more arabinan side-chains, bigger Mw and Mn value than HCl-P. Moreover, the viscosity, G' and G'' of BC-P were significantly higher than those of HCl-P and CP. More importantly, BC-P demonstrated better emulsifying activity and stability compared to HCl-P and CP. When the concentration of BC-P was increased to 1.50 %, a stable emulsion containing a 50 % soybean oil fraction could be obtained. Our results confirmed that DESs can be considered as high-effective agents for pectin extraction. Pectins extracted from grapefruit peels can be as a promising natural emulsifiers that can be used in the food industry.

Eco-friendly simultaneous extraction of pectins and phenolics from passion fruit (Passiflora edulis Sims) peel: Process optimization, physicochemical properties, and antioxidant activity.

The objective of this study was to simultaneously extract passion fruit (Passiflora edulis) peel pectins and phenolics using deep eutectic solvents, to evaluate their physicochemical properties and antioxidant activity. By taking L-proline: citric acid (Pro-CA) as the optimal solvent, the effect of extraction parameters on the yields of extracted passion fruit peel pectins (PFPP) and total phenolic content (TPC) was explored by response surfaces methodology (RSM). A maximum pectin yield (22.63%) and the highest TPC (9.68 mg GAE/g DW) were attained under 90 °C, extraction solvent pH = 2, extraction time of 120 min and L/S ratio of 20 mL/g. In addition, Pro-CA-extracted pectins (Pro-CA-PFPP) and HCl-extracted pectins (HCl-PFPP) were subjected to high performance gel permeation chromatography (HPGPC), Fourier transform infrared spectroscopy (FT-IR), thermogram analysis (TG/DTG) and rheological measurements. Results verified that the Mw and thermal stability of Pro-CA-PFPP were higher than those of HCl-PFPP. The PFPP solutions featured a non-Newtonian behavior, and compared with commercially pectin solution, PFPP solution exhibited a stronger antioxidant activity. Additionally, passion fruit peel extract (PFPE) exhibited stronger antioxidant effects than PFPP. The results of ultra-performance liquid chromatography hybrid triple quadrupole-linear ion trap mass spectrometry (UPLC-Qtrap-MS) and high performance liquid chromatography (HPLC) analysis showed that (-)-epigallocatechin, gallic acid, epicatechin, kaempferol-3-O-rutin and myricetin were the main phenolic compounds in PFPE and PFPP. Our results suggest that Pro-CA can be considered as an eco-friendly solvent for high-efficient extraction of high-value compounds from agricultural by-products.

Phenolics from noni (Morinda citrifolia L.) fruit alleviate obesity in high fat diet-fed mice via modulating the gut microbiota and mitigating intestinal damage.

Noni fruit has certain anti-obesity effect. However, the bioactive ingredients in noni fruit that contribute to anti-obesity activity as well as the relation between its anti-obesity activity and gut microbiota remain unclear. In this study, obese mice induced by high-fat diet (HFD) and were intervened with noni fruit phenolic extract (NFE) for 10 weeks. The results showed NFE supplementation decreased body weight, lipid accumulation in liver andadiposetissues, ameliorated gut microbiota dysbiosis by increasing short-chain fatty acid (SCFA)-producing bacteria and decreasing lipopolysaccharide (LPS)-producing bacteria, and mitigated intestinal inflammation and oxidative stress. Moreover, NFE supplementation improved intestinal barrier dysfunction by elevating the protein expression levels of Claudin-1, Occludin and ZO-1, alleviated the HFD-induced intestinal inflammation by repressing the LPS/TLR4/NF-κB pathway. Collectively, the findings revealed NFE intervention inhibits obesity by improving gut microbiota disorder, barrier function, and inflammation. Hence, NFE may be an effective way to ameliorate HFD-induced damage.

Noni (Morinda citrifolia L.) fruit phenolic extract supplementation ameliorates NAFLD by modulating insulin resistance, oxidative stress, inflammation, liver metabolism and gut microbiota.

The liver-protective activity of phenolics has been consistently reported, but the underlying protective mechanism of phenolic extract from noni fruit (NFE) against high-fat-diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) remains unclear. Mice were fed with HFD or combination of HFD and NFE for 10 weeks, and then the gut microbiota and liver metabolites were compared. In this study, NFE supplementation alleviated HFD-induced liver injury and metabolic comorbidities, as evidenced by reduced liver function markers, decreased lipid profile levels, and improved obesity and insulin resistance. NFE supplementation restored the composition of gut microbiota with a remarkable elevation in the relative abundance of Parabacteroides, Lactobacillus, Roseburia, Akkermansia and a significant reduction in Helicobacter, norank_f_Desulfovibrionaceae, Desulfovibrio, Mucispirillum at the genus level. Liver metabolomics demonstrated that NFE supplementation favorably regulated the metabolic pathways involved in oxidative stress and inflammation, including purine metabolism, glutathione metabolism, primary bile acid biosynthesis, glycerophospholipid metabolism, pentose phosphate pathway, ascorbate and aldarate metabolism, galactose metabolism etc. Furthermore, NFE supplementation inhibited the HFD-induced activation of the liver endotoxin - TLR4 - NF-κB pathway, and alleviated liver inflammation. In conclusion, the findings of this study provide new evidences supporting that NFE can be used as a therapeutic approach for HFD-induced NAFLD via modulating the gut microbiota composition, liver metabolite profile and suppressing inflammatory reaction.

Rhodomyrtus tomentosa (Ait.) Hassk fruit phenolic-rich extract mitigates intestinal barrier dysfunction and inflammation in mice.

In this study, the mitigative effect of Rhodomyrtus tomentosa (Ait.) Hassk fruit extract rich in phenolic compounds (RTE) on high fat diet (HFD)-induced intestinal barrier dysfunction of mice and the underlying mechanism were explored. The results revealed that RTE supplementation obviously improved gut microbiota dysbiosis induced by HFD, which was evidenced by elevated alpha diversity, suppressed Firmicutes/Bacteroidetes ratio, enriched short-chain fatty acid-producing bacteria (Odoribacter, Parabacteroides, Blautia and Akkermansia), and depleted harmful bacteria (Helicobacter, norank_f_ Desulfovibrionaceae and Mucispirillum). RTE intervention mitigated intestinal barrier dysfunction and inflammation by elevating tight junction proteins expression levels and decreasing proinflammatory cytokines levels. Furthermore, RTE administration inhibited the HFD-induced trigger of the lipopolysaccharide-toll-like receptor 4-nuclear factor kappa-B (LPS-TLR4-NF-κB) pathway in colonic tissue. Therefore, RTE supplementation may be an effective way to protect the intestinal tract in HFD-induced obese individuals.

Screening and identification of natural α-glucosidase and α-amylase inhibitors from partridge tea (Mallotus furetianus Muell-Arg) and in silico analysis.

Partridge leaves (Mallotus furetianus Muell-Arg.) have long been consumed as popular folk substitute tea for treating hyperglycemia in China. In this study, the inhibiting effects of partridge tea extracts on α-glucosidase and α-amylase were investigated, and then effect of partridge tea aqueous extracts (PTAEs) on glucose consumption capacity of 3 T3-L1 preadipocytes cells was determined. Results verified that PTAEs showed excellent anti-α-glucosidase and anti-α-amylase effects. In addition, the PTAEs evidently promoted glucose consumption capacity of 3T3L1 preadipocytes cells. To this end, a combined method of affinity ultrafiltration and HPLC-ESI-qTOF-MS/MS was used for rapidly screening and identifying the potential inhibitors in the PTAEs. Catechin, epicatechin, rutin, ferulic acid, and kaempferitrin with high affinity capacity indicated strong inhibiting effect on α-glucosidase and α-amylase. Docking studies revealed the potential interactive mechanisms between these major inhibitors and two digestive enzymes. This research shows that partridge tea is effective in preventing and treating post hyperglycemia.

Glycolipid Metabolism and Metagenomic Analysis of the Therapeutic Effect of a Phenolics-Rich Extract from Noni Fruit on Type 2 Diabetic Mice.

The phenolics of noni fruit possess antihyperglycemic activity; however, the molecular mechanisms remain unclear. To understand the potential effects it has on type 2 diabetes (T2D), the glycolipid metabolism and gut microbiota regulation of phenolic-rich extracts from noni fruit (NFEs) were investigated. The results indicated that NFE could remarkably ameliorate hyperglycemia, insulin resistance, oxidative stress, and glycolipid metabolism via the adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway in T2D mice. Furthermore, metagenomic sequencing results revealed that NFE intervention modulated the gut microbiota composition in T2D mice, characterized by increased abundance of unclassified_o_Bacteroidales, Alistipes, Prevotella, Lactobacillus, and Akkermansia and decreased abundance of Oscillibacter, Desulfovibrio, and significantly decreased the pathways related to carbohydrate metabolism, translation, amino acid metabolism, and nucleotide metabolism. Taken together, the results provided new evidence that the hypoglycemic and hypolipidemic activities of NFE in T2D were likely attributed to the activation of the liver AMPK pathway and modulation of gut microbiota.

Solvents effect on phenolics, iridoids, antioxidant activity, antibacterial activity, and pancreatic lipase inhibition activity of noni (Morinda citrifolia L.) fruit extract.

This study focused on the relationship between content levels of phytochemicals and the biological activities of noni (Morinda Citrifolia L.) fruit extracts (NFEs) prepared with traditional solvents and deep eutectic solvents (DESs). The results indicated the total phenolic content in Bet-Gly (Betaine: Glycerol) extracts (11.89 mg GAE/g DW) and total iridoid content in 70% ethanol extracts (26.38 mg CE/g DW) were the highest. A total of 17 compounds were identified and quantified in NFEs. Traditional solvent extracts, except ethyl acetate, exhibited higher antioxidant activities than DESs. Three DES extracts showed higher activities against pancreatic lipase than traditional solvent extracts. Multivariate analysis revealed that the type of extraction solvent exerts a significant influence on the phytochemical compositions and biological activities of NFEs. This study provided valuable information on the efficient extraction of phytochemicals from noni fruits and DESs are promising green solvent for the extraction of bioactive compounds from noni fruits.

Exploring the potential mechanism of Rhodomyrtus tomentosa (Ait.) Hassk fruit phenolic rich extract on ameliorating nonalcoholic fatty liver disease by integration of transcriptomics and metabolomics profiling.

Nonalcoholic fatty liver disease (NAFLD), as the commonest form of chronic liver disease, is accompanied by liver oxidative stress and inflammatory responses. Rhodomyrtus tomentosa (Ait.) Hassk fruit phenolic rich extract (RTE) possesses multiple pharmacological effects in management of chronic diseases. In this study, the liver-protective effect of RTE on mice with high-fat-diet (HFD)-induced NAFLD was investigated for the first time, and the underlying molecular mechanism was explored via integration of transcriptomics and metabolomics. The results showed that RTE mitigated liver damage, which was evidenced by declined inflammatory cell infiltration in liver, decreased liver function markers, oxidative stress indexes, lipid profile levels and inflammatory cytokines levels. The differential metabolites by metabonomics illustrated supplementation of RTE affected metabolomics pathways including tryptophan metabolism, alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, cysteine and methionine metabolism, arginine and proline metabolism, which are all involved in oxidative stress and inflammation. Furthermore, the five differential expression genes (DEGs) through liver transcriptomics were screened and recognized, namely Tnfrsf21, Ifit1, Inhbb, Mapk15 and Gadd45g, which revealed that HFD induced Cytokine-cytokine receptor interaction pathway, NF-κB signaling pathway NOD-like receptor pathway, TNF signaling pathway. Integrated analysis of transcriptomics and metabolomics confirmed the supplementation of RTE had significantly regulatory effects on the metabolic pathways involved in inflammatory responses. Additionally, RT-PCR and western blot authenticated RTE intervention regulated the mRNA levels of liver genes involved in inflammation response and inhibited the liver endotoxin-TLR4-NF-κB pathway triggered by HFD, thus alleviating NAFLD. Our findings strongly support the possibility that RTE can be regarded as a potential therapeutic method for obesity-associated NAFLD.

A randomized controlled study of a combination of internal and external treatments for albumin paclitaxel-related peripheral neurotoxicity: A randomized controlled: A study protocol.

INTRODUCTION: Albumin-bound paclitaxel (nab-PTX), a novel paclitaxel preparation, has been found to successfully blocks tumor progression in breast and lung cancer. However, at the same time of as clinical application, neurotoxicity caused by nab-PTX has become the main factor limiting the clinical application of nab-PTX, which seriously affects the quality of life of patients and increases their psychological or financial burden. In clinical applications, JHGWD combined with bloodletting therapy at the end of the extremities has a positive effect on neurotoxic symptoms such as numbness, pain, and weakness of the hands and feet caused by nab-PTX. In a single-arm experiment, it was also found that the immediate effective rate of exsanguination therapy was as high as 70%, and when combined with oral Chinese medicine treatment, it further improved the efficacy. Therefore, a randomized controlled trial (RCT) was designed to further evaluate the efficacy and safety of this treatment. METHODS: This RCT will be conducted at the Shanxi Provincial Hospital of Traditional Chinese Medicine. A total of 120 patients with Nab-PTX chemotherapy-induced neurotoxicity will be recruited. Treatment groups will be categorized into herbs alone group, bloodletting treatment alone group, and herbs combined with bloodletting group. Blank control was used. The primary outcome will be the EORTC QLQ-CIPN20 scale of the included patients, and the secondary outcomes will include EMG, peripheral neurotoxicity symptom score, NCI-CTCAE5.0 peripheral neurotoxicity grade, and WHO anti-tumor drug peripheral neurotoxicity grade. Adverse reactions will be recorded throughout the process. All data in this RCT will be analyzed by SPSS 26.0 software. DISCUSSION: The results of this RCT will contribute to treating PIPN, relieving the neurotoxic symptoms, and improving the quality of life of patients. Finally, the RCT results will be published in a relevant academic journal on completion of the trial. TRIAL REGISTRATION: ChiCTR2200060217(May22,2022).

The occurrence, transformation and control of selenium in coal-fired power plants: Status quo and development.

As a trace element, selenium can cause serious harm to organisms when the concentration is too high. Coal-fired power plants are the main source of man-made selenium emissions. How to control the selenium pollution of coal-fired power plants to realize the renewable selenium and the sustainability of coal has not attracted enough attention from the whole world. This paper outlines the conversion and occurrence of selenium in coal-fired power plants. A small part of the selenium produced by combustion can be removed by selective catalytic reduction (SCR) and electrostatic precipitator (ESP) after the gas phase undergoes physical condensation and chemical adsorption to combine with the particulate matter in the flue gas.Because the chemical precipitation method has poor selenium removal effect, the remaining part enters the flue gas desulfurization absorption tower and can be enriched in the desulfurization slurry. The occurrence situation and conversion pathway of selenium in desulfurization slurry are introduced subsequently, the research progress of selenium removal from wet desulfurization wastewater is reviewed from three aspects: physics, biology and chemistry. We believe that the coupling application of oxidation-reduction potential (ORP) and pH can optimize selenium removal in the desulfurization system by improving the oxidation control. As a technology for wet desulfurization system to treat selenium pollution, it has a good development prospect in near future.Implications: Selenium is a trace element present in coal. It is not only of great significance to the life activities of organisms, but also a kind of rare resource. As the most important source of man-made emissions, coal-fired power plants will cause waste of selenium resources and selenium pollution in the surrounding environment. In this study, the occurrence, conversion and control of selenium in coal-fired power plants were systematically sorted out and analyzed. It is helpful for scholars to study the selenium transformation process more deeply. It is of great significance for policy formulation of recommended control technologies and emission limits. It is of great value for the formulation of recommended control technology and the in-depth study of the selenium transformation process.

Bio-affinity ultra-filtration combined with HPLC-ESI-qTOF-MS/MS for screening potential α-glucosidase inhibitors from Cerasus humilis (Bge.) Sok. leaf-tea and in silico analysis.

Cerasus humilis(Bge.) Sok. leaf-tea (CLT) has a potential anti-α-glucosidase effect. However, its anti-α-glucosidase functional compositions remain unclear. Results showed that 70% methanol extract of CLT (IC50 = 36.57 µg/mL) with the highest total phenolic/flavonoid contents exhibited significantly higher α-glucosidase inhibitory activity (α-GIA) than acarbose (IC50 = 189.57 µg/mL). Additionally, phenolic constituents of the CLT extract were analyzed for the first time in this work. Ten major potential α-glucosidase inhibitors (α-GIs) with high bio-affinity degree in the CLT extract were recognized using a bio-affinity ultra-filtration and HPLC-ESI-qTOF-MS/MS method. In vitro α-GIA assay confirmed that myricetin (IC50 = 36.17 µg/mL), avicularin (IC50 = 69.84 µg/mL), quercitrin, isoquercitrin, prunin and guajavarin were responsible for the α-GIA of the CLT extract. More importantly, the interaction mechanism between α-GIs and α-glucosidase was investigated via in silico analysis. This study provides a high-throughput screening platform for identification of the potential α-GIs from natural products.

Effect of Chinese Medicine on the Biological Behavior and Magnetic Resonance Imaging of Bladder Cancer.

OBJECTIVE: This study aimed to investigate the effects of traditional Chinese medicine (TCM) on biological behavior and magnetic resonance imaging and recurrence rate of patients with bladder cancer. METHOD: Forty-seven postoperative bladder cancer patients treated in our hospital who met the criteria were selected and randomly divided into the TCM treatment group (observation group) and the group without TCM treatment (control group). In the TCM treatment group, the prescription was slightly adjusted according to the different symptoms, and the main prescription remained unchanged. According to the treatment plan, patients continued to undergo bladder irrigation chemotherapy plus TCM treatment, while the control group was only treated with bladder irrigation chemotherapy. The number of patients with recurrence at 3 and 6 months and 1 year, the effects on patients' clinical symptoms, and quality of life were observed, respectively. The changes in MRI images, blood routine, immune function, and leukocyte level and other related indexes before and after treatment were compared between the two groups. RESULTS: After the patients in the observation group were treated with traditional Chinese medicine, the patients' quality of life significantly improved. The patients' CD3+, CD4+, and CD4+/CD8+ indexes were significantly higher than those of the control group. The levels of Hb and PLT of the patients in the observation group were significantly lower than those of the patients in the control group. Patients in the observation group had higher leukocyte levels and a lower recurrence rate than patients in the control group. CONCLUSION: TCM with chemotherapy drugs can effectively improve patients' immune function, increase the level of T-lymphocyte subpopulation, and improve bone marrow hematopoietic function, which has a significant effect on the prevention and treatment of bladder cancer recurrence after surgery.

Weak yet Decisive: Molecular Halogen Bond and Competing Weak Interactions of Iodobenzene and Quinuclidine.

The halogen bonded adduct between the commonly used constituents quinuclidine and iodobenzene is based on a single weak nitrogen-iodine contact, and the isolation of this adduct was initially unexpected. Iodobenzene does not contain any electron-withdrawing group and therefore represents an unconventional halogen bond donor. Based on excellent diffraction data of high resolution, an electron density study was successfully accomplished and confirmed one of the longest N···I molecular halogen bonds with a distance of 2.9301(4) Å. The topological analysis identified the XB as a directional but weak σ hole interaction and revealed secondary contacts between peripheral regions of opposite charge. These additional contacts and their competition with a nitrogen-based interaction were confirmed by NOESY experiments in solution. Integration enabled us to determine the relative NOE ratios and provided insight regarding the existing interactions.

Photobiomodulation for Global Cerebral Ischemia: Targeting Mitochondrial Dynamics and Functions.

Hypothermia is currently the only approved therapy for global cerebral ischemia (GCI) after cardiac arrest; however, it unfortunately has multiple adverse effects. As a noninvasive procedure, photobiomodulation (PBM) therapy has emerged as a potential novel treatment for brain injury. PBM involves the use of low-level laser light therapy to influence cell behavior. In this study, we evaluated the therapeutic effects of PBM treatment with an 808-nm diode laser initiated 6 h after GCI. It was noted that PBM dose-dependently protected against GCI-induced neuronal death in the vulnerable hippocampal CA1 subregion. Functional assessments demonstrated that PBM markedly preserved both short-term (a week) and long-term (6 months) spatial learning and memory function following GCI. Further mechanistic studies revealed that PBM post-treatment (a) preserved healthy mitochondrial dynamics and suppressed substantial mitochondrial fragmentation of CA1 neurons, by reducing the detrimental Drp1 GTPase activity and its interactions with adaptor proteins Mff and Fis1 and by balancing mitochondrial targeting fission and fusion protein levels; (b) reduced mitochondrial oxidative damage and excessive mitophagy and restored mitochondrial overall health status and preserved mitochondrial function; and (c) suppressed mitochondria-dependent apoptosome formation/caspase-3/9 apoptosis-processing activities. Additionally, we validated, in an in vitro ischemia model, that cytochrome c oxidase served as a key PBM target for mitochondrial function preservation and neuroprotection. Our findings suggest that PBM serves as a promising therapeutic strategy for the functional recovery after GCI, with mechanisms involving PBM's preservation on mitochondrial dynamics and functions and the inhibition of delayed apoptotic neuronal death in GCI.

Catecholic Isoquinolines from Portulaca oleracea and Their Anti-inflammatory and ß2-Adrenergic Receptor Agonist Activity.

Isoquinoline alkaloids possess a wide range of structural features and pharmaceutical activities and are promising drug candidates. Ten water-soluble catecholic isoquinolines were isolated from the medicinal plant Portulaca oleracea, including three new (1-3) and seven known compounds (4-10), along with the known catecholamines 11 and 12 and four other known compounds (13-16). A method of polyamide column chromatography using EtOAc-MeOH as the mobile phase was developed for the isolation of catecholic isoquinolines. Alkaloids 1-12 exhibited anti-inflammatory activities (EC50 = 18.0-497.7 µM) through inhibition of NO production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among these compounds, 11, 2, 5, 4, and 8 were more potent than was the positive control, 3,4-dihydroxybenzohydroxamic acid (EC50 = 82.4 µM), with EC50 values of 18.0, 18.1, 35.4, 36.3, and 58.7 µM, respectively. Additionally, at 100 µM, compounds 1-12 showed different degrees of ß2-adrenergic receptor (ß2-AR) agonist activity in the CHO-K1/GA15 cell line which stably expressed ß2-AR as detected by a calcium assay. The EC50 values of 2 and 10 were 5.1 µM and 87.9 nM, respectively.

Synthesis and evaluation of anticancer activity of BOC26P, an ortho-aryl chalcone sodium phosphate as water-soluble prodrugs in vitro and in vivo.

Major limitations of chalcones as clinical anticancer agents are water insolubility and poor bioavailability, which may be improved by a classic phosphate prodrug strategy that targets non-specific alkaline phosphatase (ALP) for releasing the parent drug in vivo. In this study, we found that BOC26P, a phosphate prodrug of chalcone OC26, exhibits excellent water solubility and improved plasma concentration in vivo by either i.v. or p.o. compared with the parent drug. In pace with decreased inhibitory activity of BOC26P against microtubule polymerization in vitro and in cells, the antiproliferative activity of BOC26P is attenuated in A549 and HLF cells. However, the antitumor effect of BOC26P increases in an A549 xenograft model as compared to the equimolar concentration of OC26, suggesting that complex tumor microenvironment would be another important influence factor to regulate the antitumor activity of BOC26Pin vivo. In conclusion, these observations showed that the traditional phosphate prodrug strategy would be a promising and easy method to increase water solubility and anticancer activity of chalcones for the clinical developments of anticancer agents.

Low-level laser therapy for beta amyloid toxicity in rat hippocampus.

Beta amyloid (Aß) is well accepted to play a central role in the pathogenesis of Alzheimer's disease (AD). The present work evaluated the therapeutic effects of low-level laser irradiation (LLI) on Aß-induced neurotoxicity in rat hippocampus. Aß 1-42 was injected bilaterally to the hippocampus CA1 region of adult male rats, and 2-minute daily LLI treatment was applied transcranially after Aß injection for 5 consecutive days. LLI treatment suppressed Aß-induced hippocampal neurodegeneration and long-term spatial and recognition memory impairments. Molecular studies revealed that LLI treatment: (1) restored mitochondrial dynamics, by altering fission and fusion protein levels thereby suppressing Aß-induced extensive fragmentation; (2) suppressed Aß-induced collapse of mitochondrial membrane potential; (3) reduced oxidized mitochondrial DNA and excessive mitophagy; (4) facilitated mitochondrial homeostasis via modulation of the Bcl-2-associated X protein/B-cell lymphoma 2 ratio and of mitochondrial antioxidant expression; (5) promoted cytochrome c oxidase activity and adenosine triphosphate synthesis; (6) suppressed Aß-induced glucose-6-phosphate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase activity; (7) enhanced the total antioxidant capacity of hippocampal CA1 neurons, whereas reduced the oxidative damage; and (8) suppressed Aß-induced reactive gliosis, inflammation, and tau hyperphosphorylation. Although development of AD treatments has focused on reducing cerebral Aß levels, by the time the clinical diagnosis of AD or mild cognitive impairment is made, the brain is likely to have already been exposed to years of elevated Aß levels with dire consequences for multiple cellular pathways. By alleviating a broad spectrum of Aß-induced pathology that includes mitochondrial dysfunction, oxidative stress, neuroinflammation, neuronal apoptosis, and tau pathology, LLI could represent a new promising therapeutic strategy for AD.

Genistein attenuates ischemic oxidative damage and behavioral deficits via eNOS/Nrf2/HO-1 signaling.

Global cerebral ischemia, such as occurs following cardiac arrest, can lead to oxidative stress, hippocampal neuronal cell death, and cognitive defects. The current study examined the potential beneficial effect and underlying mechanisms of post-treatment with the naturally occurring isoflavonic phytoestrogen, genistein, which has been implicated to attenuate oxidative stress. Genistein (1 mg kg(-1)) was administered i.v. 5 min after reperfusion in rats subjected to four-vessel global cerebral ischemia (GCI). The results revealed that genistein exerted significant neuroprotection of hippocampal CA1 neurons following GCI, as evidenced by an increase in NeuN-positive neurons and the decrease in TUNEL-positive neurons. Furthermore, genistein treatment also resulted in significantly improved spatial learning and memory as compared to vehicle control animals. The beneficial effects of genistein appear to be mediated by an increase of phosphorylation/activation of eNOS, with subsequent activation of the antioxidant/detoxification Nrf2/Keap1 transcription system. Along these lines, genistein increased keap1 S-nitrosylation, with a corresponding nuclear accumulation and enhanced DNA binding activity of Nrf2. Genistein also enhanced levels of the Nrf2 downstream antioxidant protein, heme oxygenase (HO)-1, as compared to vehicle control groups. In accordance with its induction of Nrf2 activation, genistein exerted a robust attenuation of oxidative DNA damage and lipid peroxidative damage in hippocampal CA1 neurons after GCI, as measured by immunofluorescence staining of the oxidative stress markers, 8-hydroxy-2-deoxyguanosine (8-OHdG) and 4-Hydroxynonenal (4-HNE). Interestingly, the aforementioned effects of genistein were abolished by pretreatment with L-NAME, an inhibitor of eNOS activation. In conclusion, the results of the study demonstrate that low dose genistein can exert significant antioxidant, neuroprotective, and cognitive-enhancing effects in the hippocampal CA1 region following GCI. Mechanistically, the beneficial effects of genistein appear to be mediated by enhanced eNOS phosphorylation/activation and nitric oxide (NO)-mediated thiol modification of Keap1, with subsequent upregulation of the Nrf2/HO-1 antioxidative signaling pathway and a resultant attenuation of oxidative stress.

11C-CHO PET in optimization of target volume delineation and treatment regimens in postoperative radiotherapy for brain gliomas.

OBJECTIVE: We explored the clinical values of (11)C-choline ((11)C-CHO) PET in optimization of target volume delineation and treatment regimens in postoperative radiotherapy for brain gliomas. METHODS: Sixteen patients with the pathological confirmation of the diagnosis of gliomas prior to receiving radiotherapy (postoperative) were included, and on whom both MRI and CHO PET scans were performed at the same position for comparison of residual tumors with the two techniques. (11)C-CHO was used as the tracer in the PET scan. A plain T1-weighted, T2-weighted and contrast-enhanced T1-weighted imaging scans were performed in the MRI scan sequence. The gliomas' residual tumor volume was defined as the area with CHO-PET high-affinity uptake and metabolism (V(CHO)) and one with MRI T1-weighted imaging high signal intensity (V(Gd)), and was determined by a group of experienced professionals and clinicians. RESULTS: (1) In CHO-PET images, the tumor target volume, i.e., the highly metabolic area with a high concentration of isotopes (SUV 1.016-4.21) and the corresponding contralateral normal brain tissues (SUV0.1-0.62), was well contrasted, and the boundary between lesions and surrounding normal brain tissues was better defined compared with MRI and (18)F-FDG PET images. (2) For patients with brain gliomas of WHO Grade II, the SUV was 1.016-2.5; for those with WHO Grades III and IV, SUVs were >26-4.2. (3) Both CHO PET and MRI were positive for 10 patients and negative for 2 patients. The residual tumor consistency between these two studies was 75%. Four of the 10 CHO-PET-positive patients were negative on MRI scans. The maximum distance between V(Gd) and V(CHO) margins was 1.8 cm. (4) The gross tumor volumes (GTVs) and the ensuing treatment regimens were changed for 31.3% (5/16) of patients based on the CHO-PET high-affinity uptake and metabolism, in which the change rate was 80% (4/5), 14.3 % (1/7) and 0% (0/4) for patients with WHO Grade II III, and IV gliomas, respectively. CONCLUSION: Our data demonstrate that difference exists between CHO PET and MRI by which to judge and identify residual tumor for patients with brain gliomas. CHO PET is considered to be a supplementary diagnostic approach for MRI. Biological tumor target volume (BTV) displayed in the CHO PET images is useful in determining or delineating the radiotherapy target volume and making decisions in selecting treatment regimens. Tumor target volume may be defined more accurately and rationally when the CHO PET is combined with MRI.