Hypothalamic CRF neurons facilitate brain reward function.

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

Effects of dexmedetomidine on surgical site wound pain in patients undergoing laparoscopic cholecystectomy: A meta-analysis.

This study aimed to evaluate the effectiveness of dexmedetomidine as an adjuvant to local wound infiltration anaesthesia in reducing surgical site wound pain in patients undergoing laparoscopic cholecystectomy. The Cochrane Library, PubMed, EMBASE, China National Knowledge Infrastructure, and Wanfang databases were searched from the time of database creation until February 2023. We performed a randomised controlled trial on the effect of dexmedetomidine as an adjunct to local wound infiltration anaesthesia on postoperative wound pain in patients undergoing laparoscopic cholecystectomy. Two investigators independently screened the literature, extracted data, and evaluated the quality of each study. This study was performed using the Review Manager 5.4 software. Ultimately, 13 publications with 1062 patients were included. The results showed that dexmedetomidine was effective as an adjunct to local wound infiltration anaesthesia at 1 h (standardised mean difference [SMD]: -5.31, 95% confidence intervals [CIs]: -7.22 to -3.40, P < .001), 4 h (SMD: -3.40, P < .001), 12 h (SMD: -2.11, 95% CIs: -3.10 to -1.13, P < .001) and 24 h postoperatively (SMD: -1.98, 95% CIs: -2.76 to -1.21, P < .001) significantly reduced surgical site wound pain. However, there was no significant difference in the analgesic effect at 48 h postoperatively (SMD: -1.33, 95% CIs: -3.25 to -0.58, P = .17). Dexmedetomidine provided good postoperative wound analgesia at the surgical site when used for laparoscopic cholecystectomy.

Transcriptome profiling Revealed the potential mechanisms of Shen Lin Bai Zhu San n-butanol extract on DSS induced Colitis in Mice and LC-MS analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disorder in gastrointestinal tract. Shen Ling Bai Zhu San (SLBZS), which has a long history of use in Traditional Chinese Medicine (TCM), has been widely used to treat gastrointestinal diseases. The isolated fractions of TCM have also been proved to possess an important potential for treating diseases, which are due to their effective components. PURPOSE: In this study, we examined the possibility that SLBZS and its isolated active fractions may prevent DSS-induced colitis, and investigated the potential mechanisms by regulating genetic profile of colon. METHODS: Colitis mice were induced by 2.5% DSS for 7 days, and then SLBZS and different SLBZS extracts were administrated to protect the mice for 7 days. Body weight, diarrhea, bleeding in stool, colon length, spleen weight, cytokines of serum and colon and pathology of colon were assessed. The level of Ginsenoside Rg1, Re and Rb1 in different SLBZS extracts and qualitative analysis of n-butanol extract of SLBZS (S-Nb) was performed by HPLC and LC-MS, respectively. And the effects of S-Nb on the transcriptome in colitis were investigated. RESULTS: Our results showed that SLBZS and S-Nb significantly regained body weight, reduced DAI, splenomegaly and the length of colon and attenuated histological damage of the colon. Meanwhile, SLBZS and S-Nb markedly reduced the levels of TNF-α, IL-1ß and IL-6 and increased the level of IL-10 in serum and colon. These effects may be associated with the high levels of Ginsenoside Rg1, Re and Rb1 and rich variety of compounds in S-Nb including 6 ginsenosides, glycyrrhizin, L-tryptophan, and so on. Transcriptome analysis revealed that S-Nb selectively regulated 103 differentially expressed genes (DEGs), 36 of which were changed in DSS-induced mice. And the genes of Per2, Per3, Npy and Serpina3m were closely related to colitis and also restored by S-Nb with different extent. Remarkably, these DEGs modulated the biological functions of colitis mice, including extracellular region, response to external stimulus, MAPK signaling pathway and arginine and proline metabolism. CONCLUSIONS: These data indicated that SLBZS and S-Nb blunted DSS-induced colitis by modulating differentially expression gene profile and biological functions based on their ginsenosides and rich compounds.

External sodium acetate improved Cr(VI) stabilization in a Cr-spiked soil during chemical-microbial reduction processes: Insights into Cr(VI) reduction performance, microbial community and metabolic functions.

Interest combined chemical and microbial reduction for Cr(VI) remediation in contaminated sites has greatly increased. However, the effect of external carbon sources on Cr(VI) reduction during chemical-microbial reduction processes has not been studied. Therefore, in this study, the role of external sodium acetate (SA) in improving Cr(VI) reduction and stabilization in a representative Cr(VI)-spiked soils was systemically investigated. The results of batch experiments suggested that the soil Cr(VI) content declined from 1000 mg/kg to 2.6-5.1 mg/kg at 1-5 g C/kg SA supplemented within 15 days of reaction. The external addition of SA resulted in a significant increase in the relative abundances of Cr(VI)-reducing microorganisms, such as Tissierella, Proteiniclasticum and Proteiniclasticum. The relative abundance of Tissierella increased from 9.1% to 29.8% with the SA treatment at 5 g C/kg soil, which was the main contributors to microbial Cr(VI) reduction. Redundancy analysis indicated that pH and SA were the predominant factors affecting the microbial community in the SA treatments at 2 g C/kg soil and 5 g C/kg soil. Functional prediction suggested that the addition of SA had a positive effect on the metabolism of key substances involved in Cr(VI) microbial reduction. This work provides new insightful guidance on Cr(VI) remediation in contaminated soils.

Polysaccharides derived from Shenling Baizhu San improve colitis via modulating tryptophan metabolism in mice.

Shenling Baizhu San has beneficial effects on the metabolism of the gut microbiota, however, the mechanisms underlying microbiota metabolites mediated anti-inflammation signaling are not well understood. Previously, we have demonstrated that supplementation with Shenling Baizhu San alleviated antibiotic-associated diarrhea (AAD). The current study intends to investigate the dynamic modulation of Shenling Baizhu San polysaccharides (SP) on colitis from the gut microbiota metabolites perspective. Administration of SP effectively relieved colitis induced by DSS in mice, including alleviating body weight loss, the downregulation of colon proinflammatory mediators, and the promotion of intestinal injury repair. Whereas, the efficacy was eliminated by antibiotics, which demonstrated that the efficacy of SP was dependent on the gut microbiota. Fecal microbiota transplantation (FMT) showed that the efficacy of SP can be transferred to gut microbiota. Serum metabolomics analysis showed that supplementation with SP significantly promoted tryptophan metabolism, which was consistent with the changed structure of the gut microbiota, including Bacteroides, Bifidobacterium and Ruminococcus regulated by SP. Especially, the tryptophan metabolites-kynurenine (KYN) activated the expression of amplifying aryl-hydrocarbon receptor (AhR) and Cyp1A1 to promote IL-10 expression in colon. These data suggested that SP positively affected colitis in mice by regulating tryptophan metabolic function of their gut microbiota.

Effects of Zinc Methionine Hydroxy Analog Chelate on Laying Performance, Serum Hormone Levels, and Expression of Reproductive Axis Related Genes in Aged Broiler Breeders.

Inorganic zinc (Zn) supplements are commonly used in poultry feeds, but their low utilization results in the increase of Zn excretion. Thus, to provide a new perspective for the substitution of inorganic Zn, a novel Zn methionine hydroxy analog chelate (Zn-MHA) was studied in the present study to evaluate its effects on laying performance, serum hormone indexes and reproductive axis-related genes in broilers breeders. A total of 480 Hubbard breeders (56-week-old) were fed a basal diet (containing 27.81 mg Zn/kg) without Zn addition for 2 weeks, and then allocated to 4 groups with 6 replicates (each replicate consisting of 10 cages and 2 breeders per cage) for 10 weeks. Four treatment diets given to broiler breeders included the basal diet added with 25, 50, and 75 mg/kg of Zn-MHA and 100 mg/kg of Zn sulfate (ZnSO4). The laying rate, egg weight and feed conversation ratio increased in the 75 mg/kg Zn-MHA group compared to the ZnSO4 group. The eggshell thickness was not decreased with the addition of 50 mg/kg and 75 mg/kg Zn-MHA in the diet compared to the 100 mg/kg ZnSO4 group. There was a significant improvement in the reproductive performance of breeders in the 75 mg/kg Zn-MHA group, including the fertility and 1-day-old offspring weight. Besides, serum sex hormone levels including FSH and P4 increased significantly in 75 mg/kg Zn-MHA group. No significant effect on the ovarian weight or the number of follicles in broiler breeders was observed by supplementing Zn-MHA. Compared to the 100 mg/kg ZnSO4 group, dietary supplementation with 75 mg/kg of Zn-MHA showed an up-regulation of the FSHR mRNA in the granular layer of follicles. However, dietary supplementation of Zn-MHA had no effects on mRNA expressions of the ovarian LHR and PRLR genes. These findings reinforce the suggestion that Zn-MHA (75 mg/kg) could replace ZnSO4 (100 mg/kg) as a Zn supplement in diet of broiler breeders, which resulted in better laying and reproduction performances by regulating the expression levels of reproductive axis related genes and serum hormone levels.

Systematic study on dynamic pyrolysis behaviors, products, and mechanisms of weathered petroleum-contaminated soil with Fe2O3.

Weathered petroleum-contaminated soil (WPCS) with a high proportion of heavy hydrocarbons is difficult to remediate. Our previous research demonstrated that Fe2O3-assisted pyrolysis was a cost-effective technology for the remediation of WPCS. However, the pyrolysis behaviors, products, and mechanisms of the WPCS with Fe2O3 are still unclear. In this study, a combination of Thermogravimetric-Fourier transform infrared spectroscopy (TG-FTIR) and pyrolysis gas chromatography/mass spectrometry (Py-GC/MS) techniques were used to explore these pyrolysis characteristics. The thermal desorption/degradation of light and heavy hydrocarbons in the WPCS mainly occurred at 200-400 °C and 400-550 °C, respectively. The activation energy of thermal reaction of heavy hydrocarbons was decreased in the presence of Fe2O3 during the WPCS pyrolysis processes. In the process, the released inorganic gaseous products were mainly H2O and CO2, while the released organic gaseous compounds were primarily cycloalkanes, alkanes, acids/esters, alcohols, and aldehydes. Compared with the WPCS pyrolysis without Fe2O3, the yields of gaseous products released during the WPCS pyrolysis with Fe2O3 were reduced significantly, and some gaseous products were even not detected. This phenomenon was contributed by the following two reasons: 1) heavy hydrocarbons in the WPCS were more easily transformed into coke in the presence of Fe2O3 during pyrolysis; 2) some released gaseous products were reacted with Fe2O3 and fixed on the soil particles. Therefore, the WPCS pyrolysis with Fe2O3 can effectively reduce the burden of tail gas treatment. Criado method analysis results suggested that the reaction mechanism of heavy hydrocarbons during the WPCS pyrolysis with Fe2O3 was rendered as the synergic effects of diffusion, order-based, and random nucleation and growth reactions.

Comparative Evaluation of Forsythiae Fructus From Different Harvest Seasons and Regions by HPLC/NIR Analysis and Anti-inflammatory and Antioxidant Assays.

Forsythiae Fructus (FF), the dry fruit of Forsythia suspensa (Thunb.) Vahl, has a long history of use in traditional Chinese Medicine for its heat-clearing and detoxifying properties. It possesses clinical therapeutic effects and biological functions showing efficacy in handling different diseases. To investigate the FF differences in Henan, Shanxi, and Shaanxi in August and October, the surface morphology, mid-infrared and near-infrared spectrums, and HPLC were analyzed. Concurrently, the anti-inflammatory and antioxidant effects on LPS-induced J774A.1 cells were evaluated by western blot and RT-qPCR. The results showed that FF from different Harvest Seasons and Regions are provided with different microstructures and mid-infrared and near-infrared spectrums, and the levels of forsythiaside A and phillyrin of FF from Shanxi in August and phillygenin of FF from Shaanxi in August were the highest. Meanwhile, FF from Shanxi and Shaanxi in August markedly reduced the levels of inflammatory cytokines and mediators (TNF-α, IL-1ß, NF-κB, and iNOS) and the protein expression levels of phosphorylated total IKKα/ß and nuclear NF-κB. In August, SXFF and SAXFF also promoted the mRNA expression levels of HO-1 and NQO1 and the protein expression levels of HO-1 and nuclear Nrf2 and suppressed the protein expression levels of KEAP1. Spearman correlation analysis showed that phillygenin had a strong correlation with the protein expression on LPS-induced J774A.1 cells. In summary, our results showed that FF from harvest seasons and regions contributed to the distinct differences in microstructure, the mid-infrared and near-infrared spectrums, and compound content. More importantly, FF from Shanxi and Shaanxi in August showed marked anti-inflammatory and antioxidant activities, but with some differences, which may be because of different contents of phillygenin and phillyrin of lignans in FF.

Herbivore-induced volatiles influence moth preference by increasing the ß-Ocimene emission of neighbouring tea plants.

Herbivore-induced plant volatiles prime neighbouring plants to respond more strongly to subsequent attacks. However, the key volatiles that trigger this state and their priming mechanisms remain largely unknown. The tea geometrid Ectropis obliqua is one of the most devastating leaf-feeding pests of tea plants. Here, plant-plant communication experiments demonstrated that volatiles emitted from tea plants infested by E. obliqua larvae triggered neighbouring plants to release volatiles that repel E. obliqua adult, especially mated females. Volatile analyses revealed that the quantity of eight volatiles increased dramatically when plants were exposed to volatiles emitted by infested tea plants, including (Z)-3-hexenol, linalool, α-farnesene, ß-Ocimene and (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT). The results of behavioural bioassays demonstrated that ß-Ocimene strongly repelled mated E. obliqua females. Individual volatile compound exposure experiments revealed that (Z)-3-hexenol, linalool, α-farnesene and DMNT triggered the emission of ß-Ocimene from tea plants. Chemical inhibition experiments demonstrated that the emission of ß-Ocimene induced by (Z)-3-hexenol, linalool, α-farnesene and DMNT were dependent on Ca2+ and JA signalling. These findings help us to understand how E. obliqua moths respond to volatiles emitted from tea plants and provide new insight into volatile-mediated plant-plant interactions. They have potential significance for the development of novel insect and pest control strategies in crops.

Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway.

PURPOSE: Major depressive disorder (MDD) is a debilitating human health condition characterized by mood swings and is associated with a high probability of suicide attempts. Several studies have reported a role of neuroinflammation in MMD, yet the efficacy of natural drug substances on neuroinflammation-associated depression has not been well-investigated. The present study examined the neuroprotective effects of carvacrol on lipopolysaccharide (LPS)-induced neuroinflammation, depression, and anxiety-like behavior. METHODS: Male Sprague Dawley rats were divided into two experimental cohorts to determine the effects and the effective dose of carvacrol (whether 20 mg/kg or 50 mg/kg), and further demonstrate the mechanism of action of nuclear factor E2-related factor (Nrf2) in depression. RESULTS: We found marked neuronal alterations in the cortex and hippocampus of LPS-intoxicated animals that were associated with higher inflammatory cytokine expression such as cyclooxygenase (COX2), tumor necrosis factor-alpha (TNF-α), and c-Jun N-terminal kinase (p-JNK). These detrimental effects exacerbated oxidative stress, as documented by a compromised antioxidant system due to high lipid peroxidase (LPO). Carvacrol (20 mg/kg) significantly reverted these changes by positively modulating the antioxidant gene Nrf2, a master regulator of the downstream antioxidant pathway. To further investigate the role of Nrf2, an inhibitor of Nrf2 called all-trans retinoic acid (ATRA) was used, which further exacerbated LPS toxicity with a higher oxidative and inflammatory cytokine level. To further support our notion, we performed virtual docking of carvacrol with the Nrf2-Keap1 target and the resultant drug-protein interactions validated the in vivo findings. CONCLUSION: Collectively, our findings suggest that carvacrol (20 mg/kg) could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating LPS-induced neuroinflammation and neurodegeneration.

Potent Natural Antioxidant Carveol Attenuates MCAO-Stress Induced Oxidative, Neurodegeneration by Regulating the Nrf-2 Pathway.

Ischemic stroke is a severe neurological disorder with a high prevalence rate in developed countries. It is characterized by permanent or transient cerebral ischemia and it activates syndrome of pathological events such as membrane depolarization, glutamate excitotoxicity, and intracellular calcium buildup. Carveol is widely employed as anti-inflammatory and antioxidant in traditional Chinese medicine. In the present study, the neuroprotective effects of post-treated carveol were demonstrated against transient middle cerebral artery occlusion (MCAO) induced focal ischemic cerebral injury. Male Sprague Dawley (SD) rats were subjected to two different experimental protocols to determine the dose and effects of carveol, and to demonstrate the underlying role of the nuclear factor E2-related factor (Nrf2) pathway. Our results showed that MCAO induced marked neuronal injury in the ipsilateral cortex and striatum associated with higher inflammatory cytokines expression, along with apoptotic markers such as caspase-3 and the phosphorylated c-Jun N-terminal kinase (JNK). Furthermore, MCAO induced a marked increase in oxidative stress as evidenced by high lipid peroxidase (LPO) content accompanied by the depressed antioxidant system. Carveol significantly reversed the oxidative stress and downregulated inflammatory cascades by enhancing endogenous antioxidant mechanisms including the Nrf2 gene, which critically regulates the expression of several downstream antioxidants. Further, to determine the possible involvement of Nrf2 in carveol mediated neuroprotection, we antagonized Nrf2 by all-trans retinoic acid (ATRA), and such treatment abrogated the protective effects of carveol accompanied with exaggerated neuronal toxicity as demonstrated by higher infarction area. The target effects of carveol were further supported by molecular docking analysis of drug-protein interactions. Together, our findings suggest that carveol could activate endogenous master anti-oxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating MCAO-induced neuroinflammation and neurodegeneration.

Application of N-methyl-D-aspartate receptor nanopore in screening ligand molecules.

N-methyl-D-aspartate receptors (NMDARs) are crucial for excitatory synaptic transmission in the central nervous system. To study NMDARs more accurately and conveniently, we developed a stable NMDAR nanopore in a planar lipid bilayer. Pharmacological properties were validated using the allosteric modulator Ro 25-6981 and antagonist D-2-amino-5-phosphonopentanoic acid (D-APV). The cyanotoxin ß-N-methylamino-L-alanine (BMAA) found in fresh water systems is suspected to be associated with the development of neurodegenerative diseases. Therefore, BMAA and its two isomers L-2, 4-Diaminobutyric acid dihydrochloride (DAB) and N-(2-aminoethyl) glycine (AEG) and an endogenous excitotoxin, quinolinic acid (QA), were studied using the NMDAR nanopores to assess their effects on NMDAR modulation. We demonstrated that the NMDAR nanopore could reliably detect its ligand molecules at the single-channel level. The study also demonstrated the practicability of NMDAR nanopores, and results were validated using two-electrode voltage-clamp (TEVC) recording. Compared with TEVC recording, the NMDAR nanopores conducted ion channel gating at the single-channel level without being affected by other proteins on the cell membrane. The highly sensitive and accurate NMDAR nanopore technique thus has a unique advantage in screening NMDAR ligand molecules that could be associated with neurodegenerative disease.

The dual-functional memantine nitrate MN-08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models.

BACKGROUND AND PURPOSE: Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single-target agents have not prevented its occurrence. Memantine, a non-competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN-08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN-08 in animal models of SAH. EXPERIMENTAL APPROACH: Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN-08 were assessed in vitro. Therapeutic effects of MN-08 were investigated in vivo, using rat and rabbit SAH models. KEY RESULTS: MN-08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN-08 relaxed the pre-contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN-08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN-08 also alleviated cerebral vasospasm in a cisterna magna single-injection model in rabbits. MN-08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN-08 was greater than that of memantine. CONCLUSION AND IMPLICATIONS: MN-08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.

Proteomic analysis reveals the potential neuroprotective effects of tetramethylpyrazine dimer in neuro2a/APPswe cells.

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by pathological processes, including abnormal amyloid deposits and filament tangles, oxidative stress, neuroinflammation, and neurotrophic insufficiency, leading to chronic and prolonged neuronal loss and cognitive deficits. Tetramethylpyrazine (TMP) is one of the main active components of Ligusticum wallichii, a traditional Chinese medicine widely used for brain related disease. Here, we synthesized the TMP derivative tetramethylpyrazine dimer (DTMP), and evaluated the potential mechanisms underlying its potential neuroprotective effects using the murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (N2aAPP). ELISA results indicated that DTMP reduced the levels of Aß1-40 and Aß1-42 in N2aAPP. Then through proteomic analysis we identified a total of 208 differentially expressed proteins in N2aAPP cells compared to the wild-type N2a cells (N2aWT), including 144 increased and 64 decreased proteins. 449 differentially expressed proteins were revealed in N2aAPP cells on DTMP treatment with 69 increased and 380 decreased proteins. Bioinformatic analysis suggested that these proteins are enriched in mitochondrial function, the electronic transmission chain, ATP binding, oxidative phosphorylation, GTPase function, the transcriptional translation process, amino acid metabolism, nucleotide binding and others. Given the vital role of mitochondria in the pathogenesis of AD, we selected the electron transport chain pathway-related molecules to further validate these findings. Western-blot analysis demonstrated that DTMP significantly increased the levels of complex I (NDUAA), complex II (SDHB), complex III (UCRI), complex IV (COX5A) and complex V (ATP5A) in N2aAPP cells. The modulation of dysregulated proteins implicated in AD pathogenesis implies the pharmacological mechanisms of DTMP and its potential as a novel therapeutic choice in AD.

Dual Functional Mesoporous Silicon Nanoparticles Enhance the Radiosensitivity of VPA in Glioblastoma.

Radiotherapy is a critical strategy and standard adjuvant approach to glioblastoma treatment. One of the major challenges facing radiotherapy is to minimize radiation damage to normal tissue without compromising therapeutic effects on cancer cells. Various agents and numerous approaches have been developed to improve the therapeutic index of radiotherapy. Among them, radiosensitizers have attracted much attention because they selectively increase susceptibility of cancer cells to radiation and thus enhance biological effectiveness of radiotherapy. However, clinical translation of radiosensitizers has been severely limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this hindrance. In this study, a dual functional mesoporous silica nanoparticle (MSN) formulation of the valproic acid (VPA) radiosensitizer was developed, which specifically recognized folic acid-overexpressing cancer cells and released VPA conditionally in acidic turmeric microenvironment. The efficacy of this targeted and pH-responsive VPA nanocarrier was evaluated as compared to VPA treatment approach in two cell lines: rat glioma cells C6 and human glioma U87. Compared to VPA treatment, targeted VPA-MSNs not only potentiated the toxic effects of radiation and led to a higher rate of cell death but also enhanced inhibition on clonogenic assay. More interestingly, these effects were further accentuated by VPA-MSNs at low pH values. Western blot analysis showed that the effects were mediated via enhanced apoptosis-inducing effects. Our results suggest that the adjunctive use of VPA-MSNs may enhance the effectiveness of radiotherapy in glioma treatment by lowering the radiation doses required to kill cancer cells and thereby minimize collateral damage to healthy adjacent tissue.