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Transcriptional factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, is generally regarded as a pro-survival factor. Here, we identify that besides its effect on autophagy induction, TFEB exerts a pro-apoptotic effect in response to the cyclopentenone prostaglandin 15-deoxy-∆-(12,14)-prostaglandin J2 (15d-PGJ2). Specifically, 15d-PGJ2 promotes TFEB translocation from the cytoplasm into the nucleus to induce autophagy and lysosome biogenesis via reactive oxygen species (ROS) production rather than mTORC1 inactivation. Surprisingly, TFEB promotes rather than inhibits apoptosis in response to 15d-PGJ2. Mechanistically, ROS-mediated TFEB translocation into the nucleus transcriptionally upregulates the expression of ATF4, which is required for apoptosis elicited by 15d-PGJ2. Additionally, inhibition of TFEB activation by ROS scavenger N-acetyl cysteine or inhibition of protein synthesis by cycloheximide effectively compromises ATF4 upregulation and apoptosis in response to 15d-PGJ2. Collectively, these results indicate that ROS-induced TFEB activation exerts a novel role in promoting apoptosis besides its role in regulating autophagy in response to 15d-PGJ2. This work not only evidences how TFEB is activated by 15d-PGJ2, but also unveils a previously unexplored role of ROS-dependent activation of TFEB in modulating cell apoptosis in response to 15d-PGJ2.

The discovery of transcription factor EB (TFEB) as a master regulator of the autophagy-lysosomal pathway (ALP) has triggered increasing numbers of studies that aim to explore the therapeutic potential of targeting TFEB to treat neurodegenerative disorders (NDs) such as Alzheimer's disease and Parkinson's disease. So far, the findings are exciting and promising. Here, we delineate the dysfunction of the TFEB-mediated ALP in NDs, and we summarize small molecules that have been identified as TFEB activators, along with their protective effects in NDs. We discuss the molecular mechanisms and targets, and the pros and cons of these TFEB activators from the perspective of drug development. Specific and potent small-molecule TFEB activators with ideal brain bioavailability could provide a method for treating NDs.

Lemairamin (also known as wgx-50), is isolated from the pericarps of the Zanthoxylum plants. As an agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), it can reduce neuroinflammation in Alzheimer's disease. This study evaluated its antinociceptive effects in pain hypersensitivity and explored the underlying mechanisms. The data showed that subcutaneous lemairamin injection dose-dependently inhibited formalin-induced tonic pain but not acute nociception in mice and rats, while intrathecal lemairamin injection also dose-dependently produced mechanical antiallodynia in the ipsilateral hindpaws of neuropathic and bone cancer pain rats without affecting mechanical thresholds in the contralateral hindpaws. Multiple bi-daily lemairamin injections for 7 days did not induce mechanical antiallodynic tolerance in neuropathic rats. Moreover, the antinociceptive effects of lemairamin in formalin-induced tonic pain and mechanical antiallodynia in neuropathic pain were suppressed by the α7nAChR antagonist methyllycaconitine. In an α7nAChR antagonist-reversible manner, intrathecal lemairamin also stimulated spinal expression of IL-10 and β-endorphin, while lemairamin treatment induced IL-10 and β-endorphin expression in primary spinal microglial cells. In addition, intrathecal injection of a microglial activation inhibitor minocycline, anti-IL-10 antibody, anti-β-endorphin antiserum or μ-opioid receptor-preferred antagonist naloxone was all able to block lemairamin-induced mechanical antiallodynia in neuropathic pain. These data demonstrated that lemairamin could produce antinociception in pain hypersensitivity through the spinal IL-10/β-endorphin pathway following α7nAChR activation.

Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson’s disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β (Aβ) and hyper-phosphorylated tau accumulation are accountable for the progressive neuronal loss and cognitive impairments usually observed in AD. Currently, medications for AD offer moderate symptomatic relief but fail to cure the disease; hence development of effective and safe drugs is urgently needed for AD treatment. In this study, we investigated a Chinese medicine (CM) formulation named NeuroDefend (ND), for reducing amyloid β (Aβ) and tau pathology in transgenic AD mice models. Regular oral administration of ND improved cognitive function and memory in 3XTg-AD and 5XFAD mice. In addition, ND reduced beta-amyloid precursor protein (APP), APP C-terminal fragments (CTF-β/α), Aβ and 4G8 positive Aβ burden in 3XTg-AD and 5XFAD mice. Furthermore, ND efficiently reduced the levels of insoluble phospho-tau protein aggregates and AT8 positive phospho tau neuron load in 3XTg-AD mice. Hence, ND could be a promising candidate for the treatment of AD in humans. Keywords: Alzheimer's disease, Aβ-plaque, Neurofibrillary tangles, Chinese medicine, NeuroDefend

Fibrosis is the final stage of the development of chronic inflammation. It is characterized by excessive deposition of the extracellular matrix, leading to tissue structure damage and organ dysfunction, which is a serious threat to human health and life. However, the molecular mechanism of fibrosis is still unclear. Inflammasome is a molecular complex of proteins that has been becoming a key innate sensor for host immunity and is involved in pyroptosis, pathogen infection, metabolic syndrome, cellular stress, and tumor metastasis. Inflammasome signaling and downstream cytokine responses mediated by the inflammasome have been found to play an important role in fibrosis. The inflammasome regulates the secretion of IL-1β and IL-18, which are both critical for the process of fibrosis. Recently, researches on the function of inflammasome have attracted extensive attention, and data derived from these researches have increased our understanding of the effects and regulation of inflammasome during fibrosis. In this review, we emphasize the growing evidence for both indirect and direct effects of inflammasomes in triggering fibrosis as well as potential novel targets for antifibrotic therapies.

Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antineuropathic pain effect. This study further explored the target molecule and signaling mechanisms underlying cynandione-A-induced antineuropathic pain. Intrathecal injection of cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased spinal expression of IL-10 and β-endorphin but not dynorphin A. Cynandione A treatment also enhanced expression of IL-10 and β-endorphin but not α7 nicotinic acetylcholine receptors (nAChRs) in cultured microglia. The IL-10 antibody attenuated cynandione-A-induced spinal or microglial gene expression of β-endorphin and mechanical allodynia, whereas the β-endorphin antiserum blocked cynandione-A-induced mechanical antiallodynia but not spinal or microglial IL-10 gene expression. The α7 nAChR antagonist methyllycaconitine significantly reduced cynandione-A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Furthermore, cynandione A stimulated microglial phosphorylation of PKA, p38, and CREB in an α7-nAChR-dependent manner, and treatment with their inhibitors attenuated cynandione-A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. In addition, cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, the PKA activation inhibitor or IL-10 antibody. The STAT3 inhibitor NSC74859 also abolished cynandione-A-induced mechanical antiallodynia and spinal expression of β-endorphin. These findings suggest that cynandione A suppresses neuropathic pain through α7-nAChR-dependent IL-10/β-endorphin signaling pathway in spinal microglia.

D‐Amino acid oxidase (DAAO) specifically catalyzes the oxidative deamination of neutral and polar D‐amino acids and finally yields byproducts of hydrogen peroxide. Our previous work demonstrated that the spinal astroglial DAAO/hydrogen peroxide (H2O2) pathway was involved in the process of pain and morphine antinociceptive tolerance. This study aimed to report mouse strain specificity of DAAO inhibitors on antinociception and explore its possible mechanism. DAAO inhibitors benzoic acid, CBIO, and SUN significantly inhibited formalin‐induced tonic pain in Balb/c and Swiss mice, but had no antinociceptive effect in C57 mice. In contrast, morphine and gabapentin inhibited formalin‐induced tonic pain by the same degrees among Swiss, Balb/c and C57 mice. Therefore, mouse strain difference in antinociceptive effects was DAAO inhibitors specific. In addition, intrathecal injection of D‐serine greatly increased spinal H2O2 levels by 80.0% and 56.9% in Swiss and Balb/c mice respectively, but reduced spinal H2O2 levels by 29.0% in C57 mice. However, there was no remarkable difference in spinal DAAO activities among Swiss, Balb/c and C57 mice. The spinal expression of glutathione (GSH) and glutathione peroxidase (GPx) activity in C57 mice were significantly higher than Swiss and Balb/c mice. Furthermore, the specific GPx inhibitor D‐penicillamine distinctly restored SUN antinociception in C57 mice. Our results reported that DAAO inhibitors produced antinociception in a strain‐dependent manner in mice and the strain specificity might be associated with the difference in spinal GSH and GPx activity., Effects of DAAO inhibitors (CBIO, benzoic acid and SUN) were compared between Swiss, Balb/c and C57 mice in formalin test. The results showed that the DAAO inhibitors significantly inhibited formalin‐induced tonic pain in Balb/c and Swiss mice, but had no effect in C57 mice.

Neurodegenerative diseases (NDs) are common chronic diseases related to progressive damage of the nervous system. Globally, the number of people with an ND is dramatically increasing consistent with the fast aging of society and one of the common features of NDs is the abnormal aggregation of diverse proteins. Autophagy is the main process by which misfolded proteins and damaged organelles are removed from cells. It has been found that the impairment of autophagy is associated with many NDs, suggesting that autophagy has a vital role in the neurodegeneration process. Recently, more and more studies have reported that autophagy inducers display a protective role in different ND experimental models, suggesting that enhancement of autophagy could be a potential therapy for NDs. In this review, the evidence for beneficial effects of traditional Chinese medicine (TCM) regulate autophagy in the models of Alzheimer's disease (AD), Parkinson's disease (PD), and other NDs are presented and common autophagy-related mechanisms are identified. The results demonstrate that TCM which regulate autophagy are potential therapeutic candidates for ND treatment.

As one of the empirical models of the chronic central inflammatory response, a spinal cord injury (SCI) deteriorates the neuronal survival and results in irreversible motor and sensory dysfunction below the injury area. Our previous studies have reported that maize bran feruloylated oligosaccharides (FOs) exert significant anti-inflammatory activities both in diabetes and colitis. However, no direct evidence of FOs alleviating central nervous inflammation was stated. This study aimed to investigate the therapeutic effect of FOs on SCI and its potential mechanism. Our results indicated that 4 weeks of FO administration effectively mitigated the inflammatory response via decreasing the number of microglia (labelled with Iba1), result in the expression of IL-1α, IL-2, IL-6, IL-18 and TNF-α downregulating, but the level of IL-10 and BDNF increases in the injured spinal cord. Moreover, FOs enhanced neuronal survival, ameliorated the scar cavities, and improved behaviors, including Basso mouse scale (BMS) scores and the gait of mice after SCI. Together, these results demonstrated that administration of FOs showed superior functional recovery effects in a SCI model. Also, FOs may modulate inflammatory activities by regulating the expression of proinflammatory factors, decreasing the production of inflammatory cells, and promoting functional recovery through the MAPK pathway following SCI.

An increasing number of studies suggest that angiotensin (Ang) Ⅱ contributes to the pathology of cerebrovascular disease possibly through injuring of the brain microvascular endothelial cells (BMEC), but the mechanisms involved are not well elucidated. Recent studies reveal the importance of Ang Ⅱ in reactive oxygen species induction and endothelial injury. Hence, the present study investigated the involvement of oxidative stress in Ang Ⅱ-induced BMEC injury. Our results showed that 10^(-6) mol/L Ang Ⅱ increased lactate dehydrogenase (LDH) leakage and inhibited the viability of primary cultured BMEC. Incubation with 10^(-6) mol/L of Ang Ⅱ for 48 hr increased the extracellular and intracellular malondialdehyde (IVIDA) content and decreased the activities of intracellular glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) significantly. These effects were abolished by pretreatment with the selective AT1 receptor antagonist losartan, but not with the AT2 selective antagonist PD 123319. Combining Losartan with PD 123319 neither diminished nor promoted the effect of losartan alone. These findings indicated that Ang Ⅱ induced injury of BMEC may result from oxidative stress by activating AT1 receptors. This injury may in turn lead to the development of cerebrovascular disease.

Background Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antihypersensitivity effects in neuropathic pain. This study sought to explore the target molecule and mechanisms underlying cynandione A mechanical antiallodynia, particularly related to the spinal glial expression of IL-10/β-endorphin, cAMP/PKA/p38/CREB signaling and α7 nicotinic acetylcholine receptor (α7 nAChR) activation. Methods IL-10 and β-endorphin in the spinal cord of spinal nerve ligation-induced neuropathic pain rats and cultured primary microglia were assessed by qRT-PCR and ELISA assays. Double immunofluorescence staining of IL-10, β-endorphin with glial and neuronal cellular biomarkers was also conducted in the spinal cord and cultured primary microglia. Microglial phosphorylation of PKA, p38, CREB and STAT3 were detected using western blot. Results Cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased IL-10 and β-endorphin (but not dynorphin A) expression in the spinal cords and cultured primary microglia. The IL-10 antibody attenuated cynandione A-induced spinal or microglial gene expression of β-endorphin and mechanical antiallodynia, whereas the β-endorphin antiserum blocked cynandione A-induced mechanical antiallodynia but not spinal or microglial IL-10 gene expression. The α7 nAChR antagonist methyllycaconitine significantly declined cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated microglial phosphorylation of PKA, p38 and CREB, which was inhibited by methyllycaconitine. Treatment with the adenylyl cyclase inhibitor DDA, PKA inhibitor H-89, p38 inhibitor SB203580 and CREB inhibitor KG501 attenuated cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, H-89 and the IL-10 antibody. The STAT3 inhibitor NSC74859 weakened cynandione A-induced mechanical antiallodynia and spinal expression of β-endorphin. Conclusion Our results illustrate that cynandione A produces mechanical antiallodynia through spinal microglial expression of IL-10 via the cAMP/PKA/p38/CREB signaling and subsequent β-endorphin expression via the IL-10/STAT3 signaling, following α7 nAChR activation.

Background Cinobufagin is the major bufadienolide of Bufonis venenum (Chansu), which has been traditionally used for the treatment of chronic pain especially cancer pain. The current study aimed to evaluate its antinociceptive effects in bone cancer pain and explore the underlying mechanisms. Methods Rat bone cancer model was used in this study. The withdrawal threshold evoked by stimulation of the hindpaw was determined using a 2290 CE electrical von Frey hair. The β-endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Results Cinobufagin, given intrathecally, dose-dependently attenuated mechanical allodynia in bone cancer pain rats, with the projected Emax of 90% MPE and ED50 of 6.4 μg. Intrathecal cinobufagin also stimulated the gene and protein expression of IL-10 and β-endorphin (but not dynorphin A) in the spinal cords of bone cancer pain rats. In addition, treatment with cinobufagin in cultured primary spinal microglia but not astrocytes or neurons stimulated the mRNA and protein expression of IL-10 and β-endorphin, which was prevented by the pretreatment with the IL-10 antibody but not β-endorphin antiserum. Furthermore, spinal cinobufagin-induced mechanical antiallodynia was inhibited by the pretreatment with intrathecal injection of the microglial inhibitor minocycline, IL-10 antibody, β-endorphin antiserum and specific μ-opioid receptor antagonist CTAP. Lastly, cinobufagin- and the specific α-7 nicotinic acetylcholine receptor (α7-nAChR) agonist PHA-543613-induced microglial gene expression of IL-10/β-endorphin and mechanical antiallodynia in bone cancer pain were blocked by the pretreatment with the specific α7-nAChR antagonist methyllycaconitine. Conclusions Our results illustrate that cinobufagin produces mechanical antiallodynia in bone cancer pain through spinal microglial expression of IL-10 and subsequent β-endorphin following activation of α7-nAChRs. Our results also highlight the broad significance of the recently uncovered spinal microglial IL-10/β-endorphin pathway in antinociception.

TFEB (transcription factor EB), which is a master regulator of autophagy and lysosome biogenesis, is considered to be a new therapeutic target for Parkinson&rsquo, s disease (PD). However, only several small-molecule TFEB activators have been discovered and their neuroprotective effects in PD are unclear. In this study, a curcumin derivative, named E4, was identified as a potent TFEB activator. Compound E4 promoted the translocation of TFEB from cytoplasm into nucleus, accompanied by enhanced autophagy and lysosomal biogenesis. Moreover, TFEB knockdown effectively attenuated E4-induced autophagy and lysosomal biogenesis. Mechanistically, E4-induced TFEB activation is mainly through AKT-MTORC1 inhibition. In the PD cell models, E4 promoted the degradation of &alpha, synuclein and protected against the cytotoxicity of MPP+ (1-methyl-4-phenylpyridinium ion) in neuronal cells. Overall, the TFEB activator E4 deserves further study in animal models of neurodegenerative diseases, including PD.

Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD via a reprecipitation self-assembly procedure. The curcumin analogue-based nanoscavenger (NanoCA) is engineered to be capable of a controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP+-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer, and aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD.

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases in older individuals with specific neuropsychiatric symptoms. It is a proteinopathy, pathologically characterized by the presence of misfolded protein (Aβ and Tau) aggregates in the brain, causing progressive dementia. Increasing studies have provided evidence that the defect in protein-degrading systems, especially the autophagy-lysosome pathway (ALP), plays an important role in the pathogenesis of AD. Recent studies have demonstrated that AD-associated protein aggregates can be selectively recognized by some receptors and then be degraded by ALP, a process termed aggrephagy. In this study, we reviewed the role of aggrephagy in AD development and discussed the strategy of promoting aggrephagy using small molecules for the treatment of AD.

Thalidomide is an antiinflammatory, antiangiogenic and immunomodulatory agent which has been used for the treatment of erythema nodosum leprosum and multiple myeloma. It has also been employed in treating complex regional pain syndromes. The current study aimed to reveal the molecular mechanisms underlying thalidomide-induced pain antihypersensitive effects in neuropathic pain. Thalidomide gavage, but not its more potent analogs lenalidomide and pomalidomide, inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain rats induced by tight ligation of spinal nerves, with ED50 values of 44.9 and 23.5 mg/kg, and Emax values of 74% and 84% MPE respectively. Intrathecal injection of thalidomide also inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain. Treatment with thalidomide, lenalidomide and pomalidomide reduced peripheral nerve injury-induced proinflammatory cytokines (TNFα, IL-1β and IL-6) in the ipsilateral spinal cords of neuropathic rats and LPS-treated primary microglial cells. In contrast, treatment with thalidomide, but not lenalidomide or pomalidomide, stimulated spinal expressions of IL-10 and β-endorphin in neuropathic rats. Particularly, thalidomide specifically stimulated IL-10 and β-endorphin expressions in microglia but not astrocytes or neurons. Furthermore, pretreatment with the IL-10 antibody blocked upregulation of β-endorphin in neuropathic rats and cultured microglial cells, whereas it did not restore thalidomide-induced downregulation of proinflammatory cytokine expression. Importantly, pretreatment with intrathecal injection of the microglial metabolic inhibitor minocycline, IL-10 antibody, β-endorphin antiserum, and preferred or selective μ-opioid receptor antagonist naloxone or CTAP entirely blocked thalidomide gavage-induced mechanical antiallodynia. Our results demonstrate that thalidomide, but not lenalidomide or pomalidomide, alleviates neuropathic pain, which is mediated by upregulation of spinal microglial IL-10/β-endorphin expression, rather than downregulation of TNFα expression.

The autophagy-lysosome pathway (ALP) is a primary means by which damaged organelles and long-lived proteins are removed from cells and their components recycled. Impairment of the ALP has been found to be linked to the pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disorder characterized by the accumulation of protein aggregates and loss of dopaminergic neurons in the midbrain. In recent years, some active compounds derived from plants have been found to regulate the ALP and to exert neuroprotective effects in experimental models of PD, raising the possibility that autophagy enhancement may be an effective therapeutic strategy in PD treatment. In this review, we summarize recent findings of natural products that enhance ALP and thereby protect against PD. Research articles were retrieved from PubMed using relevant keywords in combination. Papers related to the topic were identified, and then the reliability of the experiments was assessed in terms of methodology. The results suggest that targeting the ALP with natural products is a promising strategy for PD treatment. However, risk of bias exists in some studies due to the defective methodology. Rigorous experimental design following the guidelines of autophagy assays, molecular target identification and in vivo efficacy evaluation is critical for the development of ALP enhancers for PD treatment in future studies. Copyright © 2017 John Wiley & Sons, Ltd.

The root of Chuanminshen violaceum is used as an important edible and medicinal plant in China. However, its leaves are generally considered byproducts, and therefore do not have a use. Thus, the phenolic compounds in the methanolic extracts (CVLMs) and the chemical characteristics of crude polysaccharides (CVLPs) from the leaves of C. violaceum and their in vitro antioxidant activities were explored. The results showed that chlorogenic acid and rutin were the major individual phenolic compounds in the leaves, which ranged from 1.22 &plusmn, 0.03 to 2.87 &plusmn, 0.04 mg/g DW, and from 2.25 &plusmn, 0.04 to 4.03 &plusmn, 0.05 mg/g DW, respectively. Meanwhile, the extraction yields of CVLPs from the leaves ranged from 4.73% to 5.41%. The CVLPs consisted of mannose, rhamnose, galacturonic acid, glucose, galactose, and arabinose, suggesting the existence of pectic polysaccharides. Furthermore, both CVLMs and CVLPs exhibited strong antioxidant activities. Chlorogenic acid and rutin were major contributors to the antioxidant activities of CVLMs, and the antioxidant activities of CVLPs were closely correlated to their &alpha, 1,4-D-galactosiduronic linkages. The results are beneficial for understanding the chemical properties and in vitro antioxidant activities of CVLMs and CVLPs. The leaves of C. violaceum have potential to be developed as natural antioxidants.

Background and purpose d-Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d-amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia. Experimental approach A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, and fluorescent immunostaining techniques were used. Key results The expression and enzymic activity of DAAO increased over time in the cortical peri-infarct area of the mice subjected to transient MCAO. The DAAO was specifically expressed in astrocytes, and its double immunostaining with the astrocytic intracellular marker, glial fibrillary acidic protein, in the cortical peri-infarct area was up-regulated following ischaemic insult, with peak increase on Day 5 after MCAO. Single intravenous injection of the specific and potent DAAO inhibitor Compound SUN reduced the cerebral DAAO enzymic activity and attenuated neuronal infarction and neurobehavioural deficits with optimal improvement apparent immediately after the MCAO procedure. The neuroprotective effect was dose dependent, with ED50 values of 3.9-4.5 mg·kg-1 . Intracerebroventricular injection of the DAAO gene silencer siRNA/DAAO significantly reduced cerebral DAAO expression and attenuated MCAO-induced neuronal infarction and behavioural deficits. Conclusions and implications Our results, for the first time, demonstrated that increased cerebral astrocytic DAAO expression and enzymic activity were causally associated with the development of neuronal destruction following ischaemic insults, suggesting that targeting cerebral DAAO could be a potential approach for treatment of neurological conditions following cerebral ischaemia.

Ethnopharmacological relevance Immunomodulation has become a crucial modality for cancer treatment. Chinese Herbal Medicines (CHMs) are expected as adjuvant therapy for immunomodulation against cancer, but face the key challenge of poor scientific evidence. Changes of natural killer (NK) cells on numbers and/or cytotoxicity are a novel respect to evaluate the immunomodulation of CHMs. Aim of the study The purpose of this review is to investigate the immunomodulation of Chinese Herbal Medicines (CHMs) on NK cell populations for cancer therapy. Materials and methods A systematic review was conducted and outside mainstream electronic databases were screened for potential reference articles. This review tried to report and critically analyzed all the correlative studies, especially these clinical trials (3 CHM extracts and 11 CHM formulas). Results Evidence-based functions of CHMs against cancer could be summarized as: (1) enhancement of NK cells activity or relative percentage; (2) prevention of tumor growth and metastasis; (3) relief on side-effects or complications of therapeutic strategies (i.e. chemotherapy, radiotherapy and resection). Briefly, most of cellular studies and two thirds animal studies were based on the extract or components of single herbs, whilst most of clinical trials were keen on formula or prescription of CHMs. The main components of CHMs were demonstrated active on promoting the cytotoxicity of NK cells, including Angelica sinensis, Ganoderma lucidum, Panax ginseng, Radix Astragali, Lentinus edodes, etc. Conclusions This comprehensive review demonstrated NK cells activity was positively associated with quality of life but not survival benefit of cancer patients. Thus exploring the roles of NK cells in adjuvant therapy against cancer is confirmed to be beneficial to explore the underlying relationship between immunomodulation and quality of life.

Neurodegenerative diseases (NDs), including Alzheimer’s disease (AD) and Parkinson’s disease (PD), threaten the health of an ever-growing number of older people worldwide; so far, there are no effective cures. Significant efforts have been devoted to developing new drugs for NDs in recent years, and some small molecules have been shown to be promising in preclinical studies. However, the major challenge for brain-targeting drugs is how to efficiently deliver the drugs across the blood–brain barrier (BBB) to desired targets. To address this issue, liposomal delivery systems have proved to be ideal carriers for neuroprotective small molecules. Here, we summarize recent advances in the brain-targeting liposomal delivery of small hydrophobic molecules (SHMs) and propose strategies for developing liposomal SHMs as disease-modifying neurotherapeutics for NDs.

Hippocampal neurogenesis plays a critical role in the formation of new neurons during learning and memory development. Attenuation of neurogenesis in the brain is one of the primary causes of dementia in Alzheimer’s disease (AD), and, conversely, modulating the process of hippocampal neurogenesis benefit patients with AD. Traditional Chinese medicine (TCM), particularly herbal medicine, has been in use for thousands of years in Asia and many regions of the world for the treatment of cancer, cardiovascular diseases and neurodegenerative diseases. In this review, we summarize the role of neurotrophic factors, signal transducing factors, epigenetic modulators and neurotransmitters in neurogenesis, and we also discuss the functions of several Chinese herbs and their active molecules in activating multiple pathways involved in neurogenesis. TCM herbs target pathways such as Notch, Wnt, Sonic Hedgehog and receptor tyrosine kinase pathway, leading to activation of a signaling cascade that ultimately enhances the transcription of several important genes necessary for neurogenesis. Given these pathway activating effects, the use of TCM herbs could be an effective therapeutic strategy for the treatment of AD.

Changes in temperature are known to cause a variety of physiological stress responses in insects and mites. Thermal stress responses are usually associated with the increased generation of reactive oxygen species (ROS), resulting in oxidative damage. In this study, we examined the time-related effect (durations for 1, 2, 3, and 5 h) of thermal stress conditions-i.e., relatively low (0, 5, 10, and 15 °C) or high (35, 38, 41, and 44 °C) temperatures-on the activities of antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), peroxidase (POX), glutathione S-transferases (GSTs), and total antioxidant capacity (T-AOC) of the predatory mite Neoseiulus cucumeris. Also the lipid peroxidation (LPO) levels of the predatory mite were measured under thermal stress conditions. The results confirmed that thermal stress results in a condition of so-called oxidative stress and the four antioxidant enzymes play an important role in combating the accumulation of ROS in N. cucumeris. CAT and POX activity changed significantly when the mites were exposed to cold and heat shock, respectively. The elevated levels of SOD and GSTs activity, expressed in a time-dependent manner, may have an important role in the process of antioxidant response to thermal stress. However, the levels of LPO in N. cucumeris were high, serving as an important signal that these antioxidant enzyme-based defense mechanisms were not always adequate to counteract the surplus ROS. Thus, we hypothesize that thermal stress, especially extreme temperatures, may contribute much to the generation of ROS in N. cucumeris, and eventually to its death.

The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson’s disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development.

The development, survival, and reproduction of Liposcelis decolor (Pearman) (Psocoptera: Liposcelididae), an important insect pest of infested stored products, were evaluated at eight constant temperatures (20–37.5°C). Female L. decolor had four nymphal stadia, whereas males only had three nymphal stadia. Between 20 and 37.5°C, the female developmental period from egg to adult varied from 46.2 d at 20°C to 16.1 d at 35°C, and the male developmental period from egg to adult varied from 41.8 d at 20°C to 13.6 d at 35°C. Based on a nonlinear model, the lower temperature developmental thresholds of female from egg, first through fourth stadia, and combined immature stages were estimated at 12.22, 16.08, 10.93, 8.88, 12.64, and 13.02°C, the upper temperature thresholds were 42.11, 39.44, 41.27, 40.92, 39.20, and 40.52°C, respectively, whereas the lower temperature thresholds of males ranged from 11.68 to 15.86°C, and the upper temperature thresholds ranged from 40.19 to 42.04°C. The survival rate from egg to adult was 57.3% at 32.5°C, 38.4 at 20°C, and 19% at 37.5°C, respectively. After emergence, the adult had a preoviposition period that ranged from 6.8 d at 20°C to 2.3 d at 35°C. L. decolor produced the most eggs (130.4) at 32.5°C and the fewest (24.7) at 37.5°C. The population reared at 32.5°C had the highest intrinsic rate of increase (0.0609) compared with the populations reared at seven other constant temperatures. The populations reared at 35 and 37.5°C had type III survivorship pattern, whereas populations reared at other temperatures had type I survivorship curve as determined by a Weibull frequency distribution. The optimal range of temperature for L. decolor population growth was 27.5–35°C.

Liposcelis badia Wang, Wang, and Lienhard was firstly recorded as a novel species of Liposcelididae in 2006 in China. In this study, the development, survival, and reproduction of L. badia were evaluated at eight constant temperatures (between 20 and 37.5 degrees C). The population reared at 37.5 degrees C failed to develop or reproduce. Between 20 and 35 degrees C, the developmental period from egg to adult varied from 46.5 d at 20 degrees C to 17.2 d at 32.5 degrees C. The lower temperature developmental thresholds from egg, first through third stadia, and combined immature stages were estimated at 15.0, 14.5, 9.1, 8.0, and 10.0 degrees C; and the upper temperature thresholds were 39.5, 40.0, 38.9, 39.6, and 40.0 degrees C, respectively. The survival rate from egg to adult was 48.2% at 27.5 degrees C and 19.8 and 18.0% at 20 and 35 degrees C, respectively. After emergence, the adult had a short preoviposition period that ranged from 6.4 d at 20 degrees C to 3.8 d at 30 and 32.5 degrees C. L. badia produced the most eggs at 20 degrees C and the fewest at 35 degrees C. The population reared at 27.5 degrees C had the highest intrinsic rate of increase, net reproductive rate, the shortest populations doubling time, and shorter mean generation time compared with the other temperatures. It is suggested that the optimal range of temperature for L. badia population growth is 27.5-30 degrees C.

In the title compound, C24H18F3N3O, the mol­ecule exists in the enamine–keto tautomeric form. The pyrazolone ring makes dihedral angles of 31.8 (2), 45.4 (2) and 71.2 (2)° with the 1-phenyl, aniline and methylene-bound phenyl rings, respectively. An intra­molecular N—H⋯O hydrogen bond helps to stabilize the mol­ecular conformation.