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Background: Clausena harmandiana (CH), commonly known as song fa dong, was a medicinal plant traditionally used to treat illnesses and as a health tonic. CH root extract (CHRE) exhibited various bioactivities, including neuroprotective, antioxidant, antimicrobial, antifungal, anti-inflammatory, and anti-cancer effects. However, CHRE data on neuroprotective in AD-like animal models were still scarce., Objectives: This study aimed to investigate the effects of CHRE on Aβ 1-42 -induced cognitive deficits, free radical damage, and neuronal death in rats., Methods: Forty-eight adult male Sprague-Dawley rats (250-300 g) were classified as sham control (SC), V+Aβ, Vit C+Aβ, CHRE125+Aβ, CHRE250+Aβ, and CHRE500+Aβ (n = 8 in each group). Animals were orally administered with 0.5% sodium carboxymethylcellulose, vitamin C (200 mg/kg BW), or CHRE (125, 250, and 500 mg/kg BW) and were untreated for 35 days. On day 21, all treated rats were injected with 1 µl of aggregated Aβ 1-42 (1 µg/µl) into the lateral ventricles, bilaterally, whereas untreated rats were injected with sterilized normal saline (NS). The Morris water maze test estimated the rat's learning and memory one week later. At the end of the treatment, all rats were sacrificed, and their brains were removed and divided into two hemispheres. On the left, morphological changes and neuronal density were observed in hippocampal CA1 and CA3 regions. While, on the right, changes in free radical damage markers (SOD, CAT, GPx, MDA, and Nrf2) and protein expression of active caspase-3 were evaluated in the hippocampus., Results: Pretreatment with CHRE at all doses could alleviate spatial learning and memory defects. CHRE also improved morphological changes and a decrease in neuronal density in CA1 and CA3 regions. Additionally, CHRE significantly increased the activities of antioxidant enzymes (SOD, CAT, GPx) and Nrf2 expression. This was coupled with significantly decreased MDA levels and active caspase-3 expression in the hippocampus of Aβ 1-42 -induced rats, which was similar to vitamin C exposure., Conclusions: Our findings suggested that CHRE ameliorated cognitive deficits and exhibited neuroprotective effects by reducing free radical damage and mitigating neuronal abnormality and neuronal death., (© 2024. The Author(s).)

The Trikaysornmas formula (TKM) represents a prevalent Thai traditional remedy utilized extensively in Thailand. Its traditional uses include appetite enhancement, functions as a nourishing tonic, and exhibits adaptogenic properties. Comprising Aegle marmelos fruit, Nelumbo nucifera stamen, and Jatropha multifida bark, this formula embodies the synergy among these three herbs. The objective of this study was to optimize the extraction method, determine the active compounds in the TKM, and evaluate its antioxidant activity. The optimization of the extraction method for this formula was studied using an experimental design. Phytochemical components such as total phenolics, total flavonoids, total carotenoids, and total alkaloids were assessed utilizing a colorimetric method. Antioxidant activities were assessed through DPPH free radical scavenging, ABTS radical cation decolorization, oxygen radical absorbance capacity, ferric reducing antioxidant power, metal chelating activity, and lipid peroxidation assay. For the analysis of active constituents in the formula, gallic acid, kaempferol-3-o-glucoside, imperatorin, vitexin, and scopoletin, a validated reversed-phase column high-performance liquid chromatography (HPLC) method was developed. The total active contents including phenolic, flavonoid, carotenoid, and alkaloid compounds were found in the formula. The developed HPLC method exhibited reliable results in all validation parameters. TKM demonstrated antioxidant activity in the models used in this research. The findings from this study can serve as valuable tools for standardization and quality control measures. Additionally, they can contribute to maximizing the possibilities inherent in this traditional Thai formulation., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this study., (Copyright © 2024 Suphatson Limsakul et al.)

Postmenopausal women have a higher probability of experiencing cognitive alterations compared to men, suggesting that the decline in female hormones may contribute to cognitive deterioration. Thailand traditionally uses Tri-Kaysorn-Mas (TKM), a blend of three medicinal herbs, as a tonic to stimulate appetite and relieve dyspepsia. Due to its antioxidant and anti-acetylcholinesterase activities, we investigated the effects of TKM (50 and 100 mg/kg/day, p.o ., for 8 weeks) on cognitive deficits and their underlying causes in an ovariectomized (OVX) mouse model of menopause. OVX mice showed cognitive impairment in the Y-maze, novel object recognition task (NORT), and Morris water maze (MWM) behavioral tests, along with atrophic changes to the uterus, altered levels of serum 17β-estradiol, and down-regulated expression of estrogen receptors (ERα and ERβ). These behavioral effects were reversed by TKM. TKM decreased malondialdehyde (MDA) levels and mitigated oxidative stress in the brain by enhancing the activity of superoxide dismutase (SOD) and catalase (CAT) and by up-regulating the antioxidant-related gene Nrf2 while down-regulating Keap1. TKM also counteracted OVX-induced neurodegeneration by enhancing the expression of the neurogenesis-related genes BDNF and CREB. The results indicate that TKM extract alleviates oxidative brain damage and neurodegeneration while enhancing cognitive behavior in OVX mice, significantly improving cognitive deficiencies related to menopause/ovariectomy through multiple targets.

The first investigation of the phytochemical profile of the flowers of Croton krabas led to the isolation of two new clerodane diterpenes, 6 S -crotocaudin ( 1 ) and crotocaudin B ( 2 ), together with two known clerodanes, 6 S -crotoeurin C ( 3 ) and isoteucvin ( 4 ). The structures and absolute configurations of isolated clerodanes were elucidated by extensive analysis of NMR spectroscopic data, mass spectrometry and ECD calculations. Compounds 1 - 4 demonstrated significant inhibitory activity towards acetylcholinesterase (AChE). Notably, compound 2 exhibited the strongest AChE inhibition (IC 50 1.01 µM). Compounds 3 and 4 showed potent butyrylcholinesterase (BChE) inhibitory activity with IC 50 values of 1.09 and 1.12 µM, respectively. The molecular docking results revealed that 2 bound to the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE, while 3 occupied in the CAS of BChE.

Diacetylcurcumin manganese complex (DiAc-Cp-Mn) is a diacetylcurcumin (DiAc-Cp) derivative synthesized with Mn (II) to mimic superoxide dismutase (SOD). It exhibited superior reactive oxygen species (ROS) scavenging efficacy, particularly for the superoxide radical. The present study investigated the ROS scavenging activity, neuroprotective effects, and underlying mechanism of action of DiAc-Cp-Mn in a cellular model of Parkinson's disease. This study utilized rotenone-induced neurotoxicity in SH-SY5Y cells to assess the activities of DiAc-Cp-Mn by measuring cell viability, intracellular ROS, mitochondrial membrane potential (MMP), SOD, and catalase (CAT) activities. The mRNA expression of the nuclear factor erythroid 2 p45-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), inducible nitric oxide synthase (iNOS), and Interleukin 1β (IL-1β), which are oxidative and inflammatory genes, were also evaluated to clarify the molecular mechanism. The results of the in vitro assays showed that DiAc-Cp-Mn exhibited greater scavenging activity against superoxide radicals, hydrogen peroxide, and hydroxyl radicals compared to DiAc-Cp. In cell-based assays, DiAc-Cp-Mn demonstrated greater neuroprotective effects against rotenone-induced neurotoxicity when compared to its parent compound, DiAc-Cp. DiAc-Cp-Mn maintained MMP levels, reduced intracellular ROS levels, and increased the activities of SOD and CAT by activating the Nrf2-Keap1 signaling pathway. In addition, DiAc-Cp-Mn exerted its anti-inflammatory impact by down-regulating the mRNA expression of iNOS and IL-1β that provoked neuro-inflammation. The current study indicates that DiAc-Cp-Mn protects against rotenone-induced neuronal damage by reducing oxidative stress and inflammation.

Aging is a well-known factor that accelerates brain deterioration, resulting in impaired learning and memory functions. This current study evaluated the potential of an extract of Alternanthera philoxeroides (AP), an edible flavonoid-rich plant, to ameliorate D-galactose-induced brain aging in male mice. Chronic administration of D-galactose (150 mg/kg/day) in mice mimicked the characteristics of aging by accelerating senescence via downregulation of the following telomere-regulating factors: mouse telomerase reverse transcriptase (mTERT) and mouse telomeric repeat-binding factors 1 (mTRF1) and 2 (mTRF2). D-galactose also decreased the activities of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), while increasing expression of neuroinflammatory cytokines in the frontal cortex and hippocampus. Daily treatment of D-galactose-induced aging mice with AP at 250 and 500 mg/kg/day or vitamin E (100 mg/kg/day) significantly increased the activities of SOD and CAT, as well as expression of mTERT, mTRF1, and mTRF2, which are involved in telomere stabilization, but decreased the levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α. In the behavioral portion of the study, AP improved aging-related cognitive deficits in short-term memory as shown by the Y-maze task and the novel object recognition test (NORT) and long-term memory as shown by the Morris water maze test (MWMT). The flavones kaempferol- O -glucoside ( 1 ), quercetin ( 2 ), alternanthin B ( 3 ), demethyltorosaflavone D ( 4 ), and chrysoeriol-7- O -rhamnoside ( 5 ), which could be responsible for the observed effects of AP in the D-galactose-induced aging mice, were identified by HPLC analysis.

Chromatographic separation of the leaves of Croton krabas resulted in the isolation of one new clerodane, crotoeurin D (1), along with two known compounds, 6S-crotoeurin C (2) and blumenol A (3). Their structures were determined based on extensive nuclear magnetic resonance spectroscopic data analysis and mass spectrometry. The absolute configuration of the new clerodane was assigned by nuclear overhauser effect spectroscopy correlations and electronic circular dichroism calculations. Compound 1 exhibited significant acetylcholinesterase and butyrylcholinesterase inhibitory activities. Moreover, the binding modes of 1 revealed that its structure formed strong hydrogen bonds and hydrophobic interactions with the active sites of both enzymes., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Major depressive disorder (MDD) is one life-threatening disorder that is prevalent worldwide. The evident etiology of this disease is still poorly understood. Currently, herbal medicine is gaining more interest as an alternative antidepressant. Oroxylum indicum , which is used in traditional medicine and contains a potential antidepressive compound, baicalein, could have an antidepressive property. An in vitro monoamine oxidase-A (MAO-A) inhibitory assay was used to preliminarily screening for the antidepressant effect of O. indicum seed ( OIS ) extract. Mice were subjected to unpredictable chronic mild stress (UCMS) for 6 weeks, and the daily administration of OIS extract started from week 4. The mechanisms involved in the antidepressive activity were investigated. The OIS extract significantly alleviated anhedonia and despair behaviors in the UCMS-induced mouse model via two possible pathways: (i) it normalized the HPA axis function via the restoration of negative feedback (decreased FKBP5 and increased GR expressions) and the reduction in the glucocorticoid-related negative gene (SGK-1), and (ii) it improved neurogenesis via the escalation of BDNF and CREB expressions in the hippocampus and the frontal cortex. In addition, an HPLC analysis of the OIS extract showed the presence of baicalin, baicalein, and chrysin as major constituents. All of the results obtained from this study emphasize the potential of OIS extract containing baicalin and baicalein as an effective and novel alternative treatment for MDD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and neuronal death. Fifteen flavonoids from Millettia brandisiana were evaluated for the multifunctional effect against AD pathogenesis, including butyrylcholine esterase (BuChE) inhibition, anti-amyloid beta (Aβ) aggregation and neuroprotection against hydrogen peroxide (H 2 O 2 ) toxicity in differentiated human neuroblastoma SH-SY5Y cell. To understand the mechanism and structure-activity relationship, binding interactions between flavonoids and the BuChE and Aβ were investigated in silico . Furthermore, drug-likeness properties and ADMET parameters were evaluated in silico using SwissADME and pKCSM tools. All flavonoids exhibit a good drug-likeness profile. Six flavonoids have potency in BuChE inhibition, and four flavonoids show potency in anti-Aβ aggregation. Flavonoids with the 6″,6″-dimethylchromeno- [2″,3″:7,8]-flavone structure show a favorable multifunctional effect. In silico analysis showed that flavonoids can bind in various positions to the catalytic triad, anionic site, and acyl pocket. In Aβ 1-42 , potential flavonoids can attach to the central hydrophobic region and the C terminal hydrophobic and interfere with Aβ interchain hydrogen binding. When compared together, it can inhibit multifunctional action with a favorable ADMET parameter and drug-likeness profile. In addition, candidine can prevent neuronal damage in differentiated SH-SY5Y neuroblastoma cells induced by H 2 O 2 in a dose-dependent manner., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Supercritical fluid extraction (SFE) is an innovative green technology for the extraction of phytochemicals from plants. Therefore, this study aimed to evaluate the application of SFE and to optimize the extraction conditions of the Thai herbal formula, Kleeb Bua Daeng (KBD). A Box-Behnken design (BBD) with response surface methodology (RMS) was used to determine the effect of the extraction time (30-90 min), temperature (30-60 °C), and pressure (200-300 bar) on response variables including the extraction yield, total phenolic content (TPC), total flavonoid content (TFC), total carotenoid content (TCC), and total anthocyanin content (TAC) of the KBD formula. The highest percentage extraction yield (3.81%) was achieved at 60 °C, 300 bar, and 60 min of the extraction time. The highest TPC (464.56 mg gallic acid equivalents/g extract), TFC (217.19 mg quercetin equivalents/g extract), and TCC (22.26 mg β-carotene equivalents/g extract) were all achieved at 60 °C, 250 bar, and 90 min of the extraction time. On the contrary, it was not possible to quantify the total anthocyanin content as anthocyanins were not extracted by this method. The results indicated that SFE-CO 2 is a suitable method of extraction for a green recovery of phytochemicals with low and moderate polarity from the KBD formula.

A cytokine known as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has the ability to precisely cause the death of cancer cells, while normal cells are left undisturbed. Recent studies show that certain cancer cells are sensitive to the apoptotic effect of TRAIL. In this study, HT29 colorectal adenocarcinoma cells exposed to TRAIL were treated with heptaphylline and 7-methoxyheptaphylline from Clausena harmandiana in an effort to comprehend the mechanisms involved behind this activity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test was utilized to determine cell survival, and phase contrast microscopy was used to examine cell morphology. Through using real-time RT-PCR, Western blotting, and RT-PCR, the molecular mechanisms were investigated. According to the findings, whilst hepataphylline caused cytotoxicity in normal colon FHC cells, in comparison to healthy colon FHC cells, 7-methoxyheptaphylline inhibited cancer cells in a concentration-dependent manner. Heptaphylline alone or in conjunction with TRAIL showed no discernible effect on TRAIL-induced HT29 cell death, but 7-methoxyheptaphylline boosted caspase-3 cleavage. The study showed that the c-Jun N-terminal kinase (JNK) pathway was responsible for the 7-methoxyheptaphylline's enhancement of the death receptor 5 (DR5) mRNA, TRAIL receptor, and protein. The results demonstrated that the 7-methoxyheptaphylline of Clausena harmandiana increased the expression of DR5 via the JNK pathway, intensifying TRAIL-induced HT29 cell death.

The effects of Mesua ferrea Linn flower (MFE) extract on the pathogenic cascade of Alzheimer's disease (AD) were determined by an in vitro and cell culture model in the search for a potential candidate for the treatment of AD. The 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay exhibited that the MFE extract had antioxidant activities. According to the Ellman and the thioflavin T method's result, the extracts could inhibit acetylcholinesterase and β-amyloid (Aβ) aggregation. Studies on neuroprotection in cell culture found that the MFE extract could reduce the death of human neuroblastoma cells (SH-SY5Y) caused by H 2 O 2 and Aβ. Western blot analysis exhibited that the MFE extract alleviated H 2 O 2 -induced neuronal cell damage by downregulating the pro-apoptotic proteins, including cleaved caspase-3, Bax, and by enhancing the expression of anti-apoptotic markers including MCl 1 , BCl xl , and survivin. Moreover, MFE extract inhibited the expression of APP, presenilin 1, and BACE, and increased the expression of neprilysin. In addition, the MFE extract could enhance scopolamine-induced memory deficit in mice. Overall, results showed that the MFE extract had several modes of action related to the AD pathogenesis cascade, including antioxidants, anti-acetylcholinesterase, anti-Aβ aggregation, and neuroprotection against oxidative stress and Aβ. Therefore, the M. ferrea L. flower might be a possibility for further development as a medication for AD.

7‑Methoxyheptaphylline (7‑MH) is a carbazole extracted from Clausena harmandiana , a medicinal plant that is used to treat headaches and stomachaches. The aim of the present study was to examine the neuroprotective effects and anticancer activity of 7‑MH. Cell death was assessed using an MTT assay and flow cytometry. The expression of apoptosis‑related proteins was determined by western blot analysis. An animal model was used to test anti‑metastasis. The interactions between 7‑MH and the molecular target were observed using molecular docking. The results revealed that 7‑MH provided protection against hydrogen peroxide (H 2 O 2 )‑induced neuronal cell death. In cancer cells, 7‑MH induced SH‑SY5Y, 4T1, HT29, HepG2, and LNCaP cell death. 7‑MH inhibited metastasis of HT29 cells in vitro and 4T1‑Luc cells in vitro and in vivo . 7‑MH inhibited proteins, including P‑glycogen synthase kinase (GSK)‑3, and cleaved caspase‑3, but it activated anti‑apoptotic proteins in H 2 O 2 ‑induced SH‑SY5Y cell death. By contrast, 7‑MH activated the cleaving of caspase‑3 and GSK‑3, but it suppressed anti‑apoptotic proteins in SH‑SY5Y cells. 7‑MH reduced the levels of NF‑κB and STAT3 in 4T1 cells; phospho‑p65, Erk, and MAPK13 in LNCaP cells; and phospho‑Erk and matrix metalloproteinase‑9 in HT29 cells. Molecular docking analysis showed that 7‑MH targets TAK1 kinase. The present study indicated that 7‑MH induced apoptosis of cancer cells and provided protection against H 2 O 2 ‑induced neuron cell death via TAK1 kinase.

Pain is the most common presenting physical symptom and a primary reason for seeking medical care, which chronically affects people's mental health and social life. Ca V 3.2 channel plays an essential role in the peripheral processing maintenance of pain states. This study was designed to identify novel drug candidates targeting the Ca V 3.2 channel. Whole-cell patch-clamp, cellular thermal shift assay, FlexStation, in vivo and in vitro Ca V 3.2 knock-down, site-directed mutagenesis, and double-mutant cycle analysis were employed to explore the pain-related receptors and ligand-receptor direct interaction. We found that toddaculin efficiently inhibits the Ca V 3.2 channel and significantly reduced the excitability of dorsal root ganglion neurons and pain behaviors. The Carbonyl group of coumarins directly interacts with the pore domain of Ca V 3.2 via van der Waals (VDW) force. Docking with binding pockets further led us to identify glycycoumarin, which exhibited more potent inhibition on the Ca V 3.2 channel and better analgesic activity than the parent compound. Toddaculin and its analog showed beneficial therapeutic effects in pain models. Toddaculin binding pocket on Ca V 3.2 might be a promising docking site for the design of drugs., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Masson SAS.)

This study was designed to investigate the effects of the root-bark extract of Clausena harmandiana (CH) and its active constituents (nordentatin and 7-methoxyheptaphylline) on pharmacological activities regarding selected targets associated with AD, namely, its antioxidant activity, inhibition of Aβ aggregation, acetylcholinesterase (AChE) activity, and neuroprotective effects. The effect of the CH extract on the cognitive impairment induced by scopolamine was also evaluated in mice. The effects of the CH extract and its active constituents on radical scavenging, Aβ aggregation, and AChE activity were investigated with a 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assay, a thioflavin-T assay, and Ellman's method. The neuroprotective effects of the extract against hydrogen-peroxide and Aβ toxicity were evaluated with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. In addition, the effects on cognitive impairment induced by scopolamine in mice were evaluated using Morris-water-maze and modified-Y-maze test models. The results of the present study demonstrate that the root-bark extract of CH shows multimodal actions relevant to the AD pathological cascade, including antioxidant effects, the inhibition of Aβ aggregation, the inhibition of AChE function, and neuroprotection against oxidative stress and Aβ toxicity. The extracts could improve both the short- and long-term memory deficits induced by scopolamine in mice.

Kleeb Bua Daeng (KBD) formula has long been used in Thailand as a traditional herbal medicine for promoting brain health. Our recent reports illustrated that KBD demonstrates multiple modes of action against several targets in the pathological cascade of Alzheimer's disease (AD). The main purpose of the present study was to determine the protective effect and mechanism of KBD in amyloid beta (Aβ)-induced AD rats and its toxicity profiles. Pretreatment with the KBD formula for 14 days significantly improved the short- and long-term memory performance of Aβ-induced AD rats as assessed by the Morris Water Maze (MWM) and object-recognition tests. KBD treatment increased the activities of the antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase; reduced the malondialdehyde content, and; decreased the acetylcholinesterase activity in the rat brain. An acute toxicity test revealed that the maximum dose of 2000 mg/kg did not cause any mortality or symptoms of toxicity. An oral, subchronic toxicity assessment of KBD at doses of 125, 250, and 500 mg/kg body weight/day for 90 days showed no adverse effects on behavior, mortality, hematology, or serum biochemistry. Our investigations indicate that KBD is a nontoxic traditional medicine with good potential for the prevention and treatment of AD.

Cognitive impairment is a neurological symptom caused by reduced estrogen levels in menopausal women. The Thai traditional medicine, Yakae-Prajamduen-Jamod (YPJ), is a formula consisting of 23 medicinal herbs and has long been used to treat menopausal symptoms in Thailand. In the present study, we investigated the effects of YPJ on cognitive deficits and its underlying mechanisms of action in ovariectomized (OVX) mice, an animal model of menopause. OVX mice showed cognitive deficits in the Y-maze, the novel object recognition test, and the Morris water maze. The serum corticosterone (CORT) level was significantly increased in OVX mice. Superoxide dismutase and catalase activities were reduced, while the mRNA expression of IL-1β, IL-6, and TNF-α inflammatory cytokines were up-regulated in the frontal cortex and hippocampus of OVX mice. These alterations were attenuated by daily treatment with either YPJ or 17β-estradiol. HPLC analysis revealed that YPJ contained antioxidant and phytoestrogen constituents including gallic acid, myricetin, quercetin, luteolin, genistein, and coumestrol. These results suggest that YPJ exerts its ameliorative effects on OVX-induced cognitive deficits in part by mitigating HPA axis overactivation, neuroinflammation, and oxidative brain damage. Therefore, YPJ may be a novel alternative therapeutic medicine suitable for the treatment of cognitive deficits during the menopausal transition.

The present study aimed to investigate the effect of acridone alkaloids on cancer cell lines and elucidate the underlying molecular mechanisms. The ten acridone alkaloids from Atalantia monophyla were screened for cytotoxicity against LNCaP cell lines by a WST-8 assay. Then, the most potential acridone, buxifoliadine E, was evaluated on four types of cancer cells, namely prostate cancer (LNCaP), neuroblastoma (SH SY5Y), hepatoblastoma (HepG2), and colorectal cancer (HT29). The results showed that buxifoliadine E was able to significantly inhibit the proliferation of all four types of cancer cells, having the most potent cytotoxicity against the HepG2 cell line. Western blotting analysis was performed to assess the expression of signaling proteins in the cancer cells. In HepG2 cells, buxifoliadine E induced changes in the levels of Bid as well as cleaved caspase-3 and Bax through MAPKs, including Erk and p38. Moreover, the binding interaction between buxifoliadine E and Erk was investigated by using the Autodock 4.2.6 and Discovery Studio programs. The result showed that buxifoliadine E bound at the ATP-binding site, located at the interface between the N- and C-terminal lobes of Erk2. The results of this study indicate that buxifoliadine E suppressed cancer cell proliferation by inhibiting the Erk pathway.

The present study describes investigation of the effects of the bark resin extract of Garcinia nigrolineata (Clusiaceae) on the cognitive function and the induction of oxidative stress in both frontal cortex and hippocampus by unpredictable chronic mild stress (UCMS). By using behavioral mouse models, i.e., the Y-maze test, the Novel Object Recognition Test (NORT), and the Morris Water Maze Test (MWMT), it was found that the negative impact of repeated mild stress-induced learning and memory deficit through brain oxidative stress in the UCMS mice was reversed by treatment with the bark resin extract G. nigrolineata . Moreover, the prenylated xanthones viz. cowagarcinone C, cowaxanthone, α-mangostin, cowaxanthone B, cowanin, fuscaxanthone A, fuscaxanthone B, xanthochymusxanthones A, 7- O -methylgarcinone E, and cowagarcinone A, isolated from the bark resin of G. nigrolineata , were assayed for their inhibitory activities against β-amyloid (Aβ) aggregation and monoamine oxidase enzymes (MAOs).

Background: Alzheimer's disease (AD) pathogenesis is associated with amyloid-β (Aβ)-induced neuroinflammation. In AD, the activation of microglia caused by Aβ accumulation is followed by the synthesis and release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα), and ultimately leads to cognitive impairments. Clausena harmandiana (CH) is a medicinal plant in the Rutaceae family and has been used in folk medicine to relieve illnesses such as stomachache and headache, and as a health tonic. Interestingly, CH root extract (CHRE) has several anti-inflammatory and other pharmacological activities, but there are no studies in AD-like animal models., Objectives: This study aims to evaluate the effects of CHRE on cognitive impairments, increased Aβ 1-42 protein levels, and neuroinflammation in Aβ 1-42 -induced rats., Methods: Forty-eight adult male Sprague-Dawley rats (250-300 g) were randomly divided into 6 groups (n = 8) of the sham control, V + Aβ, CB + Aβ CHRE125 + Aβ, CHRE250 + Aβ, and CHRE500 + Aβ. Sodium carboxymethylcellulose, Celebrex (10 mg/kg BW) and CHRE (125, 250, and 500 mg/kg BW) were given orally or without any treatment for 35 days. On day 21, aggregated Aβ 1-42 at a concentration of 1 μg/μl were injected into both lateral ventricles (1 μl/side) of all treated rats, while sterilized normal saline were injected to untreated rats. Ten days later, the novel object recognition test was performed to assess their recognition memory. At the end of the test period, an overdose of thiopental sodium (120 mg/kg BW) and transcardial perfusion with 0.9% normal saline solution were used to euthanize all rats. Then Aβ 1-42 protein levels and the expression of inflammatory markers (CD11b-positive microglia, IL-1β, and TNFα) were investigated in the cerebral cortex and hippocampus., Results: Pretreatment with CHRE at all doses could attenuate short- and long-term impairments in recognition memory. Additionally, CHRE also inhibited the increase of Aβ 1-42 protein levels and the expression of inflammatory markers in both brain regions as well as receiving Celebrex., Conclusions: This suggests that preventive treatment of CHRE might be a potential therapy against cognitive impairments via reducing Aβ 1-42 protein levels and neuroinflammation caused by Aβ 1-42 ., (© 2022. The Author(s).)

Individuals with mild cognitive impairment (MCI) were at increased risk of conversion to dementia. The Kleeb Bua Daeng (KBD) formula could be the alternative treatment option for MCI through multitarget activities. Lacking of clinical trial information brought about the study in our research. Forty patients with MCI were randomly assigned to receive the KBD capsule or placebo at a dose of 1,000 mg twice a day for three months. Their cognitive functions were monitored by the Montreal Cognitive Assessment (MoCA) and blood chemistry assessment every one month. We found that the KBD-treated group had no significant differences in the MoCA test compared to placebo. Moreover, there was no alteration in biochemical parameters of the liver and renal function was observed which could confirm the safety of this KBD formula., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Natdanai Musigavong et al.)

Cancer is caused by abnormal cell changes leading to uncontrolled cell growth. The specific characteristics of cancer cells, including the loss of apoptotic control and the ability to migrate into and invade the surrounding tissue, result in cancer cell metastasis to other parts of the body. Therefore, the inhibition of the proliferation, migration, and invasion of cancer cells are the principal goals in the treatment of cancer. This study aimed to investigate the inhibitory activity of nordentatin, a coumarin derivative isolated from Clausena harmandiana, regarding the proliferation and migration of human neuroblastoma cells (SH-SY5Y). Nordentatin at a concentration of 100 µM showed cell cytotoxicity toward SH-SY5Y that was significantly different from that of the control group (p < 0.01) at 24, 48, and 72 h. Moreover, nordentatin inhibited SH-SY5Y proliferation by inhibiting the antiapoptotic protein Mcl-1, leading to the cleavage of caspase-3 and resulting in the inhibition of a migratory protein, MMP-9, through the GSK-3 pathway (compared with cells treated with a GSK inhibitor). These results suggest that nordentatin inhibited the proliferation and migration of neuroblastoma cells through the GSK-3 pathway.

Ten acridones isolated from Atalantia monophylla were evaluated for effects on Alzheimer's disease pathogenesis including antioxidant effects, acetylcholinesterase (AChE) inhibition, prevention of beta-amyloid (Aβ) aggregation and neuroprotection. To understand the mechanism, the type of AChE inhibition was investigated in vitro and binding interactions between acridones and AChE or Aβ were explored in silico. Drug-likeness and ADMET parameters were predicted in silico using SwissADME and pKCSM programs, respectively. All acridones showed favorable drug-likeness and possessed multifunctional activities targeting AChE function, Aβ aggregation and oxidation. All acridones inhibited AChE in a mixed-type manner and bound AChE at both catalytic anionic and peripheral anionic sites. In silico analysis showed that acridones interfered with Aβ aggregation by interacting at the central hydrophobic core, C-terminal hydrophobic region, and the key residues 41 and 42. Citrusinine II showed potent multifunctional action with the best ADMET profile and could alleviate neuronal cell damage induced by hydrogen peroxide and Aβ 1-42 toxicity.

Major depressive disorder (MDD) is a common and debilitating psychiatric disease characterized by persistent low mood, lack of energy, hypoactivity, anhedonia, decreased libido, and impaired cognitive and social functions. However, the multifactorial etiology of MDD remains largely unknown due the complex interaction between genetics and environment involved. Kleeb Bua Daeng (KBD) is a Thai traditional herbal formula that has been used to promote brain health. It consists of a 1:1:1 ratio of the aerial part of Centella asiatica , Piper nigrum fruit, and the petals of Nelumbo nucifera . According to the pharmacological activities of the individual medicinal plants, KBD has good potential as a treatment for MDD. The present study investigated the antidepressant activity of KBD in an unpredictable chronic mild stress (UCMS) mouse model. Daily administration of KBD to UCMS mice ameliorated both anhedonia, by increasing 2% sucrose intake, and hopeless behavior, by reducing immobility times in the forced swimming test (FST) and tail suspension test (TST) without any effect on locomotor activity. The mechanism of KBD activity was multi-modal. KBD promoted neurogenesis by upregulation of brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element binding (CREB) mRNA expression in the frontal cortex and hippocampus. Daily treatment with KBD significantly reversed UCMS-induced HPA axis dysregulation by upregulating the glucocorticoid receptor (GR) while downregulating serum- and glucocorticoid-inducible kinase 1 (SGK1) and FK506 binding protein 5 (FKBP5) mRNA expression. KBD treatment also normalized proinflammatory cytokine expression including tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-1β and IL-6. KBD and its component extracts also exhibited an inhibitory effect in vitro on monoamine oxidase (MAO) A and B. The multiple antidepressant actions of KBD emphasize its potential as an effective, novel treatment for MDD.

Ethanolic extract of Nelumbo nucifera petals showed preferential cytotoxic activity against HeLa human cervical cancer cell line with a PC 50 value of 10.4 μg/mL. This active extract was subjected to a phytochemical investigation study which led to the isolation of nine benzylisoquinoline alkaloids ( 1 - 9 ). The isolated compounds exhibited potent antiausterity activities. Moreover, under nutrient-deprived conditions, (-)-lirinidine ( 8 ) induced remarkable alterations in HeLa cell morphology including cell shrinkage and plasma blebbing leading to total cell death within 10 h. Mechanistically, 8 was found to inhibit Akt/mTOR signaling pathway. It also induced apoptosis by promoting caspase-3 activation and inhibiting Bcl-2 expression. Therefore, benzylisoquinoline alkaloids skeleton can be considered as a promising scaffold for the anticancer drug development against cervical cancer., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

The crude ethanol extract of the whole plant of Alternanthera philoxeroides (Mart.) Griseb was investigated for its potential as antidementia, induced by estrogen deprivation, based on in vitro antioxidant activity, β-amyloid aggregation inhibition and cholinesterase inhibitory activity, as well as in vivo Morris water maze task (MWMT), novel object recognition task (NORT), and Y-maze task. To better understand the effect of the extract, oxidative stress-induced brain membrane damage through lipid peroxidation in the whole brain was also investigated. Additionally, expressions of neuroinflammatory cytokines (IL-1β, IL-6 and TNF-α) and estrogen receptor-mediated facilitation genes such as PI3K and AKT mRNA in the hippocampus and frontal cortex were also evaluated. These effects were confirmed by the determination of its serum metabolites by NMR metabolomic analysis. Both the crude extract of A. philoxeroides and its flavone constituents were found to inhibit β-amyloid (Aβ) aggregation.

The aim of the study was to investigate the inhibitory activity of candidone, the active constituent of Derris (D.) indica, on the proliferation, migration, and invasiveness of human hepatoblastoma (HepG2) cells. Cancer cell death was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis-associated morphological changes were observed by phase contrast microscopy. Additionally, Western blotting was used to study protein expression following treatment with candidone, and transwell migration and invasion assays were used for observing cancer cell migration and invasiveness, respectively. The results suggest that candidone possesses potent inhibitory activity against HepG2 cells (concentration, 100 µM; 24 h treatment). Cancer cells treated with candidone exhibited apoptosis-associated changes, including detachment, cell shrinkage and death. Furthermore, candidone was shown to promote cell death by activating caspase-3 and -9, and decreasing the expression of antiapoptotic proteins, including p65, induced myeloid leukemia cell differentiation protein Mcl-1, B-cell lymphoma 2 (Bcl2), Bcl2-associated agonist of cell death and survivin. Moreover, candidone inhibited the migration and invasion abilities of HepG2 cells and decreased the levels of proteins associated with these processes, including phospho-p38 and active matrix metallopeptidase 9. Collectively, the results of the present study indicate that candidone is able to inhibit the proliferation, migration and invasive potential of HepG2 cells.

Background and Purpose: Itching is the most frequent pathology in dermatology that has significant impacts on people's mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few selecetive and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti-pruritus pharmacology., Experimental Approach: FlexStation and calcium fluorescence imaging were conducted to track the functional compounds. Whole-cell patch clamp was used to record itch-related ion channel currents. Homologous recombination and site-directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti-pruritus assay., Key Results: An acridone alkaloid (citrusinine-II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC 50 ) of 12.43 μM. Citrusinine-II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine-II (143 ng/skin site) nearly completely inhibited itch behaviours. It also shows significant analgesic effects. Little side effects of the compound are observed., Conclusion and Implications: By acting as a selective and potent inhibitor of TRPV3 channel, citrusinine-II shows valuable therapeutic effects in pruritus animal models and is a promising candidate drug and/or lead molecule for the development of anti-pruritus drugs., (© 2021 The British Pharmacological Society.)

Coumarins, naturally occurring phytochemicals, display a wide spectrum of biological activities by acting on multiple targets. Herein, nine coumarins from the root of Toddalia asiatica were evaluated for activities related to pathogenesis of Alzheimer's disease (AD). They were examined for acetylcholinesterase (AChE) and AChE- or self-induced amyloid beta (Aβ) aggregation inhibitory activities, as well as neuroprotection against H 2 O 2 - and Aβ 1-42 -induced human neuroblastoma SH-SY5Y cell damage. Moreover, in order to understand the mechanism, the binding interactions between coumarins and their targets: (i) AChE and (ii) Aβ 1-42 peptide were investigated in silico . All coumarins exhibited mild to moderate AChE and self-induced Aβ aggregation inhibitory actions. In addition, the coumarins substituted with the long alkyl chain at position 6 or 8 illustrated ability to inhibit AChE-induced Aβ aggregation, resulting from their dual binding site at catalytic anionic site and peripheral active site in AChE. Moreover, the most potent multifunctional coumarin, phellopterin, could attenuate neuronal cell damage induced by H 2 O 2 and Aβ 1-42 toxicity. Conclusively, seven out of nine coumarins were identified as multifunctional agents inhibiting the pathogenesis of AD. The structure-activity relationship information obtained might be applied for further optimization of coumarins into a useful drug which may combat AD., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The Kleeb Bua Daeng formula (KBD) is a Thai traditional medicine for brain health promotion. On the basis of the activities of its individual components, the KBD could have good potential for the treatment of Alzheimer's disease (AD). Herein, we investigated the KBD as an AD treatment. The ethanol extracts of KBD and its components, i.e., Nelumbo nucifera (NN), Piper nigrum fruits (BP), and the aerial part of Centella asiatica (CA) exhibited antioxidant activity, as determined by both ABTS and DPPH assays. The Ellman's assay revealed that the KBD, NN, and BP showed an ability to inhibit acetylcholinesterase. The thioflavin T assay indicated that the KBD, NN, BP, and CA inhibited beta-amyloid aggregation. The neuroprotection and Western blot analysis revealed that the KBD reduced H 2 O 2 -induced neuronal cell death by inhibiting the expression of pro-apoptotic factors, i.e., cleaved caspase-9 and -3, p-P65, p-JNK, and p-GSK-3β, as well as by inducing expression of anti-apoptotic factors, i.e., MCl 1 , BCl xl , and survivin. Furthermore, the KBD could improve scopolamine induced memory deficit in mice. Our results illustrate that the KBD with multimode action has the potential to be employed in AD treatment. Thus, the KBD could be used as an alternative novel choice for the prevention and treatment of patients with AD.

Thai traditional herbal formula ''Kleeb Bua Daeng (KBD)''consists of a 1:1:1 ratio (dry weight) of three medicinal plants: Piper nigrum fruit, the aerial part of Centella asiatica and the petals of Nelumbo nucifera . Oral administration of KBD to unpredictable chronic mild stress (UCMS) mice significantly improved their cognitive function caused by chronic mild stress. Daily administration of KBD significantly decreased the serum corticosterone (CORT) and malondialdehyde (MDA) levels but increased the catalase and superoxide dismutase activities in both frontal cortex and hippocampus. The effects of KBD were similar to those caused by oral administration of vitamin E. HPLC analysis of the KBD extract revealed the presence of piperine, madecassoside, asiaticoside, luteolin-7- O -glucoside, rutin, kaempferol-3-glucoside, quercetin, kaempferol and ferulic acid as major constituents.

A new flavonoid, atalantraflavone (1) as well as eight known compounds including atalantoflavone (2), racemoflavone (3), 5,4'-dihydroxy-(3″,4″-dihydro-3″,4″-dihydroxy)-2″,2″-dimethylpyrano-(5″,6″:7,8)-flavone (4), lupalbigenin (5), anabellamide (6), citrusinine I (7), p-hydroxybenzaldehyde (8), and frideline (9), were isolated from the leaves of Atalantia monophylla (L.) DC. Focusing on Alzheimer's disease, acetylcholine esterase (AChE) inhibition and antioxidant activity were evaluated using the modified Ellman's method and the ABTS scavenging assay, respectively. It was found that isoflavonoid 5, lupalbigenin, showed 79% inhibition to AChE and was 1.4-fold stronger than the tacrine standard. In addition, acridone 7, citrusinine I, displayed 90.68% antioxidant activity.

The chemical investigation of the methanol extract of Hymenodictyon orixense bark, a Thai medicinal herb, provided five compounds. Their structures were identified on the basis of 1D NMR and MS data, as well as by comparison of the data with published values, as an iridoid glycoside: loganin (1), four coumarins: scopoletin (2), scopolin (3), hymexelsin (4) and scopoletin 7-O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside (5). Compounds 1-5 showed acetylcholinesterase (AChE) inhibitory activity in the range of 13.92-34.18% at a concentration of 100 μg/mL. In addition, compounds 1 and 5 are reported for the first time from this genus.

Structure modification of a lead compound (NSC13378) was accomplished in the present work by an in silico target-based design aimed at ligands acting on the nicotinic acetylcholine receptor (nAChR) for neurodegenerative diseases. A 187-compound focused library derived from the scaffold of the lead compound was screened against acetylcholine-binding proteins (AChBPs). Six compounds were identified and synthesized for binding and biological evaluations. Five compounds were found to bind with AChBPs. Among these compounds, QN1 and BZ1 showed the highest affinity binding with AChBP, with Kd values of 260 and 10 nm, respectively. Functional assays on isolated cell lines containing ligand-gated ion channels revealed that QN1 and BZ1 are a4b2-nAChR antagonists. QN1 and BZ1 significantly alleviated the memory impairment caused by the muscarinic cholinergic antagonist scopolamine (p < 0.05) in mice. Our findings demonstrate the potential of nAChR antagonists in drug development for cognitive impairments., (© 2015 John Wiley & Sons A/S.)

The α7 nicotinic acetylcholine receptor (nAChR) is a recognized drug target for dementias of aging and certain developmental disorders. Two selective and potent α7-nAChR agonists, winnowed from a list of 43 compounds characterized in a companion article (DOI: 10.1021/acschemneuro.5b00058), 5-((quinuclid-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indole (IND8) and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (QND8), were evaluated for cognitive improvement in both short- and long-term memory. Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU-282987, a congeneric α7 nAChR agonist, were employed as reference standards. Three behavioral tests, modified Y-maze, object recognition test (ORT), and water maze, were performed in scopolamine-induced amnesic mice. Intraperitoneal injection of these two compounds significantly improved the cognitive impairment in a modified Y-maze test (5 μmol/kg for IND8 and 10 μmol/kg for QND8), ORT (10 μmol/kg), and water maze test (25 μmol/kg). For delay induced memory deficit or natural memory loss in mice, IND8 and QND8 at 10 μmol/kg were able to enhance memory comparable to PNU-282987 when evaluated using ORT time delay model. Cognitive enhancement of IND8 and QND8 was mediated through α7-nAChRs as evidenced by its complete abolition after pretreatment with a selective α7-nAChR antagonist, methyllycaconitine. These data demonstrate that IND8 and QND8 and their congeners are potential candidates for treatment of cognitive disorders, and the substituted triazole series formed by cycloaddition of alkynes and azides warrant further preclinical optimization.

Administration of praziquantel for treatment of liver fluke infection may affect the host, with mild and severe effects after treatment caused by host immune response. Therefore, we focused on the antioxidant property, inflammatory and anthelmintic effects of the traditional folk medicine, G. mangostana pericarp extract, in hamster opisthorchiasis. Syrian hamsters were divided into four groups: normal (control) (N); administered G. mangostana alone (GM); infected with Opisthorchis viverrini alone (OV); and infected with O. viverrini and administered G. mangostana extract for 1.5 months (OVGM). Hamster livers were collected 45 days after infection to determine histopathological changes, i.e. aggregation of inflammatory cells. The morphology of adult O. viverrini (body size and sizes of reproductive organs) was analyzed, as well as worm burden, eggs per worm and eggs per gram of feces. Toxicity was tested by kidney function (blood urea nitrogen and creatinine); the results demonstrated that G. mangostana had no renal toxic effect. ABTS radical-scavenging assay indicated that the extract had antioxidant property. Reduction in aggregation of inflammatory cells surrounding the hepatic bile duct, especially at the hilar region, was found in the OVGM group. Worm burden was similar in both infected groups (treated or untreated with G. mangostana), but the average size of adults in the OV group was larger than in the OVGM group; moreover, eggs per worm and eggs per gram of feces were also comparatively higher. The present study suggests that G. mangostana extract possesses anti-inflammatory and antioxidant properties and can interfere with parasite development by affecting adult size and egg production. This may be useful for controlling the spread of OV infection and other parasites in endemic areas., (Copyright © 2015 Elsevier Inc. All rights reserved.)

New tacrine-carbazole hybrids were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. The developed compounds showed high inhibitory activity on acetylcholinesterase (AChE) with IC50 values ranging from 0.48 to 1.03 μM and exhibited good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modeling studies revealed that these tacrine-carbazole hybrids interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The derivatives containing methoxy group showed potent ABTS radical scavenging activity. Considering their neuroprotection, our results indicate that these derivatives can reduce neuronal death induced by oxidative stress and β-amyloid (Aβ). Moreover, S1, the highest potency for both radical scavenging and AChE inhibitory activity, exhibited an ability to improve both short-term and long-term memory deficit in mice induced by scopolamine. Overall, tacrine-carbazole derivatives can be considered as a candidate with potential impact for further pharmacological development in Alzheimer's therapy., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Heptaphylline derivatives are carbazoles in Clausena harmandiana, a medicinal plant that is utilized for headache, stomach ache, and other treatments of illness. The present study examined the effects of heptaphylline and 7-methoxyheptaphylline on apoptosis of human colon adenocarcinoma cells (HT-29 cell line). Quantification of cell viability was performed using cell proliferation assay (MTT assay) and of protein expression through immunoblotting. The results showed that only heptaphylline, but not 7-methoxyheptaphylline, significantly significantly activated cleaved of caspase-3 and poly (ADP-ribose) polymerase (PARP-1) which resulted in HT-29 cell death. We found that heptaphylline activated BH3 interacting-domain death agonist (Bid) and Bak, proapoptotic proteins. In contrast, it suppressed X-linked inhibitor-of-apoptosis protein (XIAP), Bcl-xL and survivin, inhibitors of apoptosis. In addition, heptaphylline inhibited activation of NF-κB/p65 (rel), a regulator of apoptotic regulating proteins by suppressing the activation of Akt and IKKα, upstream regulators of p65. The findings suggested that heptaphylline induces apoptosis in human colon adenocarcinoma cells .

Aims: The aims of the present study were to investigate the effect of crebanine on memory and cognition impairment in mice and to elucidate the underlying molecular mechanisms., Main Methods: The memory-enhancing effects of crebanine were assessed with a water maze test using scopolamine-induced amnesic mice. The molecular mechanism was explored in silico by docking crebanine against acetylcholine binding proteins (AChBPs) and in vitro with a radioligand competition assay using (±)-[(3)H]-epibatidine. The pharmacological behavior was assessed by observing changes to the functional activity of α7-nAChRs expressed in Xenopus oocytes and by fluorescent assays on recombinant ligand gated ion channel (LGIC) receptors expressed in mammalian cells., Key Findings: The administration of crebanine significantly improved the cognitive deficits induced by scopolamine, as measured by the water maze test. The docking results demonstrated that crebanine bound to the active binding site of the AChBP template with a good docking energy. Crebanine significantly inhibited the binding of (±)-[(3)H]-epibatidine to AChBPs with K(i) values of 179 nM and 538 nM for Ls and Ac, respectively. Further functional assays performed using two separate protocols indicated that crebanine is an antagonist of the α7-nAChR with an IC(50) of 19.1μM., Significance: The observed actions of crebanine against amnesia and its effect on α7-nAChRs will be beneficial for target-based drug design; crebanine or its scaffold can be used as the starting point to develop a drug for Alzheimer's disease. The cognition-enhancing effects of crebanine and the underlying mechanism based on α7-nAChRs are consistent with its traditional use. These findings demonstrate the potential utility of crebanine in the development of neurodegenerative therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The present study reports the development of a template for the active binding site of Cdk5 for structure-based drug design. The developed template of Cdk5 was validated by redocking with ligands I (PBD code 1UNG), II (PBD code 1UNL) and III (PBD code 1UNH). The results demonstrate a good match of the docked and the crystallographic binding orientations with RMSD less than 2.0Å. The validation results show that the constructed Cdk5 template is a good model system for predicting ligand binding orientations and binding affinities. Furthermore, the developed template was applied to predict binding mode and binding affinity of thirty-six known Cdk5 inhibitors. The results showed that the binding energy of almost Cdk5 inhibitors related to their biological evaluation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Four new carbazole alkaloids, claurailas A-D (1-4), as well as 12 known carbazoles and three known coumarins were isolated from the roots of Clausena harmandiana. Heptaphylline (6) and 7-methoxyheptaphylline (7) showed strong cytotoxicity against NCI-H187 and KB cell lines with IC(50) values ranging from 1.3 to 2.7 μM. Compound 7 showed no cytotoxicity against Vero cells.

Two carbazoles (compounds 1 and 2) and one coumarin (compound 8) from Clausena harmandiana exhibited significant glucose uptake activity in L6 myotubes in a time and dose dependent manner. In addition, compounds 2 and 8 were inhibited by p38 mitogen-activated protein kinases and phosphatidylinositol 3-kinases, respectively., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Tryptoline, a core structure of ochrolifuanine E, which is a hit compound from virtual screening of the Thai herbal database against BACE1 was used as a scaffold for the design of BACE1 inhibitors. The tryptoline was linked with different side chains by 1,2,3-triazole ring readily synthesized by catalytic azide-alkyne cycloaddition reactions. Twenty two triazolyl tryptoline derivatives were synthesized and screened for the inhibitory action against BACE1. JJCA-140 was the most potent inhibitor (IC(50)=1.49 μM) and was 100 times more selective for BACE1 than for Cat-D., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Cholangiocarcinoma (CCA) is an aggressive malignancy with a very high morbidity and mortality for which an effective treatment is lacking. In this study, seventeen zerumbone derivatives were synthesized and evaluated for in vitro cytotoxicity against cholangiocarcinoma cell lines. 5 showed the most potent antiproliferative activity against KKU-100 cell line with an IC(50) value of 16.44 microM. To investigate the potential molecular target of the most active compound, the docking was performed using different enzymes and receptor proteins including CDK-2, CDK-5, EGFR, and GSK-3. The docking results revealed that 5 exhibited better binding interaction to EGFR than CDK-2, CDK-5 and GSK-3. All results indicate that 5 should be a promising candidate for treatment of cancer., (2010 Elsevier Masson SAS. All rights reserved.)

NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-(N'-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrol-3-yl}-propionic acid, was designed as FGF receptor 1 inhibitor by computational study and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 10 microM. NP506 inhibited the tyrosine phosphorylation in FGF, VEGF, and PDGF receptors and the activation of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal-kinase (JNK) and AKT after the rhFGF-2 stimulation. The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3-d]pyrimidine scaffold led to the inhibitory effect in two signaling pathways: inhibition of AKT activation in the phosphatidyl inositol 3'-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway.

NP603, the 6-dimethoxy phenyl indolin-2-one, was designed as FGF receptor 1 inhibitor by computational study. NP603 was synthesized and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 0.4 microM but with similar potency as SU16g. NP603 inhibited the tyrosine phosphorylation in FGF receptor and the activation of extracellular signal-regulated kinase and c-Jun-N-terminal-kinase after the rhFGF-2 stimulation. The increase in activity of NP603 supports the role of Lys514 movement in ligand-receptor binding in modeling study as the movement accommodates the hydrophobic interaction at the receptor pocket leading to the enhancement of binding capacity.

N(alpha)-vanillyl-N(omega)-nitroarginine (N - 1) that combines the active functions of natural antioxidant and nitric oxide synthase inhibitor was developed for its neuroprotective properties. N - 1 exhibited protective effects against hydrogen peroxide-induced cell damage and the inhibitory effect on nitric oxide 'NO' production induced by calcium ionophore in NG 108-15 cells. N - 1 inhibited the constitutive NOS isolated from rat cerebellar in a greater extent than constitutive NOS from human endothelial cells. Low binding energy (-10.2 kcal/mol) obtained from docking N - 1 to nNOS supported the additional mode of action of N - 1 as an nNOS inhibitor. The in vivo neuroprotective effect on kainic acid-induced nitric oxide production and neuronal cell death in rat brain was investigated via microdialysis. Rats were injected intra-peritonially with N - 1 at 75 micromol/kg before kainic acid injection (10 mg/kg). The significant suppression effect on kainic acid-induced NO and significant increase in surviving cells were observed in the hippocampus at 40 min after the induction.

A series of chroman amide and nicotinyl amide derivatives was designed and synthesized for the treatment of traumatic and ischemic CNS injury. Five compounds were significantly more potent inhibitors of lipid peroxidation in vitro than the reference antioxidant, trolox (p < 0.01). Quantitative structure activity studies demonstrated that the inhibitory action was related to the ability to donate electrons, charge on hydroxy group and E(LUMO), to scavenging radicals and to the lipophilicity log P, which determines penetration of membrane lipids. ESR study indicated the ability of 12 to scavenge the hydroxyl radicals. The most promising compound, [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2yl)ca rbonyl]-3'-(aminoethyl) indole (12), inhibited ex vivo lipid peroxidation in a head injury model and showed potent in vivo neuroprotective efficacy. Improvement of neurological recovery within 1 h of injury (grip test score) by as much as 200% was observed together with significant anti-anoxia activity. Compound 12 was a potent antagonist of methamphetamine-induced hypermotility resulting from dopamine release in the mouse brain. These results support the importance of cerebroprotective radical-scavenging agents for the treatment of traumatic injury and anoxia as well as provide additional evidence for the role of oxygen radicals and dopamine in brain damage.