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Activation of Nrf2 signaling by sitagliptin and quercetin combination against β-amyloid induced Alzheimer's disease in rats

Li Y, Tian Q, Li Z, Dang M, Lin Y, Hou X

Drug Dev Res, 2019 09;80(6):837-845.
PMID: 31301179 DOI: 10.1002/ddr.21567

The objective of this study was to evaluate the neuroprotective effect of sitagliptin (Sita), quercetin (QCR) and its combination in β-amyloid (Aβ) induced Alzheimer's disease (AD). Male Sprague-Dawley rats, weighing between 220 and 280 g were used for experiment. Rats were divided into 5 groups (n = 10) and the groups were as follows: (a) Sham control; (b) Aβ injected; (c) Aβ injected + Sita 100; (d) Aβ injected + QCR 100; and (e) Aβ injected + Sita 100 + QCR 100. Cognitive performance was observed by the Morris water maze (MWM), biochemical markers, for example, MDA, SOD, CAT, GSH, Aβ1-42 level, Nrf2/HO-1 expression and histopathological study of rat brain were estimated. Pretreatment with Sita, QCR and their combination showed a significant increase in escape latency in particular MWM cognitive model. Further co-administration of sita and QCR significantly reduced Aβ1-42 level when compared with individual treatment. Biochemical markers, for example, increased SOD, CAT and GSH, decreased MDA were seen, and histopathological studies revealed the reversal of neuronal damage in the treatment group. Additionally, Nrf2/HO-1 pathway in rat's brain was significantly increased by Sita, QCR and their combination. Pretreatment with QCR potentiates the action of Sita in Aβ induced AD in rats. The improved cognitive memory could be because of the synergistic effect of the drugs by decreasing Aβ1-42 level, antioxidant activity and increased expression of Nrf2/HO-1 in rat brain.

Matched MeSH terms: Signal Transduction/drug effects
Identifying Potential Therapeutics for Osteoporosis by Exploiting the Relationship between Mevalonate Pathway and Bone Metabolism

Hasan WNW, Chin KY, Jolly JJ, Ghafar NA, Soelaiman IN

Endocr Metab Immune Disord Drug Targets, 2018;18(5):450-457.
PMID: 29683099 DOI: 10.2174/1871530318666180423122409

BACKGROUND: Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling.
OBJECTIVE: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential.
DISCUSSION: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans.
CONCLUSION: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

Matched MeSH terms: Signal Transduction/drug effects
para-Phenylenediamine induces apoptosis through activation of reactive oxygen species-mediated mitochondrial pathway, and inhibition of the NF-κB, mTOR, and Wnt pathways in human urothelial cells

Reena K, Ng KY, Koh RY, Gnanajothy P, Chye SM

Environ Toxicol, 2017 Jan;32(1):265-277.
PMID: 26784575 DOI: 10.1002/tox.22233

para-Phenylenediamine (PPD) has long been used in two-thirds of permanent oxidative hair dye formulations. Epidemiological studies and in vivo studies have shown that hair dye is a suspected carcinogen of bladder cancer. However, the toxicity effects of PPD to human bladder remains elusive. In this study, the effects of PPD and its involvement in the apoptosis pathways in human urothelial cells (UROtsa) was investigated. It was demonstrated that PPD decreased cell viability and increased the number of sub-G1 hypodiploid cells in UROtsa cells. Cell death due to apoptosis was detected using Annexin V binding assay. Further analysis showed PPD generated reactive oxygen species (ROS), induced mitochondrial dysfunction through the loss of mitochondrial membrane potential and increased caspase-3 level in UROtsa cells. Western blot analysis of PPD-treated UROtsa cells showed down-regulation of phosphorylated proteins from NF-κB, mTOR, and Wnt pathways. In conclusion, PPD induced apoptosis via activation of ROS-mediated mitochondrial pathway, and possibly through inhibition of NF-κB, mTOR, and Wnt pathways. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 265-277, 2017.

Matched MeSH terms: Signal Transduction/drug effects*
NCI in vitro and in silico anticancer screen, cell cycle pertubation and apoptosis-inducing potential of new acylated, benzylidene and isopropylidene derivatives of andrographolide

Wong CC, Sagineedu SR, Sumon SH, Sidik SM, Phillips R, Lajis NH, et al.

Environ Toxicol Pharmacol, 2014 Sep;38(2):489-501.
PMID: 25168151 DOI: 10.1016/j.etap.2014.07.016

Andrographolide (AGP) is the main bioactive constituent isolated from the traditional medicinal, Andrographis paniculata which contributes towards its various biological activities, including anticancer property. In this study, a series of new AGP derivatives were semi-synthesised and screened against the NCI in vitro 60 cell lines. From the screening results, we had identified SRS07 as the most potent AGP derivative, against breast and colon cancer cell lines. Subsequently, SRS07 was tested for its capability to induce cell cycle arrest and apoptosis in MCF-7 and HCT116 cancer cells. SRS07 effectively induced G1 cell cycle arrest in both cell lines and ultimately apoptosis by inducing DNA fragmentation in HCT116 cells. The apoptotic cell death induced by SRS07 was confirmed via FITC Annexin-V double staining. Western blot analysis of SRS07-treated HCT116 cells revealed that the compound induced apoptosis be activating caspase 8 which in turn cleaved Bid to t-Bid to initiate cell death cascade. Prediction of the possible mode of action of SRS07 by utilising NCI COMPARE analysis failed to reveal a distinct mechanism category. Hence, it is speculated that SRS07 possesses novel mechanism of action. In conclusion, SRS07 demonstrated superior in vitro anticancer profiles and emerged as a potential lead anticancer candidate.

Matched MeSH terms: Signal Transduction/drug effects
The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions

Wu H, Sun Y, Wong WL, Cui J, Li J, You X, et al.

Eur J Med Chem, 2020 Mar 01;189:112042.
PMID: 31958737 DOI: 10.1016/j.ejmech.2020.112042

Transforming growth factor-β (TGF-β) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-β signaling pathway is a potential target for therapeutic intervention in the development of many diseases, such as fibrosis and cancer. Most currently available inhibitors of TGF-β signaling function as TGF-β receptor I (TβR-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-β receptor II (TβR-II) to interfere with the protein-protein interactions (PPIs) between TGF-β and its receptors. One compound, CJJ300, inhibited TGF-β signaling by disrupting the formation of the TGF-β-TβR-I-TβR-II signaling complex. Treatment of A549 cells with CJJ300 resulted in the inhibition of downstream signaling events such as the phosphorylation of key factors along the TGF-β pathway and the induction of EMT markers. Concomitant with these effects, CJJ300 significantly inhibited cell migration. The present study describes for the first time a designed molecule that can regulate TGF-β-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-β signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-β signaling and to design more potent TGF-β signaling antagonists.

Matched MeSH terms: Signal Transduction/drug effects
The effects of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone on proinflammatory signaling pathways and CLP-induced lethal sepsis in mice

Tham CL, Lam KW, Rajajendram R, Cheah YK, Sulaiman MR, Lajis NH, et al.

Eur J Pharmacol, 2011 Feb 10;652(1-3):136-44.
PMID: 21114991 DOI: 10.1016/j.ejphar.2010.10.092

We previously showed that 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone (BHMC), suppressed the synthesis of various proinflammatory mediators. In this study we explain the mechanism of action of BHMC in lipopolysaccharide (LPS)-induced U937 monocytes and further show that BHMC prevents lethality of CLP-induced sepsis. BHMC showed dose-dependent inhibitory effects on p38, JNK and ERK 1/2 activity as determined by inhibition of phosphorylation of downstream transcription factors ATF-2, c-Jun and Elk-1 respectively. Inhibition of these transcription factors subsequently caused total abolishment of AP-1-DNA binding. BHMC inhibited p65 NF-κB nuclear translocation and DNA binding of p65 NF-κB only at the highest concentration used (12.5μM) but failed to alter phosphorylation of JNK, ERK1/2 and STAT-1. Since the inhibition of p38 activity was more pronounced we evaluated the possibility that BHMC may bind to p38. Molecular docking experiments confirmed that BHMC fits well in the highly conserved hydrophobic pocket of p38 MAP kinase. We also show that BHMC was able to improve survival from lethal sepsis in a murine caecal-ligation and puncture (CLP) model.

Matched MeSH terms: Signal Transduction/drug effects*
Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation

Ravishankar D, Albadawi DAI, Chaggar V, Patra PH, Williams HF, Salamah M, et al.

Eur J Pharmacol, 2019 Nov 05;862:172627.
PMID: 31461638 DOI: 10.1016/j.ejphar.2019.172627

Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties. However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85 μM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100 μM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50 > 100 μM) but inhibited collagen induced platelet aggregation at 50 μM and 100 μM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion. Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100 μM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85 μM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor.

Matched MeSH terms: Signal Transduction/drug effects
Proteomic analysis of flavokawain C-induced cell death in HCT 116 colon carcinoma cell line

Phang CW, Gandah NA, Abd Malek SN, Karsani SA

Eur J Pharmacol, 2019 Jun 15;853:388-399.
PMID: 31014923 DOI: 10.1016/j.ejphar.2019.04.032

Flavokawain C (FKC), a naturally occurring chalcone, has previously been shown to inhibit the growth of colon carcinoma HCT 116 cells through induction of apoptosis and cell cycle arrest. However, the possible underlying mechanisms of cell death as a response to FKC treatment remains unclear. In this study, we performed proteomic analysis of HCT 116 cells treated with FKC to identify proteins that change in abundance. This was followed by bioinformatic analysis to predict possible associated molecular targets or pathways involved in the observed effects of FKC. A total of 35 proteins that changed in abundance (17 increased and 18 decreased) were identified through two-dimensional gel electrophoresis followed by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Using the Ingenuity Pathway Analysis (IPA), these proteins were predicted to be involved in cell death and survival, cell cycle, cellular growth and proliferation, protein synthesis, post-translational modification and amino acid metabolism by. Further analysis of the transcript levels of selected proteins using qPCR showed that some of the genes exhibited similar change of profile to that of the proteins'. Our results have provided novel insights into the potential molecular mechanisms underlying FKC-induced apoptosis or cell death in colon cancer cells.

Matched MeSH terms: Signal Transduction/drug effects
Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes

Abu Bakar MH, Sarmidi MR, Tan JS, Mohamad Rosdi MN

Eur J Pharmacol, 2017 Mar 15;799:73-83.
PMID: 28161417 DOI: 10.1016/j.ejphar.2017.01.043

Accumulating evidence indicates that mitochondrial dysfunction-induced inflammation is among the convergence points for the greatest hallmarks of hepatic insulin resistance. Celastrol, an anti-inflammatory compound from the root of Tripterygium Wilfordii has been reported to mitigate insulin resistance and inflammation in animal disease models. Nevertheless, the specific mechanistic actions of celastrol in modulating such improvements at the cellular level remain obscure. The present study sought to explore the mechanistic roles of celastrol upon insulin resistance induced by palmitate in C3A human hepatocytes. The hepatocytes exposed to palmitate (0.75mM) for 48h exhibited reduced both basal and insulin-stimulated glucose uptake, mitochondrial dysfunction, leading to increased mitochondrial oxidative stress with diminished fatty acid oxidation. Elevated expressions of nuclear factor-kappa B p65 (NF-κB p65), c-Jun NH(2)-terminal kinase (JNK) signaling pathways and the amplified release of pro-inflammatory cytokines including IL-8, IL-6, TNF-α and CRP were observed following palmitate treatment. Consistently, palmitate reduced and augmented phosphorylated Tyrosine-612 and Serine-307 of insulin receptor substrate-1 (IRS-1) proteins, respectively in hepatocytes. However, celastrol at the optimum concentration of 30nM was able to reverse these deleterious occasions and protected the cells from mitochondrial dysfunction and insulin resistance. Importantly, we presented evidence for the first time that celastrol efficiently prevented palmitate-induced insulin resistance in hepatocytes at least, via improved mitochondrial functions and insulin signaling pathways. In summary, the present investigation underlines a conceivable mechanism to elucidate the cytoprotective potential of celastrol in attenuating mitochondrial dysfunction and inflammation against the development of hepatic insulin resistance.

Matched MeSH terms: Signal Transduction/drug effects
The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways

Rengarajan T, Yaacob NS

Eur J Pharmacol, 2016 Oct 15;789:8-16.
PMID: 27377217 DOI: 10.1016/j.ejphar.2016.07.001

Epidemiological studies show that consumption of diets rich in fruits and vegetables is associated with lower risks of cancer. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds is fisetin (3,7,3,4-tetrahydroxyflavone), a flavonol that is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. Fisetin has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. Fisetin targets many components of intracellular signaling pathways including regulators of cell survival and apoptosis, tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. Current evidence supports the idea that fisetin is a promising agent for cancer treatment. This review summarizes reported anticancer effects of fisetin, and re-emphasizes its potential therapeutic role in the treatment of cancer.

Matched MeSH terms: Signal Transduction/drug effects*
IOP lowering effect of topical trans-resveratrol involves adenosine receptors and TGF-β2 signaling pathways

Razali N, Agarwal R, Agarwal P, Froemming GRA, Tripathy M, Ismail NM

Eur J Pharmacol, 2018 Nov 05;838:1-10.
PMID: 30171854 DOI: 10.1016/j.ejphar.2018.08.035

Trans-resveratrol was earlier shown to lower intraocular pressure (IOP) in rats; however, its mechanisms of action remain unclear. It has been shown to modulate adenosine receptor (AR) and TGF-β2 signaling, both of which play a role in regulating IOP. Hence, we investigated effects of trans-resveratrol on AR and TGF-β2 signaling. Steroid-induced ocular hypertensive (SIOH) rats were pretreated with A1AR, phospholipase C (PLC) and ERK1/2 inhibitors and were subsequently treated with single drop of trans-resveratrol. Metalloproteinases (MMP)-2 and -9 were measured in aqueous humor (AH). In another set of experiments, effect of trans-resveratrol on AH level of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) was determined after single and multiple drop administration in SIOH rats. Effect of trans-resveratrol on ARs expression, PLC and pERK1/2 activation and MMPs, tPA and uPA secretion was determined using human trabecular meshwork cells (HTMC). Further, effect of trans-resveratrol on TGF-β2 receptors, SMAD signaling molecules and uPA and tPA expression by HTMC was determined in the presence and absence of TGF-β2. Pretreatment with A1AR, PLC and ERK1/2 inhibitors antagonized the IOP lowering effect of trans-resveratrol and caused significant reduction in the AH level of MMP-2 in SIOH rats. Trans-resveratrol increased A1AR and A2AAR expression, cellular PLC, pERK1/2 levels and MMP-2, tPA and uPA secretion by HTMC. Additionally, it produced TGFβRI downregulation and SMAD 7 upregulation. In conclusion, IOP lowering effect of trans-resveratrol involves upregulation of A1AR expression, PLC and ERK1/2 activation and increased MMP-2 secretion. It downregulates TGFβRI and upregulates SMAD7 hence, inhibits TGF-β2 signaling.

Matched MeSH terms: Signal Transduction/drug effects*
Fulltext Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?

Agarwal R, Agarwal P

Exp Biol Med (Maywood), 2017 Feb;242(4):374-383.
PMID: 27798117 DOI: 10.1177/1535370216675065

Disturbances of extracellular matrix homeostasis are associated with a number of pathological conditions. The ability of extracellular matrix to provide contextual information and hence control the individual or collective cellular behavior is increasingly being recognized. Hence, newer therapeutic approaches targeting extracellular matrix remodeling are widely investigated. We reviewed the current literature showing the effects of resveratrol on various aspects of extracellular matrix remodeling. This review presents a summary of the effects of resveratrol on extracellular matrix deposition and breakdown. Mechanisms of action of resveratrol in extracellular matrix deposition involving growth factors and their signaling pathways are discussed. Involvement of phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways and role of transcription factors and sirtuins on the effects of resveratrol on extracellular matrix homeostasis are summarized. It is evident from the literature presented in this review that resveratrol has significant effects on both the synthesis and breakdown of extracellular matrix. The major molecular targets of the action of resveratrol are growth factors and their signaling pathways, phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways, transcription factors, and SIRT-1. The effects of resveratrol on extracellular matrix and the molecular targets appear to be related to experimental models, experimental environment as well as the doses.

Matched MeSH terms: Signal Transduction/drug effects
Newer targets for modulation of intraocular pressure: focus on adenosine receptor signaling pathways

Agarwal R, Agarwal P

Expert Opin Ther Targets, 2014 May;18(5):527-39.
PMID: 24579961 DOI: 10.1517/14728222.2014.888416

The homeostatic role of adenosine in regulating intraocular pressure (IOP) is now widely recognized, and hence, the drugs targeting adenosine receptors have become the focus of investigation. In this review, we summarize the adenosine receptor signaling pathways, which could be potential therapeutic targets for the management of glaucoma.

Matched MeSH terms: Signal Transduction/drug effects*
Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway

Break MKB, Hossan MS, Khoo Y, Qazzaz ME, Al-Hayali MZK, Chow SC, et al.

Fitoterapia, 2018 Mar;125:161-173.
PMID: 29355749 DOI: 10.1016/j.fitote.2018.01.006

Cardamonin is a natural chalcone that has been shown to exhibit high anticancer activity. In an attempt to discover analogues of cardamonin with enhanced anticancer activity, 19 analogues were synthesized and tested against A549 and HK1 cell lines. Results of the MTS cell viability assay showed that several derivatives possessed cytotoxic activities that were several-fold more potent than cardamonin. SAR analysis showed the importance of the ketone and alkene groups for bioactivity, while substituting cardamonin's phenolic groups with more polar moieties resulted in activity enhancement. As part of the SAR study and further exploration of chemical space, the effect of metal coordination on cytotoxicity was also investigated, but it was only possible to successfully obtain the Cu (II) complex of cardamonin (19). Compound 19 was the most active analogue possessing IC50 values of 13.2μM and 0.7μM against A549 and HK1 cells, corresponding to a 5- and 32-fold increase in activity, respectively. It was also able to significantly inhibit the migration of A549 and HK1 cells. Further mode of action studies have shown that the most active analogue, 19, induced DNA damage resulting in G2/M-phase cell- cycle arrest in both cell lines. These events further led to the induction of apoptosis by the compound via caspase-3/7 and caspase-9 activation, PARP cleavage and downregulation of Mcl-1 expression. Moreover, 19 inhibited the expression levels of p-mTOR and p-4EBP1, which indicated that it exerted its anticancer activity, at least in part, via inhibition of the mTOR signalling pathway.

Matched MeSH terms: Signal Transduction/drug effects*
Sciadonic acid attenuates high-fat diet-induced bone metabolism disorders in mice

Yao S, Lu H, Zhou T, Jiang Q, Jiang C, Hu W, et al.

Food Funct, 2024 Apr 22;15(8):4490-4502.
PMID: 38566566 DOI: 10.1039/d3fo04527g

High-fat diet (HFD) has been associated with certain negative bone-related outcomes, such as bone metabolism disruption and bone loss. Sciadonic acid (SC), one of the main nutritional and functional components of Torreya grandis seed oil, is a unique Δ5-unsaturated-polymethylene-interrupted fatty acid (Δ5-UPIFA) that has been claimed to counteract such disorders owing to some of its physiological effects. However, the role of SC in ameliorating bone metabolism disorders due to HFD remains unclear. In the present investigation, we observed that SC modulates the OPG/RANKL/RANK signaling pathway by modifying the lipid metabolic state and decreasing inflammation in mice. In turn, it could balance bone resorption and formation as well as calcium and phosphorus levels, enhance bone strength and bone mineral density (BMD), and improve its microstructure. In addition, SC could inhibit fat vacuoles in bone, reverse the phenomenon of reduced numbers and poor continuity of bone trabeculae, and promote orderly arrangement of collagen fibers and cartilage repair. This study provides some theoretical basis for SC as a dietary intervention agent to enhance bone nutrition.

Matched MeSH terms: Signal Transduction/drug effects
Meeting report: 4th Biennial Meeting of the Society for Free Radical Research--Asia, held during July 9-12, 2009 at Langkawi, Malaysia

Free Radic Res, 2009 Dec;43(12):1248-53.
PMID: 19905987 DOI: 10.3109/10715760903236820
Matched MeSH terms: Signal Transduction/drug effects
The antinociceptive activity of Muntingia calabura aqueous extract and the involvement of L-arginine/nitric oxide/cyclic guanosine monophosphate pathway in its observed activity in mice

Zakaria ZA, Sulaiman MR, Jais AM, Somchit MN, Jayaraman KV, Balakhrisnan G, et al.

Fundam Clin Pharmacol, 2006 Aug;20(4):365-72.
PMID: 16867020

The present study was carried out to investigate on the possible involvement of L-arginine/nitric oxide/cyclic guanosine monophosphate (L-arginine/NO/cGMP) pathway in the aqueous extract of Muntingia calabura (AEMC) leaves antinociception in mice assessed by abdominal constriction test. The AEMC, obtained by soaking the dried leaves in distilled water (DH(2)O) (1 : 2; w/v) for 24 h, was prepared in concentrations of 10%, 50% and 100% that were approximately equivalent to doses of 27, 135 and 270 mg/kg, and administered subcutaneously (s.c.) 5 min after pre-treatment (s.c.) of mice with DH(2)O, L-arginine (20 mg/kg), N(G)-monomethyl-L-arginine acetate (L-NMMA; 20 mg/kg), N(G)-nitro-L-arginine methyl esters (L-NAME; 20 mg/kg), methylene blue (MB) (20 mg/kg), respectively. The AEMC was found to exhibit a concentration-dependent antinociception after pre-challenge with DH(2)O. Interestingly, pre-treatment with L-arginine was found to block significantly (P < 0.05) the AEMC antinociception but only at the highest concentration (100%) of AEMC used. On the other hand, pre-treatment with L-NAME was found to significantly (P < 0.05) enhance the low concentration but inhibit the high concentration AEMC antinociception. MB was found to significantly (P < 0.05) enhance AEMC antinociception at all concentrations used. Except for the higher concentration of AEMC used, co-treatment with L-NAME was found to insignificantly and significantly (P < 0.05) reverse the L-arginine effect when given alone or with low concentration AEMC, respectively. In addition, co-treatment with MB significantly (P < 0.05) reversed the L-arginine effect when given alone or with 10% concentration AEMC but failed to affect the activity of the rest of concentrations used. As a conclusion, this study has demonstrated the involvement of L-arginine/NO/cGMP pathway in AEMC antinociception.

Matched MeSH terms: Signal Transduction/drug effects*
Fulltext Targeting the B-cell lymphoma 2 anti-apoptotic proteins for cervical cancer treatment

Abdul Rahman SF, Xiang Lian BS, Mohana-Kumaran N

Future Oncol, 2020 Oct;16(28):2235-2249.
PMID: 32715755 DOI: 10.2217/fon-2020-0389

The B-cell lymphoma 2 (BCL-2) anti-apoptotic proteins have become attractive therapeutic targets especially with the development of BH3-mimetics which selectively target these proteins. However, it is important to note that expression levels of the anti-apoptotic proteins and their relevance in inhibiting apoptosis varies between different cell lineages. This addiction to certain anti-apoptotic proteins for survival, can be determined with various techniques and targeted effectively with selective BH3-mimetics. Studies have highlighted that anti-apoptotic proteins BCL-XL and MCL-1 are crucial for cervical cancer cell survival. Co-targeting BCL-XL and MCL-1 with selective BH3-mimetics yielded promising results in cervical cancer cell lines. In this review, we focus on the expression levels of the anti-apoptotic proteins in cervical cancer tissues and how to possibly target them with BH3-mimetics.

Matched MeSH terms: Signal Transduction/drug effects
Selective targeting of cancer signaling pathways with nanomedicines: challenges and progress

Barkat HA, Das SS, Barkat MA, Beg S, Hadi HA

Future Oncol, 2020 Dec;16(35):2959-2979.
PMID: 32805124 DOI: 10.2217/fon-2020-0198

Cancer is one of the leading causes of death worldwide. Regardless of advances in understanding the molecular mechanics of cancer, its treatment is still lacking and the death rates for many forms of the disease remain the same as six decades ago. Although a variety of therapeutic agents and strategies have been reported, these therapies often failed to provide efficient therapy to patients as a consequence of the inability to deliver right and adequate chemotherapeutic agents to the right place. However, the situation has started to revolutionize substantially with the advent of novel 'targeted' nanocarrier-based cancer therapies. Such therapies hold great potential in cancer management as they are biocompatible, tailored to specific needs, tolerated and deliver enough drugs at the targeted site. Their use also enhances the delivery of chemotherapeutics by improving biodistribution, lowering toxicity, inhibiting degradation and increasing cellular uptake. However, in some instances, nonselective targeting is not enough and the inclusion of a ligand moiety is required to achieve tumor targeting and enhanced drug accumulation at the tumor site. This contemporary review outlines the targeting potential of nanocarriers, highlighting the essentiality of nanoparticles, tumor-associated molecular signaling pathways, and various biological and pathophysiological barriers.

Matched MeSH terms: Signal Transduction/drug effects
Tissue-selective expression of a conditionally-active ROCK2-estrogen receptor fusion protein

Samuel MS, Rath N, Masre SF, Boyle ST, Greenhalgh DA, Kochetkova M, et al.

Genesis, 2016 Dec;54(12):636-646.
PMID: 27775859 DOI: 10.1002/dvg.22988

The serine/threonine kinases ROCK1 and ROCK2 are central mediators of actomyosin contractile force generation that act downstream of the RhoA small GTP-binding protein. As a result, they have key roles in regulating cell morphology and proliferation, and have been implicated in numerous pathological conditions and diseases including hypertension and cancer. Here we describe the generation of a gene-targeted mouse line that enables CRE-inducible expression of a conditionally-active fusion between the ROCK2 kinase domain and the hormone-binding domain of a mutated estrogen receptor (ROCK2:ER). This two-stage system of regulation allows for tissue-selective expression of the ROCK2:ER fusion protein, which then requires administration of estrogen analogues such as tamoxifen or 4-hydroxytamoxifen to elicit kinase activity. This conditional gain-of-function system was validated in multiple tissues by crossing with mice expressing CRE recombinase under the transcriptional control of cytokeratin14 (K14), murine mammary tumor virus (MMTV) or cytochrome P450 Cyp1A1 (Ah) promoters, driving appropriate expression in the epidermis, mammary or intestinal epithelia respectively. Given the interest in ROCK signaling in normal physiology and disease, this mouse line will facilitate research into the consequences of ROCK activation that could be used to complement conditional knockout models. Birth Defects Research (Part A) 106:636-646, 2016. © 2016 Wiley Periodicals, Inc.

Matched MeSH terms: Signal Transduction/drug effects

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