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  1. Angelopoulou E, Paudel YN, Piperi C, Mishra A
    J Biochem Mol Toxicol, 2021 Jan 24.
    PMID: 33491302 DOI: 10.1002/jbt.22720
    Parkinson's disease (PD) is the most common neurodegenerative movement disorder with obscure etiology and no disease-modifying therapy to date. Hence, novel, safe, and low cost-effective approaches employing medicinal plants are currently receiving increased attention. A growing body of evidence has revealed that cinnamon, being widely used as a spice of unique flavor and aroma, may exert neuroprotective effects in several neurodegenerative diseases, including PD. In vitro evidence has indicated that the essential oils of Cinnamomum species, mainly cinnamaldehyde and sodium benzoate may protect against oxidative stress-induced cell death, reactive oxygen species generation, and autophagy dysregulation, thus acting in a potentially neuroprotective manner. In vivo evidence has demonstrated that oral administration of cinnamon powder and sodium benzoate may protect against dopaminergic cell death, striatal neurotransmitter dysregulation, and motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models of PD. The underlying mechanisms of its action include autophagy regulation, antioxidant effects, upregulation of Parkin, DJ-1, glial cell line-derived neurotrophic factor, as well as modulation of the TLR/NF-κB pathway and inhibition of the excessive proinflammatory responses. In addition, in vitro and in vivo studies have shown that cinnamon extracts may affect the oligomerization process and aggregation of α-synuclein. Herein, we discuss recent evidence on the novel therapeutic opportunities of this phytochemical against PD, indicating additional mechanistic aspects that should be explored, and potential obstacles/limitations that need to be overcome, for its inclusion in experimental PD therapeutics.
  2. Mohebali N, Pandurangan AK, Mustafa MR, Anandasadagopan SK, Alagumuthu T
    J Biochem Mol Toxicol, 2020 Dec;34(12):e22587.
    PMID: 32726518 DOI: 10.1002/jbt.22587
    Colorectal cancer is one of the most leading death-causing cancers in the world. Vernodalin, a cytotoxic sesquiterpene, has been reported to possess anticancer properties against human breast cancer cells. We aimed to examine the anticancer mechanism of vernodalin on human colon cancer cells. Vernodalin was used on human colon cancer cells, HT-29 and HCT116. The cytotoxicity of vernodalin on human colon cancer cells was determined through in vitro 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Small interfering RNA was used to analyze the cascade activation of mitogen-activated protein kinase (MAPK) pathway, c-Jun N-terminal kinase (JNK) in HT-29, and HCT116 cells against vernodalin treatment. The protein expressions of caspase 3, Bcl-2, and Bax were examined through Western blot analysis. Immunoblot analysis on the JNK, ERK, and p38 MAPK pathways showed increased activation due to vernodalin treatment. It was proven from the JNK and p38 inhibition test that both pathways are significantly activated by vernodalin to induce apoptosis. Our results, collectively, showed the apoptosis-induced anticancer mechanism of vernodalin on human colon cancer cells that was mediated through the activation of JNK pathway and apoptotic regulator proteins. These results suggest that vernodalin could be developed as a potent chemotherapeutic agent for human colorectal cancer treatment.
  3. Lee WQ, Affandi IS, Feroz SR, Mohamad SB, Tayyab S
    J Biochem Mol Toxicol, 2017 Feb;31(2).
    PMID: 27636401 DOI: 10.1002/jbt.21839
    Interaction of pendimethalin (PM) herbicide with the major transporter in human circulation, human serum albumin (HSA), was studied using fluorescence, circular dichroism (CD), and molecular modeling methods. The attenuation of the fluorescence intensity of HSA in the presence of PM revealed formation of the PM-HSA complex. Analysis of the fluorescence quenching data showed moderately strong binding affinity between PM and HSA. Both hydrophobic interactions and hydrogen bonding were suggested to stabilize the PM-HSA complex, based on thermodynamic data. Binding of PM to HSA induced perturbation in the microenvironment around the aromatic fluorophores as well as secondary and tertiary structural changes in the protein. Complexation of PM with HSA led to an increase in its thermal stability. Both site marker displacement and molecular modeling results suggested site I, located in subdomain IIA as the preferred binding site of PM on HSA.
  4. Chinigarzadeh A, Karim K, Muniandy S, Salleh N
    J Biochem Mol Toxicol, 2017 Apr;31(4).
    PMID: 27891704 DOI: 10.1002/jbt.21878
    We hypothesized that genistein could affect the chloride (Cl(-) ) and bicarbonate (HCO3(-) ) secretory mechanisms in uterus. Ovariectomized female rats were given estradiol or estradiol plus progesterone with 25, 50, or 100 mg/kg/day genistein. Following completion of the treatment, uterine fluid Cl(-) and HCO3(-) concentrations were determined by in vivo uterine perfusion. Uteri were subjected for molecular biological analysis (Western blot, qPCR, and immunohistochemistry) to detect levels of expression of Cystic Fibrosis transmembrane regulator (CFTR), Cl(-) /HCO3(-) exchanger (SLC26a6), Na(+) /HCO3(-) cotransporter (SLC4a4), and estrogen receptor (ER)-α and β. Coadministration of genistein resulted in decrease in Cl(-) and HCO3(-) concentrations and expression of CFTR, SLC26a6, SLC4a4, and ER-α and ER-β in the uteri of estradiol-treated rats. In estradiol plus progesterone-treated rats, a significant increase in the above parameters were observed following high-dose genistein treatment except for the SLC24a4 level. In conclusion, genistein-induced changes in the uterus could affect the reproductive processes that might result in infertility.
  5. Guo G, Zhang W, Dang M, Yan M, Chen Z
    J Biochem Mol Toxicol, 2019 Apr;33(4):e22268.
    PMID: 30431692 DOI: 10.1002/jbt.22268
    Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in breast cancer. The major snag faced by the human population is the development of chemoresistance to HER2 inhibitors by advanced stage breast cancer cells. Moreover, recent researchers focussed on fisetin as an antiproliferative and chemotherapeutic agent. Therefore, this study was intended to analyze the effects of fisetin on HER2/neu-overexpressing breast cancer cell lines. Our results depicted that fisetin induced apoptosis of these cells by various mechanisms, such as inactivation of the receptor, induction of proteasomal degradation, decreasing its half-life, decreasing enolase phosphorylation, and alteration of phosphatidylinositol 3-kinase/Akt signaling.
  6. Abubakar K, Mailafiya MM, Chiroma SM, Danmaigoro A, Zyoud TYT, Abdul Rahim E, et al.
    J Biochem Mol Toxicol, 2020 Jun;34(6):e22483.
    PMID: 32125074 DOI: 10.1002/jbt.22483
    INTRODUCTION: Lead (Pb) is a ubiquitous toxic heavy metal that inflicts numerous clinical consequences on humans. Curcumin is the principal component of turmeric, which is reported to have antioxidative properties. This study aimed at evaluating the ameliorative effects of curcumin on Pb-induced hepatorenal toxicity in a rat model.

    METHODS: Thirty-six male Sprague-Dawley rats were randomly assigned into five groups with 12 rats in the control (normal saline) and six rats each for the lead-treated group (LTG) (50 mg/kg lead acetate [Pb acetate] for 4 weeks), recovery group (50 mg/kg Pb acetate for 4 weeks and left with no treatment for another 4 weeks), treatment group 1 (Cur100) (50 mg/kg Pb acetate for 4 weeks, followed by 100 mg/kg curcumin for 4 weeks), and treatment group 2 (Cur200) (50 mg/kg Pb acetate for 4 weeks, followed by 200 mg/kg curcumin for 4 weeks). All the experimental groups received oral treatments via orogastric-tube on alternate days. Pb concentration in the liver and kidney of the rats were evaluated using inductive-coupled plasma mass spectrometry techniques.

    RESULTS: Pb-administered rats revealed significant alteration in oxidative status and increased Pb concentration in their liver and kidney with obvious reduction of hemogram and increased in leukogram as well as aberration in histological architecture of the liver and kidney. However, treatment with curcumin reduces the tissue Pb concentrations and ameliorates the above mention alterations.

    CONCLUSIONS: The results in this study suggested that curcumin attenuates Pb-induced hepatorenal toxicity via chelating activity and inhibition of oxidative stress.

  7. Wei J, Yang F, Gong C, Shi X, Wang G
    J Biochem Mol Toxicol, 2019 Jun;33(6):e22319.
    PMID: 30897277 DOI: 10.1002/jbt.22319
    Oxidative stress is performing an essential role in developing Alzheimer's disease (AD), and age-related disorder and other neurodegenerative diseases. In existing research, we have aimed at investigating the daidzein (4',7-dihydroxyisoflavone) effect (10 and 20 mg/kg of body weight), as a free radical scavenger and antioxidant in streptozotocin (STZ) infused AD in rat model. Daidzein treatment led to significant improvement in intracerebroventricular-streptozotocin (ICV-STZ)-induced memory and learning impairments that was evaluated by Morris water maze test and spontaneous locomotor activity. It significantly restored the alterations in malondialdehyde, catalase, superoxide dismutase, and reduced glutathione levels. In addition, histopathological observations in cerebral cortex and hippocampal areas confirmed the neuroprotective effect of daidzein. These outcomes provide experimental proof showing preventive effect of daidzein on memory, learning dysfunction and oxidative stress in case of ICV-STZ rats. In conclusion, daidzein offers a potential treatment module for various neurodegenerative disorders with regard to mental deficits like AD.
  8. Alavi N, Maghami P, Fani Pakdel A, Rezaei M, Avan A
    J Biochem Mol Toxicol, 2023 Feb 27.
    PMID: 36843533 DOI: 10.1002/jbt.23325
    We evaluated the activity of core-shell ZnO nanoparticles (ZnO-NPs@polymer shell) containing Oxaliplatin via polymerization through in vitro studies and in vivo mouse models of colorectal cancer. ZnO NPs were synthesized in situ when the polymerization step was completed by co-precipitation. Gadolinium coordinated-ZnONPs@polymer shell (ZnO-Gd NPs@polymer shell) was synthesized by exploiting Gd's oxophilicity (III). The biophysical properties of the NPs were studied using powder X-ray diffraction (PXRD), Fourier transforms infrared spectroscopy, Ultraviolet-visible spectroscopy (UV-Vis), field emission electron microscopy (FESEM), transmission electron microscopy (TEM), atomic force microscopy, dynamic light scattering, and z-potential. (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) was used to determine the antiproliferative activity of ZnO-Gd-OXA. Moreover, a xenograft mouse model of colon cancer was exerted to survey its antitumor activity and effect on tumor growth. In the following, the model was also evaluated by histological staining (H-E; Hematoxylin & Eosin and trichrome staining) and gene expression analyses through the application of RT-PCR/ELISA, which included biochemical evaluation (MDA, thiols, SOD, CAT). The formation of ZnO NPs, which contained a crystallite size of 16.8 nm, was confirmed by the outcomes of the PXRD analysis. The Plate-like morphology and presence of Pt were obtained in EDX outcomes. TEM analysis displayed the attained ZnO NPs in a spherical shape and a diameter of 33 ± 8.5 nm, while the hydrodynamic sizes indicated that the particles were highly aggregated. The biological results demonstrated that ZnO-Gd-OXA inhibited tumor growth by inducing reactive oxygen species and inhibiting fibrosis, warranting further research on this novel colorectal cancer treatment agent.
  9. Yan L, Luo H, Tang X, Wang H
    J Biochem Mol Toxicol, 2023 Feb;37(2):e23260.
    PMID: 36453646 DOI: 10.1002/jbt.23260
    Cannabinoids (CBs) are psychoactive compounds, with reported anticancer, anti-inflammatory, and anti-neoplastic properties. The study was aimed at assessing the hepatoprotective effects of CB against ethanol (EtOH)-induced liver toxicity in rats. The animals were divided into seven groups: control (Group I) and Group II were treated with 50% ethanol (EtOH 5 mg/kg). Groups III, IV, and VI were treated with (EtOH + CB 10 mg/kg), (EtOH + CB 20 mg/kg), and (EtOH + CB 30 mg/kg), respectively. Groups V and VII consisted of animals treated with 20 and 30 mg/kg, of CB, respectively. Biochemical analysis revealed that Group IV (EtOH + CB 20 mg/kg) had reduced levels of ALT-alanine transferase, AST-aspartate aminotransferase, ALP-alanine peroxidase, MDA-malondialdehyde and increased levels of GSH-reduced glutathione. Histopathological analysis of liver and kidney tissues showed that EtOH + CB (20 and 30 mg/kg) treated animal groups exhibited normal tissue architecture similar to that of the control group. ELISA revealed that the inflammatory markers were reduced in the animal groups that were treated with EtOH + CB 20 mg/kg, in comparison to the animals treated only with EtOH. The mRNA expression levels of COX-2, CD-14, and MIP-2 showed a remarkable decrease in EtOH + CB treated animal groups to control groups. Western blot analysis revealed that CB downregulated p38/JNK/ERK thereby exhibiting its hepatoprotective property by inhibiting mitogen-activated protein kinase pathways. Thus, our findings suggest that CB is a potential candidate for the treatment of alcohol-induced hepatotoxicity.
  10. Syed MH, Rubab SA, Abbas SR, Qutaba S, Mohd Zahari MAK, Abdullah N
    J Biochem Mol Toxicol, 2023 Aug;37(8):e23382.
    PMID: 37128655 DOI: 10.1002/jbt.23382
    Cadmium (Cd) is a heavy metal with various human exposure sources. It accumulates in the liver, forming a complex with metallothionein protein and progresses to other organs. As a heavy metal, cadmium can replace calcium and other divalent ions and disturb their cascades, ultimately affecting the vital organs. Since cadmium acetate (CA) is considered more lethal than other Cd compounds, the current study examines the effect of different concentrations of CA doses in drinking water for different exposure times in murine models (Mus musculus). After the exposure period, the murine models were then examined histopathologically and biochemically. The histopathological examination of the heart, liver, and kidneys of the experimental group showed extensive degenerative effects. Atomic absorption spectroscopy was used to determine the quantity of cadmium in serum, kidney, and hepatic tissues. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of hepatic proteins, especially metallothionein, directly related to Cd administration. The biochemical parameters, including creatine kinase, alanine aminotransferase, aspartate aminotransferase, total proteins, glucose, urea, uric acid, and creatinine, were also analyzed. After thorough histochemical and biochemical analysis, it was concluded that even low dose exposure of CA is hazardous to murine models with damaging effects.
  11. Hussain MS, Gupta G, Goyal A, Thapa R, Almalki WH, Kazmi I, et al.
    J Biochem Mol Toxicol, 2023 Nov;37(11):e23482.
    PMID: 37530602 DOI: 10.1002/jbt.23482
    Inflammation is an essential immune response that helps fight infections and heal tissues. However, chronic inflammation has been linked to several diseases, including cancer, autoimmune disorders, cardiovascular diseases, and neurological disorders. This has increased interest in finding natural substances that can modulate the immune system inflammatory signaling pathways to prevent or treat these diseases. Luteolin is a flavonoid found in many fruits, vegetables, and herbs. It has been shown to have anti-inflammatory effects by altering signaling pathways in immune cells. This review article discusses the current research on luteolin's role as a natural immune system modulator of inflammatory signaling mechanisms, such as its effects on nuclear factor-kappa B, mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, and inflammasome signaling processes. The safety profile of luteolin and its potential therapeutic uses in conditions linked to inflammation are also discussed. Overall, the data point to Luteolin's intriguing potential as a natural regulator of immune system inflammatory signaling processes. More research is needed to fully understand its mechanisms of action and possible therapeutic applications.
  12. Ren G, Hao X, Yang S, Chen J, Qiu G, Ang KP, et al.
    J Biochem Mol Toxicol, 2020 Sep;34(9):e22544.
    PMID: 32619082 DOI: 10.1002/jbt.22544
    Breast cancer is one of the leading causes of death in cancer categories, followed by lung, colorectal, and ovarian among the female gender across the world. 10H-3,6-diazaphenothiazine (PTZ) is a thiazine derivative compound that exhibits many pharmacological activities. Herein, we proceed to investigate the pharmacological activities of PTZ toward breast cancer MCF-7 cells as a representative in vitro breast cancer cell model. The PTZ exhibited a proliferation inhibition (IC50  = 0.895 µM) toward MCF-7 cells. Further, cell cycle analysis illustrated that the S-phase checkpoint was activated to achieve proliferation inhibition. In vitro cytotoxicity test on three normal cell lines (HEK293 normal kidney cells, MCF-10A normal breast cells, and H9C2 normal heart cells) demonstrated that PTZ was more potent toward cancer cells. Increase in the levels of reactive oxygen species results in polarization of mitochondrial membrane potential (ΔΨm), together with suppression of mitochondrial thioredoxin reductase enzymatic activity suggested that PTZ induced oxidative damages toward mitochondria and contributed to improved drug efficacy toward treatment. The RT2 PCR Profiler Array (human apoptosis pathways) proved that PTZ induced cell death via mitochondria-dependent and cell death receptor-dependent pathways, through a series of modulation of caspases, and the respective morphology of apoptosis was observed. Mechanistic studies of apoptosis suggested that PTZ inhibited AKT1 pathways resulting in enhanced drug efficacy despite it preventing invasion of cancer cells. These results showed the effectiveness of PTZ in initiation of apoptosis, programmed cell death, toward highly chemoresistant MCF-7 cells, thus suggesting its potential as a chemotherapeutic drug.
  13. Zhang H, Ramamoorthy A, Rengarajan T, Iyappan P, Alahmadi TA, Wainwright M, et al.
    J Biochem Mol Toxicol, 2024 Jan;38(1):e23578.
    PMID: 37927152 DOI: 10.1002/jbt.23578
    Lung cancer is one of the most common cancers in men. Although many diagnostic and treatment regimens have been followed in the treatment for lung cancer, increasing mortality rate due to lung cancer is depressing and hence requires alternative plant based therapeutics with with less side-effects. Myrtenol exhibits anti-inflammatory and antioxidant properties. Hence we intended to study the effect of Myrtenol on B(a)P-induced lung cancer. Our study showed that B(a)P lowered hematological count, decreased phagocyte and avidity indices, nitroblue tetrazolium (NBT) reduction, levels of immunoglubulins, antioxidant levels, whereas Myrtenol treatment restored them back to normal levels. On the other hand, xenobiotic and liver dysfunction marker enzymes and pro-inflammatory cytokines were elevated on B(a)P exposure, which retuned back to normal by Myrtenol. This study thus describes the immunomodulatory and antioxidant effects of Myrtenol on B[a]P-induced immune destruction.
  14. Li W, Wang F, Wang X, Xu W, Liu F, Hu R, et al.
    J Biochem Mol Toxicol, 2024 Feb;38(2):e23645.
    PMID: 38348716 DOI: 10.1002/jbt.23645
    Prostate cancer (PCa) is an extremely common genitourinary malignancy among elderly men. Many evidence have shown the efficacy of curcumin (CUR) in inhibiting the progression of PCa. However, the pharmacological function of CUR in PCa is still not quite clear. In this research, CUR was found to suppress the proliferation and enhance the apoptotic rate in in vitro PCa cell models in a dose- and time-dependent manner. In a xenograft animal model, the administration of CUR contributed to a significant decrease in the growth of the xenograft tumor induced by the transplanted PC-3 cells. Ubiquitin-conjugating enzyme E2 C is implicated in the modulation of multiple types of cancers. In humans, the expression levels of UBE2C are significantly higher in PCa versus benign prostatic hyperplasia. Treatment with CUR decreased the expression of UBE2C, whereas it increased miR-483-3p expression. In contrast with the control mice, the CUR-treated mice showed a significant reduction in UBE2C and Ki-67 in PCa cells. The capability of proliferation, migration, and invasion of PCa cells was inhibited by the knockdown of UBE2C mediated by siRNA. Furthermore, dual luciferase reporter gene assay indicated the binding of miR-483-3p to UBE2C. In summary, CUR exerts its antitumor effects through regulation of the miR-483-3p/UBE2C axis by decreasing UBE2C and increasing miR-483-3p. The findings may also provide new molecular markers for PCa diagnosis and treatment.
  15. Angelopoulou E, Nath Paudel Y, Piperi C, Mishra A
    J Biochem Mol Toxicol, 2021 Feb 15.
    PMID: 33587308 DOI: 10.1002/jbt.22711
    Parkinson's disease (PD) is the most common neurodegenerative movement disorder with obscure etiology and no disease-modifying therapy to date. Hence, novel, safe, and low cost-effective approaches employing medicinal plants are currently receiving increased attention. A growing body of evidence has revealed that cinnamon, being widely used as a spice of unique flavor and aroma, may exert neuroprotective effects in several neurodegenerative diseases, including PD. In vitro evidence has indicated that the essential oils of Cinnamomum species, mainly cinnamaldehyde and sodium benzoate, may protect against oxidative stress-induced cell death, reactive oxygen species generation, and autophagy dysregulation, thus acting in a potentially neuroprotective manner. In vivo evidence has demonstrated that oral administration of cinnamon powder and sodium benzoate may protect against dopaminergic cell death, striatal neurotransmitter dysregulation, and motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models of PD. The underlying mechanisms of its action include autophagy regulation, antioxidant effects, upregulation of Parkin, DJ-1, glial cell line-derived neurotrophic factor, as well as modulation of the Toll-like receptors/nuclear factor-κB pathway and inhibition of the excessive proinflammatory responses. In addition, in vitro and in vivo studies have shown that cinnamon extracts may affect the oligomerization process and aggregation of α-synuclein. Herein, we discuss recent evidence on the novel therapeutic opportunities of this phytochemical against PD, indicating additional mechanistic aspects that should be explored and potential obstacles/limitations that need to be overcome for its inclusion in experimental PD therapeutics.
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