Cancer cells are usually recognized as foreign particles by the immune cells. Mounting evidence suggest an important link between toll-like receptors (TLRs) and carcinogenesis. This review article ...focused on the role of TLRs, especially TLR4, in breast cancer.
Research data on TLRs and cancer was explored in PubMed, Scopus, Google Scholar and reviewed. Although some pioneer works are referenced, papers published in the last ten years were mostly cited.
TLRs are widely investigated pattern recognition receptors (PRR), and TLR4 is the most studied TLRs, implicated with the occurrence of several types of cancers, including breast cancer. TLR4 activation occurs via the binding of its ligand lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria. Upon LPS binding, TLR4 dimerizes and recruits downstream signalling and/or adapter molecules, leading to gene expression related to cancer cell proliferation, survival, invasion, and metastasis. Although LPS/TLR4 signalling seems a single signal transduction pathway, the TLR4 activation results in the activation of multiple diverse intracellular networks with huge cellular responses in both immune and cancer cells. The role of TLR4 in the growth, invasion, and metastasis of breast cancer is attracting huge attention in oncology research. Several clinical and preclinical studies utilize both TLR4 agonists and antagonists as a treatment option for cancer therapy, either as monotherapy or adjuvants for vaccine development.
This review narrates the role of LPS/TLR4 signalling in breast cancer development and future prospects for targeting LPS/TLR4 axis in the treatment of breast cancer.
Toll-like receptors (TLRs) recognise pathogen‑associated molecular patterns, which allow the detection of microbial infection by host cells. Bacterial-derived toxin lipopolysaccharide activates TLR4 ...and leads to the activation of the Smad2 transcription factor. The phosphorylation of the Smad2 transcription factor is the result of the activation of the transforming growth factor-β receptor 1 (TGFBR1). Therefore, we sought to investigate LPS via TLR4-mediated Smad2 carboxy terminal phosphorylation dependent on the transactivation of the TGFBR1. The in vitro model used human aortic vascular smooth muscle cells to assess the implications of TLR4 transactivation of the TGFBR1 in vascular pathophysiology. We show that LPS-mediated Smad2 carboxy terminal phosphorylation is inhibited in the presence of TGFBR1 inhibitor, SB431542. Treatment with MyD88 and TRIF pathway antagonists does not affect LPS-mediated phosphorylation of Smad2 carboxy terminal; however, LPS-mediated Smad2 phosphorylation was inhibited in the presence of MMP inhibitor, GM6001, and unaffected in the presence of ROCK inhibitor Y27632 or ROS/NOX inhibitor DPI. LPS via transactivation of the TGFBR1 stimulates PAI-1 mRNA expression. TLRs are first in line to respond to exogenous invading substances and endogenous molecules; our findings characterise a novel signalling pathway in the context of cell biology. Identifying TLR transactivation of the TGFBR1 may provide future insight into the detrimental implications of pathogens in pathophysiology.
We investigated the aqueous and ethanolic extracts of different forms (local names: mura and chora) of turmeric (Curcuma longa) from the Khulna and Chittagong divisions of Bangladesh for their ...antioxidant properties and polyphenol, flavonoid, tannin, and ascorbic acid contents. The antioxidant activity was determined using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging activity and ferric reducing antioxidant power (FRAP) values. The ethanolic extract of Chittagong’s mura contained the highest concentrations of polyphenols (16.07%), flavonoids (9.66%), and ascorbic acid (0.09 mg/100 g) and chora resulted in high yields (17.39%). The ethanolic extract of Khulna’s mura showed a higher DPPH radical-scavenging activity with the lowest 50% inhibitory concentration (IC50) (1.08 μg/mL), while Khulna’s chora had the highest FRAP value (4204.46±74.48 μM Fe II per 100 g). Overall, the ethanolic extract had higher antioxidant properties than those in the aqueous extract. However, the tannin concentration was lower in the ethanolic extract. We conclude that the turmeric varieties investigated in this study are useful sources of natural antioxidants, which confer significant protection against free radical damage.
Atherosclerosis is a vascular disease in which inflammation plays a pivotal role. Receptor-mediated signaling pathways regulate vascular inflammation and the pathophysiology of atherosclerosis. ...Emerging evidence has revealed the role of the Wnt pathway in atherosclerosis progression. The Wnt pathway influences almost all stages of atherosclerosis progression, including endothelial dysfunction, monocyte infiltration, smooth muscle cell proliferation and migration, and plaque formation. Targeting the Wnt pathway to treat atherosclerosis represents a promising therapeutic approach that remains understudied. Blocking Wnt signaling utilizing small molecule inhibitors, recombinant proteins, and/or neutralizing antibodies ameliorates atherosclerosis in preclinical models. The Wnt pathway can be potentially manipulated through targeting Wnt ligands, receptors, co-receptors, and downstream signaling molecules. However, there are challenges associated with developing a real world therapeutic compound that targets the Wnt pathway. This review focuses on the role of Wnt signaling in atherosclerosis development, and the rationale for targeting this pathway for the treatment of atherosclerosis.
Protease activated receptors (PARs) transactivate both epidermal growth factor receptors (EGFR) and transforming growth factor (TGF)-β receptors (TGFBR1) in vascular smooth muscle leading to the ...increased expression of genes (CHST11 and CHSY1) which are rate limiting for the enzymes that mediate hyperelongation of glycosaminoglycan (GAG) chains on the lipid-binding proteoglycan, biglycan. This is an excellent model to investigate mechanisms of transactivation as the processes are biochemically distinct. EGFR transactivation is dependent on the classical matrix metalloprotease (MMP) based triple membrane bypass mechanism and TGFBR1 transactivation is dependent on Rho/ROCK signalling and integrins. We have shown that all kinase receptor signalling is targeted towards phosphorylation of the linker region of the transcription factor, Smad2. We investigated the mechanisms of thrombin mediated kinase receptor transactivation signalling using anti-phospho antibodies and Western blotting and gene expression by RT-PCR. Thrombin stimulation of phospho-Smad2 (Ser 245/250/255) and of phospho-Smad2(Thr220) via EGFR transactivation commences quickly and extends out to at least 4 h whereas transactivation via TGFBR1 is delayed for 120 min but also persists for at least 4 h. Signalling of thrombin stimulated Smad linker region phosphorylation is approximately equally inhibited by the MMP inhibitor, GM6001 and the ROCK inhibitor, Y27632, and similarly expression of CHST11 and CHSY1 is approximately equally inhibited by GM6001 and Y27632. The data establishes Smad linker region phosphorylation as a central target of all transactivation signalling of GAG gene expression and thus an upstream kinase may be a target to prevent all transactivation signalling and its pathophysiological consequences.
The present study was designed to investigate the cardioprotective effects of Sundarban honey (SH) in rats with isoproterenol- (ISO-) induced myocardial infarction. Adult male Wistar Albino rats were ...pretreated with Sundarban honey (5 g/kg) daily for a period of 6 weeks. After the treatment period, ISO (85 mg/kg) was subcutaneously injected into the rats at 24 h intervals for 2 days. ISO-induced myocardial damage was indicated by increased serum cardiac specific troponin I levels and cardiac marker enzyme activities including creatine kinase-MB, lactate dehydrogenase, aspartate transaminase, and alanine transaminase. Significant increases in serum total cholesterol, triglycerides, and low-density lipoprotein-cholesterol levels were also observed, along with a reduction in the serum high-density lipoprotein-cholesterol level. In addition to these diagnostic markers, the levels of lipid peroxide products were significantly increased. The activities of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and glutathione reductase were significantly decreased in the hearts after ISO-induced myocardial infarction. However, pretreatment of ischemic rats with Sundarban honey brought the biochemical parameters to near normalcy, indicating the protective effect of Sundarban honey against ISO-induced ischemia in rats. Histopathological findings of the heart tissues further confirmed the biochemical findings, indicating that Sundarban honey confers protection against ISO-induced oxidative stress in the myocardium.
Autonomously spiking dopaminergic neurons of the substantia nigra pars compacta (SNpc) are exquisitely specialized and suffer toxic iron-loading in Parkinson's disease (PD). However, the molecular ...mechanism involved remains unclear and critical to decipher for designing new PD therapeutics. The long-lasting (L-type) CaV1.3 voltage-gated calcium channel is expressed at high levels amongst nigral neurons of the SNpc, and due to its role in calcium and iron influx, could play a role in the pathogenesis of PD. Neuronal iron uptake via this route could be unregulated under the pathological setting of PD and potentiate cellular stress due to its redox activity. This Commentary will focus on the role of the CaV1.3 channels in calcium and iron uptake in the context of pharmacological targeting. Prospectively, the audacious use of artificial intelligence to design innovative CaV1.3 channel inhibitors could lead to breakthrough pharmaceuticals that attenuate calcium and iron entry to ameliorate PD pathology.
Honey, a supersaturated natural product of honey bees, contains complex compounds with antioxidant properties and therefore has a wide a range of applications in both traditional and modern medicine. ...In the present study, the protective effects of Sundarban honey from Bangladesh against acetaminophen- (APAP-) induced hepatotoxicity and nephrotoxicity in experimental rats were investigated. Adult male Wistar rats were pretreated with honey (5 g/kg) for 4 weeks, followed by the induction of hepatotoxicity and nephrotoxicity via the oral administration of a single dose of APAP (2 g/kg). Organ damage was confirmed by measuring the elevation of serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), total protein (TP), total bilirubin (TB), urea, creatinine, and malondialdehyde (MDA). Histopathological alterations observed in the livers and the kidneys further confirmed oxidative damage to these tissues. Animals pretreated with Sundarban honey showed significantly markedly reduced levels of all of the investigated parameters. In addition, Sundarban honey ameliorated the altered hepatic and renal morphology in APAP-treated rats. Overall, our findings indicate that Sundarban honey protects against APAP-induced acute hepatic and renal damage, which could be attributed to the honey’s antioxidant properties.
The study reports on major and trace elements as well as antioxidant properties of honey samples from Bangladesh. Four major cationic elements, seven trace elements, and three heavy metals were ...determined in the 12 honey samples using atomic absorption spectrophotometer. Nutritional values in these honey samples were further investigated according to their antioxidant properties. The content of major elements was in the range of 62.75–616.58, 579.48–2219.43, 69.42–632.25, and 0.13–1.20 mg/kg for sodium, potassium, magnesium, and calcium, respectively. The trace elements varied in the range of 0.41–28, 0.12–3.54, 1.54–2.85, 0.29–0.59, 0.02–0.35, and 0.01–0.06 mg/kg for iron, zinc, copper, nickel, cobalt, and cadmium, respectively. Among the heavy metals, only lead (0.17–2.19 mg/kg) was detected. The results of antioxidant analysis based on phenolics, flavonoids, ascorbic acid, reducing sugar, and proteins (as nonphenolic antioxidants) revealed that multifloral raw honey samples contain significantly higher levels of reducing agents than monofloral and commercial brand honeys. The study provides a useful insight on the minerals, heavy metals, and antioxidant properties of honey samples commonly consumed in Bangladesh and found to be rich source of antioxidants and minerals. Some samples might pose some risk to the health due to lead contamination.
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