Phytochemicals inhibit the immunosuppressive functions of myeloid-derived suppressor cells (MDSC): Impact on cancer and age-related chronic inflammatory disorders.

Traditional herbal medicine has provided natural remedies against cancers and many age-related inflammatory diseases for thousands of years. Modern drug discovery techniques have revealed several active ingredients and their medicinal targets have been characterized. Concurrently, there has been great progress in understanding the pathological mechanisms underpinning cancers and inflammatory diseases. These studies have demonstrated that immature myeloid-derived suppressor cells (MDSCs) have a crucial role in the immune escape of cancer cells thus promoting tumor growth. Inflammatory factors stimulate the recruitment, expansion, and activation of MDSCs in tumors and inflamed tissues. The immunosuppression generated by MDSCs has an important role in the resolution of acute inflammation but in chronic inflammatory disorders, the activation of MDSCs suppresses the innate and adaptive immune responses thus aggravating the disease processes in association with tumors, chronic infections, and many degenerative diseases. Currently, MDSCs are important drug discovery targets in cancers and chronic inflammatory diseases. Interestingly, there are promising reports that certain phytochemicals can function as potent inhibitors of the immunosuppressive MDSCs that could partially explain the therapeutic benefits of herbal medicine. We will briefly describe the immune suppressive functions of MDSCs in cancers and age-related inflammatory diseases and then review in detail the chemically characterized phytochemicals of different herbal categories, e.g. flavonoids, terpenoids, retinoids, curcumins, and ß-glucans, which possess the MDSC-dependent antitumor and anti-inflammatory properties.

Phytochemicals suppress nuclear factor-κB signaling: impact on health span and the aging process.

PURPOSE OF REVIEW: We will briefly review the current knowledge on the major molecular targets of plant-derived phytochemicals, particularly their connections to nuclear factor-κB (NF-κB) signaling, and accordingly link these observations to their anti-inflammatory properties and beneficial effects on the aging process and age-related degenerative diseases. RECENT FINDINGS: Many of the major phytochemicals, for example, flavonoids and terpenoids, possess significant therapeutic properties including anti-inflammatory and anticancer effects. Although phytochemicals have multiple molecular targets, recent studies have indicated that many of them can activate signaling pathways driven by AMP-activated protein kinase and nuclear factor-erythroid 2-related factor 2. These pathways are potent inhibitors of NF-κB signaling, a crucial inducer of inflammatory responses and cancer formation. Current opinion suggests that inflammation has a critical role in the aging process and in the pathogenesis of age-related degenerative diseases and, thus, anti-inflammatory properties of phytochemicals could explain their beneficial effects on health span and lifespan. SUMMARY: Plant-derived phytochemicals are promising lead compounds helping modern drug discovery to develop potent and safe inhibitors for age-related inflammatory disorders driven by NF-κB signaling.

Celastrol: Molecular targets of Thunder God Vine.

Celastrol, a quinone methide triterpene, is a pharmacologically active compound present in Thunder God Vine root extracts used as a remedy of inflammatory and autoimmune diseases, e.g. rheumatoid arthritis. Celastrol is one of the most promising medicinal molecules isolated from the plant extracts of traditional medicines. Molecular studies have identified several molecular targets which are mostly centered on the inhibition of IKK-NF-kappaB signaling. Celastrol (i) inhibits directly the IKKalpha and beta kinases, (ii) inactivates the Cdc37 and p23 proteins which are co-chaperones of HSP90, (iii) inhibits the function of proteasomes, and (iv) activates the HSF1 and subsequently triggers the heat shock response. It seems that the quinone methide structure present in celastrol can react with the thiol groups of cysteine residues, forming covalent protein adducts. In laboratory experiments, celastrol has proved to be a potent inhibitor of inflammatory responses and cancer formation as well as alleviating diseases of proteostasis deficiency. Celastrol needs still to pass several hurdles, e.g. ADMET assays, before it can enter the armoury of western drugs.

NF-kappaB signaling as a putative target for omega-3 metabolites in the prevention of age-related macular degeneration (AMD).

Age-related macular degeneration (AMD) is the major reason of blindness of the elderly all over the world. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, the highly specialized region of the retina responsible for sharp and color visual acuity. Degeneration and cell death of retinal pigment epithelial cells (RPE) cause secondarily adverse effects on neural retina leading to visual loss. Most AMD patients cannot benefit from any treatment modalities. The prevalence of AMD is rising as a consequence of the aging of the population. As the RPE cells age, they are subject to continued oxidative stress and this believed to induce inflammation and progression of AMD. Interestingly, many clinical trials have revealed that dietary intakes of omega-3 fatty acids can reduce the risk of both early and late AMD, although their molecular targets in cellular signaling in AMD pathology are not understood. Recently, it has been proposed that the omega-3 fatty acid metabolites, resolvins and protectins, function as endogenous anti-inflammatory compounds. In this review, we propose that resolvins and protectins mediate their beneficial effects by preventing NF-kappaB signaling and this that may represent a new target for regulating the inflammatory responses in AMD.

Changes in DNA binding pattern of transcription factor YY1 in neuronal degeneration.

Molecular events under the neuronal degeneration are widely studied but still not defined. Here we compared the effects of both excitotoxic and apoptotic insults on the DNA binding profile of multifunctional transcription factor YY1 protein in cultured cerebellar granule neurons. We report that L-glutamate-induced excitotoxic insult but not ionophore A23187 treatment caused the disappearance of the larger DNA binding complex of YY1 and a simultaneous appearance of the smaller YY1 complex in cerebellar granule neurons. MK-801 (NMDA receptor antagonist) as well as benzamide (PARP inhibitor), MDL 28170 (calpain inhibitor) and roscovitine (cyclin-dependent kinase inhibitor) inhibited the glutamate response to the YY1 complexes. Herbimycin, PD169316, wortmannin, JAK3 inhibitor, KN-93, H-7 and LY294002 were not effective. Apoptosis induced by okadaic acid but not that induced by etoposide or trichostatin A caused a similar excitotoxic reorganization in YY1 complexes. We suggest that despite the different cell death mechanisms, glutamate and okadaic acid activate signalling cascades that affect the formation of YY1 complexes and probably YY1-mediated gene regulation.