Serum immune mediators as novel predictors of response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients with high tissue-PD-L1 expression.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes with better overall survival, but only 15-40% of the patients respond to ICIs therapy. The search for predictive biomarkers of responses is warranted for better clinical outcomes. We aim here to identify pre-treatment soluble immune molecules as surrogate biomarkers for tissue PD-L1 (TPD-L1) status and as predictors of response to anti-PD-1/PD-L1 therapy in NSCLC patients. Sera from 31 metastatic NSCLC patients, eligible for anti-PD-1/PD-L1 or combined chemoimmunotherapy, were collected prior to treatment. Analysis of soluble biomarkers with TPD-L1 status showed significant up/down regulation of the immune inhibitory checkpoint markers (sSiglec7, sSiglec9, sULBP4 and sPD-L2) in patients with higher TPD-L1 (TPD-L1 >50%) expression. Moreover, correlation analysis showed significant positive linear correlation of soluble PD-L1 (sPD-L1) with higher TPD-L1 expression. Interestingly, only responders in the TPD-L1 >50% group showed significant down regulation of the immune inhibitory markers (sPD-L2, sTIMD4, sNectin2 and CEA). When responders vs. non-responders were compared, significant down regulation of other immune inhibitory biomarkers (sCD80, sTIMD4 and CEA) was recorded only in responding patients. In this, the optimal cut-off values of CD80 <91.7 pg/ml and CEA <1614 pg/ml were found to be significantly associated with better progression free survival (PFS). Indeed, multivariate analysis identified the cutoff-value of CEA <1614 pg/ml as an independent predictor of response in our patients. We identified here novel immune inhibitory/stimulatory soluble mediators as potential surrogate/predictive biomarkers for TPD-L1 status, treatment response and PFS in NSCLC patients treated with anti-PD-1/PD-L1 therapy.

Autophagy/ Apoptosis Induced by Geraniol through HIF-1α/BNIP3/Beclin-1 Signaling Pathway in A549 CoCl2 Treated Cells.

Purpose: During cancer growth, hypoxia occurs along with autophagy as an adaptive responseto overcome cellular stress. Geraniol (GE) is a natural isoprenoid known for its wide anticanceractivity and autophagy induction in the cancer cell. To investigate the antihypoxic potential ofGE with the incidence of autophagy and apoptotic cell death in A549 CoCl2 treated cells. Methods: A549 cells were incubated for 24 hours with GE and CoCl2 either alone or incombination. We examined the cytotoxicity and cell viability of GE either alone or incombination therapy using MTT and trypan blue assay.GE modulating effect was determined onlipid peroxidation, antioxidant capacity markers, gene expression levels of hypoxia induciblefactor-1 (HIF-1), NF-κB, vascular endothelial growth factor (VEGF), autophagy factors in differentgroups, besides apoptotic bodies using acridine orange/ethidium bromide (AO/EB). Results: GE and CoCl2 combination therapy downregulated the expression of HIF-1α thatsuppressed A549 cell growth through downregulation of BNIP3 and beclin-1 gene expression.This resulted in autophagy and apoptotic cell death, in addition to the downregulation of NF-kBand VEGF expression. Also, GE treatment significantly reduced the oxidative stress markers andrestored the antioxidant capacity. Conclusion: GE possesses an antihypoxic effect on A549 CoCl2 treated cells and induces celldeath via autophagy along with apoptosis through HIF-1α/BNIP3/beclin-1 signaling pathway.

Geraniol activates Nrf-2/HO-1 signaling pathway mediating protection against oxidative stress-induced apoptosis in hepatic ischemia-reperfusion injury.

Geraniol (GOH) is a natural essential oil that possesses antioxidant, anti-inflammatory, and antiapoptotic properties by various signaling pathways. Liver ischemia-reperfusion injury (IRI) is a serious event that triggers liver dysfunction or even failure. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional factor, maintains cellular defense mechanism through antioxidant and anti-inflammatory properties. To detect GOH effect against liver IRI through the activation of the Nrf2/HO-1 antioxidant pathway, five groups of rats were randomized to normal, sham, IR, GOH, and GOH/IR. Blood samples and liver tissues were collected to measure various biochemical parameters related to liver function, and oxidative stress as well as inflammatory and apoptotic indicators besides liver tissue histopathology was evaluated by light microscopy. GOH induces activation of Nrf2 along with the upregulation of HO-1 expression. Also, the antioxidant activity of GOH was shown by the elevation of total antioxidant capacity and GSH levels, together with normalizing malondialdehyde. Regarding the anti-inflammatory effect of GOH, it suppresses the levels of TNF-α, iNOS, and COX-2. Additionally, the antiapoptotic effect of GOH, Bax, and caspase-3, 9 were reduced in liver tissue. GOH is a promising hepatoprotective agent in liver IRI through the activation of Nrf2/HO-1 antioxidant pathway.

Physical & mental activities enhance the neuroprotective effect of vinpocetine & coenzyme Q10 combination against Alzheimer & bone remodeling in rats.

BACKGROUND: Alzheimer's disease is a neurodegenerative disorder characterized by a progressive decline of cognitive abilities as well as bone loss. Physical and mental activities maintain cognitive functions as well as increase bone mass by inhibiting bone resorption. VIN and CoQ10 are neuroprotective drugs that possess anti-inflammatory and antioxidant properties. AIMS: To study the effect of PH&M on enhancing the neuroprotective role of VIN and CoQ10 combination during induction of AD model in rats besides their role against bone mass loss associated with AD model. MAIN METHODS: Six groups of rats were received saline, AlCl3, and PH&M daily either alone or with a combination of VIN and CoQ10 for 4 weeks. Various biochemical analyses were performed to evaluate the extent of brain damage such as ACHE, ß-secretase, chitinase, Aß, tau protein, and monoamines besides the inflammatory and antioxidant parameters. Serum levels of minerals as well as 25-OHD, PTH, RANKL, and OPG levels were measured to detect the extent of bone impairment. Also, histopathological changes were evaluated in different brain regions and hind paw. KEY FINDINGS: VIN and CoQ10 combination together with PH&M significantly attenuated the neurodegeneration induced by AlCl3 administration through the improvement of AD markers in brain tissue as well as oxidant and inflammatory markers. Bone resorption markers, serum minerals, and PTH levels were also normalized too. SIGNIFICANCE: Neuroprotective drugs together with PH&M have a more protective effect against AD and bone loss rather than PH&M alone.