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The current study has been designed to assess the role of Persea americana (P. americana) pulp extract on potassium dichromate‐induced hepatotoxicity in rats. P. americana pulp extract administration improved the hepatic vascular congestion, blood extravasation, inflammatory cellular infiltration, Kupffer cell hyperplasia, and nuclear changes. It also significantly ameliorated hepatic interstitial and peri‐portal fibrosis and caused retrieval of the PAS‐positive reaction in the liver parenchyma and around the central vein with restoration of the glycogen granules. P. americana also significantly attenuated the immunohistochemical expression of NF‐kβ p65 and its downstream inflammatory cytokines IL6 and TNFα in the liver parenchyma. The antioxidant effect of P. americana was evidenced by significant modulation of the three major components of the thioredoxin (Trx) antioxidant system, the Trx, the thioredoxin reductase (TrxR), and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase along with significant increase in the level of superoxide dismutase and glutathione, and decrease in the lipid peroxidation product malondialdehyde. P. americana pulp extract also caused significant elevation of hepatic protein phosphatase 5 with subsequent down‐regulation of Apoptosis signal‐regulating kinase1 (ASK1) and its downstream signaling targets MAPK kinase 4 (MKK4), p38 mitogen‐activated protein kinases (p38‐MAPKs), the c‐JUN N‐terminal kinase (JNK), and the extracellular signal‐regulated kinase 1/2 (ERK 1/2). Also, In conclusion, P. americana pulp extract has anti‐oxidative and anti‐inflammatory effects against potassium dichromate‐induced hepatotoxicity.

Introduction: TLRs are fundamental elements in the orchestration of innate immune system. These receptors seem to be responsible for the inflammation and fibrosis in chronic dacryocystitis. The aim of the present study was to investigate the role of toll-Like receptors (TLR2 and TLR4) signaling pathway and its downstream effector chemokine genes in the pathogenesis of chronic dacryocystitis. Method: This study was conducted on 20 patients diagnosed with chronic dacryocystitis and underwent external dacryocystorhinostomy. Estimation of gene expression of TLR2, TLR4, CCL2, CCL4, CXCL3, CXCR4 and c-FOS genes in the lacrimal sac tissues was performed together with assessment of the inflammatory markers TNFα, IL-1β, IFN-γ and IL-22. Histopathological examination of the lacrimal sac walls using hematoxylin and eosin (H&E) stain, in addition to immunohistochemical staining of the CD68 and CD163 macrophage markers were also performed. Results: Our results showed that TLR2, TLR4 and c-FOS gene expressions were significantly increased in chronic dacryocystitis group with subsequent increase in their downstream effector chemokine genes CCL2, CCL4 and CXCL3. This up-regulation of genes was accompanied by macrophage shift of polarization toward the M1 pro-inflammatory phenotype (increased CD68 and decreased CD163 expression), leading to increased levels of the pro-inflammatory cytokines (TNF-α, IL-1β and IFN-γ) and decreased anti-inflammatory marker IL-22 with chronic dacryocystitis. Conclusion: It is essential to fine tune TLR activation through emerging therapeutic approaches. Targeting of TLR signaling at the level of receptors or downstream adaptor molecules represents a new challenge for treatment of chronic dacryocystitis.

Background: Circular RNA-HIPK3 (CircHIPK3) has been shown to be aberrantly expressed in a variety of diseases, contributing to disease initiation and progression. The aim of the present study is to investigate the role of the circHIPK3 RNA/microRNA-124a interaction in the pathogenesis of rheumatoid arthritis (RA). Methods: This study included 79 RA patients and 30 control individuals. The patients involved were classified according to the disease activity score (DAS28) into mild (24 patients), moderate (24 patients), and severe (31 patients). Serum samples were collected to estimate the relative gene expression of circHIPK3 RNA and its target gene microRNA-124a by quantitative real time-PCR. Moreover, ELISA was used to detect the serum levels of monocyte chemoattractant protein-1 (MCP-1). Routine laboratory estimation of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor (RF) was also done. Results: In all grades of RA groups, there was a significantly substantial elevation of circHIPK3 RNA gene expression, with subsequent downregulation of miRNA-124a when compared to the control group. CircHIPK3 and microRNA-124a expression have been established to be inversely linked. Also, estimation of serum levels of MCP-1, ESR, CRP, and RF exhibited a significant increase in all grades of RA as compared to the control group. Conclusions: CircHIPK3 and microRNA-124a might be regarded as key players in the pathogenesis of RA. The cross-talk between them appears to be responsible for inducing joint inflammation by increasing MCP-1 production. Targeting circHIPK3 and microRNA-124a, and their downstream adaptor molecules, poses a new challenge for RA therapy.

Background: Parkinson's disease (PD) is the most common age-related motor neurodegenerative disease. Current therapeutic modalities for PD are directed at controlling the motor symptoms to slow disease progression, while no exact therapy exists to repair the immient neuronal damage. Despite the involvement of exosomes in the pathogenesis of PD, they serve as a promising therapeutic tool. Exosomes can restore the homeostasis of oxidative stress, neuro-inflammation, and cell apoptosis. Although H2S is involved in the pathogenesis of PD, it has antioxidant, anti-inflammatory and anti-apoptotic neuroprotective effects, giving hope for the role of this gaseous molecule in PD therapy. Objective: We aimed to evaluate the therapeutic effect of exosomes and/ or H2S-donor (NaHS) on PD, through modulation of PI3K/AKT signaling pathway, and to compare their combined effect with the standard treatment, L-DOPA. Methods: This study was conducted on forty-eight female white albino rats divided equally into 6 groups: control group, Parkinson group induced by 6-hydroxydopamine (6-OHDA), 3 Parkinson groups treated with either L-DOPA, exosomes, or H2S-donor (NaHS), and Parkinson group treated with both exosomes and NaHS. The following parameters were assessed in the rat brain tissues: gene expression of Nrf2, Keap1, α-synuclein, and miRNA-141, protein levels of PI3K, AKT, Dopamine, TNF-α and caspase-3. GSH and MDA levels were also measured. In addition, behavioral function tests and histo-pathological examination of rat brain tissues were also performed. Results: In the Parkinson group, there was a significant deficit in behavioral functions, along with down-regulation of the Nrf2 gene and its downstream antioxidant GSH, and increased levels of the lipid peroxidation biomarker MDA. Also, there was increased neuro-inflammation as evidenced by increased levels of TNF-α with decreased levels of the neurotransmitter Dopamine. Moreover, there was increased gene expression of Keap-1, miRNA-141, and αsynuclein associated with decreased levels of AKT, PI3K and increased caspase-3 levels. On the other hand, all treated groups, especially the combined exosomes and H2S donor-treated group, significantly reversed the deteriorating impacts of 6-OHDA on rat brains, as evidenced by the improvement of the behavioral dysfunction and the histopathological picture, which agrees with the biochemical and molecular findings of PI3K/AKT signaling pathway. Conclusion: These data suggest that combined exosomes and H2S-donor could be considered as a potential and effective line for treating PD.