Bitis arietans Snake Venom and Kn-Ba, a Snake Venom Serine Protease, Induce the Production of Inflammatory Mediators in THP-1 Macrophages

Bitis arietans is a snake of medical importance found throughout sub-Saharan Africa and in savannas and pastures of Morocco and western Arabia. The effects of its venom are characterized by local and systemic alterations, such as inflammation and cardiovascular and hemostatic disturbances, which can lead to victims’ death or permanent disability. To better characterize the inflammatory process induced by this snake’s venom, the participation of eicosanoids and PAF (platelet- activating factor) in this response were demonstrated in a previous study. In addition, edema and early increased vascular permeability followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity were accompanied by the production of the eicosanoids LTB4, LTC4, TXB2, and PGE2, and local and systemic production of IL-6 and MCP-1. In this context, the present study focused on the identification of inflammatory mediators produced by human macrophages derived from THP-1 cells in response to Bitis arietans venom (BaV), and Kn-Ba, a serine protease purified from this venom. Here, we show that Kn-Ba, and even the less intensive BaV, induced the production of the cytokine TNF and the chemokines RANTES and IL-8. Only Kn-Ba was able to induce the production of IL-6, MCP-1, and IP-10, whereas PGE2 was produced only in response to BaV. Finally, the release of IL-1β in culture supernatants suggests the activation of the inflammasomes by the venom of Bitis arietans and by Kn-Ba, which will be investigated in more detail in future studies.

Ginkgolide B Regulates CDDP Chemoresistance in Oral Cancer via the Platelet-Activating Factor Receptor Pathway

The platelet-activating factor receptor (PAFR) is a key molecule that participates in intracellular signaling pathways, including regulating the activation of kinases. It is involved in cancer progression, but the detailed mechanism of its chemosensitivity is unknown. The purpose of the current study was to elucidate the mechanism regulating cisplatin (CDDP) sensitivity through PAFR functions in oral squamous cell carcinoma (OSCC). We first analyzed the correlation between PAFR expression and CDDP sensitivity in seven OSCC-derived cell lines based upon cell viability assays. Among them, we isolated 2 CDDP-resistant cell lines (Ca9-22 and Ho-1-N-1). In addition to conducting PAFR-knockdown (siPAFR) experiments, we found that ginkgolide B (GB), a specific inhibitor of PAFR, enhanced both CDDP chemosusceptibility and apoptosis. We next evaluated the downstream signaling pathway of PAFR in siPAFR-treated cells and GB-treated cells after CDDP treatment. In both cases, we observed decreased phosphorylation of ERK and Akt and increased expression of cleaved caspase-3. These results suggest that PAFR is a therapeutic target for modulating CDDP sensitivity in OSCC cells. Thus, GB may be a novel drug that could enhance combination chemotherapy with CDDP for OSCC patients.

Platelet-activating factor acetyl hydrolase IB2 dysregulated cell proliferation in ovarian cancer

Background Ovarian cancer is the leading cause of death from gynaecologic illnessed worldwide. Platelet-activating factor acetyl hydrolase IB2 (PAF-AH IB2) is an intracellular serine esterase that hydrolyzes platelet-activating factor, a G-protein-like trimer with two catalytic subunits and one regulatory subunit. The regulatory role of PAF-AH IB2 in the oncogenesis of ovarian cancer is not well understood. Methods In this study, the TCGA dataset and clinical cancer tissue microarray were utilized to investigate abnormal overexpression of PAF-AH IB2 in ovarian cancer. To investigate the impact on the cell proliferation, migration, and tumorigenicity in vitro, PAF-AH IB2 stable knocking down (KD) ovarian cancer cells were established by ShRNA. The whole transcription profiling, tyrosine kinase profiling and standard cell functional assays were integrated to explore the biological importance and mechanism of PAF-AH IB2 modulated in ovarian cancer. Results PAF-AH IB2 was identified significantly overexpression in four subtypes of ovarian cancer. In vitro, PAF-AH IB2 KD significantly inhibited cancer cell proliferation, migration, and tumorigenicity, activated caspases and caused cell cycle arrest, and made the cells more sensitive to PAF. PAF-AH 1B2 KD cells down-regulated several key regulators of the multiple tyrosine kinases-mediated signaling pathway, suggesting a novel interaction network between the growth factor receptors pathway and PAF-AH 1B2 mediated PAF signalling. Conclusions These findings revealed a previously undiscovered role for PAF-AH IB2 as a potenial therapy target and essential signaling mediators in ovarian cancer pathogenesis, as well as new possible preventive and therapeutic strategies to inhibit this enzyme in clinical treatment for ovarian cancer.

Rupatadine to prevent local allergic reactions to sublingual allergy immunotherapy: a case series

Background Sublingual immunotherapy tablets (SLIT-T) are an effective treatment for allergic rhinitis (AR), but some patients experience local allergic reactions (LAR) in the first few weeks of treatment that can lead to treatment discontinuation. Although oral antihistamines are recommended for the treatment and pretreatment of LAR associated with SLIT-T, there are no clinical trial data to support this recommendation. Rupatadine is an H1 antihistamine that also inhibits platelet activating factor activity. The objective of this case series is to describe real-world clinical situations in which rupatadine was used to treat or mitigate SLIT-T–related LAR. Case presentations Five cases are presented by the managing allergist and off-label use of rupatadine is their expert opinion only. Patients in all 5 cases were treated with a SLIT-T (e.g. ragweed, tree, grass, or house dust mites) for the management of allergic rhinitis and experienced bothersome LAR with the first SLIT-T administration. In 3 cases, rupatadine 10 mg was administered for the immediate treatment of LAR (either in-office with the first SLIT-T dose or for subsequent LAR experienced at home) and the symptoms resolved. In 3 cases, pretreatment with other second-generation H1 antihistamines was unable to prevent LAR and the patients discontinued the SLIT-T. In these 3 cases, switching to pretreatment with rupatadine allowed the patients to restart and tolerate SLIT-T treatment with minimal or no LAR. In these patients with an established history of LAR, proactive pretreatment with rupatadine in subsequent seasons or with initiation of a different SLIT-T mitigated the previously experienced LARs. Conclusions In the cases presented, treatment with rupatadine resolved LAR associated with SLIT-T treatment and rupatadine pretreatment appeared to mitigate subsequent LAR. Rupatadine may be an option to treat or improve the tolerability of the SLIT-T, potentially improving early treatment persistence.

The dietary supplement of Ginkgo biloba: a comprehensive review of its potential interactions based on pre-clinical and clinical evidences

This review present Gingko biloba (GB) interactions, based on clinical and pre-clinical presentations. Literature was retrieved using databases; ScienceDirect, PubMed, Google scholar, Web of Science, Scopus etc. 14/45 interactions were found with clinical presentations. More interactions (80%) were reported with drugs followed by herbs (11.1%), and nutraceuticals (6.7%) with major mechanisms of interaction observed as; inhibition of Cytochrome metabolizing enzymes (44.4%) and platelet-activating factor (PAF) i.e. 15.6%. Major clinical features were; increased bleeding (eye, parietal), hematomas (subdural), and seizures as well as increased blood pressure, priapism, loss of infection/antiviral failure, and coma. Drugs with major interactions belonged to anti-platelet/anti-coagulant and NSAIDs. Synergistic effects were observed for GB vs herbs (except cannabis which showed rhabdomyolysis), foods, and nutraceuticals (except pyridoxine where neurotoxicity was seen). GB use should be monitored and the patient may seek proper advice from a healthcare professional.

PAF Physiology in Target Organ Systems—A Deep Dive to Understand the PAF Mystery in Pathogenesis of Disease

The purpose of this literature review is to gain an overview of the role of platelet-activating factor (PAF) within each of the body systems and how it contributes to normal and pathophysiological states. The review showed that there are multiple functions of PAF that are common to several body systems; however, there is little evidence to explain why PAF has this affect across multiple systems. Interestingly, there seems to be conflicting research as to whether PAF is an overall protective or pathogenic pathway. Within this research, it was found that there are different pathways depending on the specific body system, as well as between body systems. However, one universal function reported in the literature is of PAF as a pro-inflammatory molecule. Overall, this review identified five major functions of PAF: vasoconstriction, increased inflammation, vascular remodeling, increased edema, and endothelial permeability.

Investigating platelet-activating factor as a potent proinflammatory mediator in coronary atherosclerotic patients

The inflammatory reaction is one of the complications in patients with coronary atherosclerosis. This study aimed to determine the diagnostic value of platelet-activating factor (PAF) compared with high sensitivity C reactive protein (hs-CRP) in coronary atherosclerotic patients. Fifty patients with coronary atherosclerosis and 30 subjects with normal angiography were considered as the control group attending Cardiac Center-Surgical Specialty Hospital - in Erbil city / Iraq. The levels of PAF and hs-CRP were estimated quantitatively using a sandwich enzyme-linked immunosorbent assay and a particle-enhanced immune turbid metric assay, respectively. Lipid profiles and some hematological indexes were also used in this study. The levels of the inflammatory biomarkers of PAF and hs-CRP increased significantly in the patients group compared with controls (p<0.05). Although the patients group showed the highest level of low-density lipoprotein (LDL), the difference was not significant (p>0.05) compared with the healthy control. However, the incidence of risk factors such as smoking and obesity showed a significant difference (p<0.05) in the patients group. Additionally, the PAF level correlated positively and significantly with hs-CRP (p<0.05), and negatively with high-density lipoprotein (HDL) (p>0.05). Although hs-CRP was a valuable diagnostic marker for coronary atherosclerosis, the PAF level showed to be a better prognostic indicator than hs-CRP in coronary atherosclerosis patients.

Dengue Shock Syndrome: Its Similarity with Anaphylaxis and with the Homeopathic Medicine Apis mellifica (European Honeybee)

Dengue, with four viral serotypes, causes epidemics in tropical and sub-tropical regions. Allopathic antiviral therapies and a vaccine of general use are lacking. The homeopathic medicine Apis mellifica, advised in anaphylaxis from honeybee sting, is proposed to address the life-threatening dengue shock syndrome, which develops from dengue hemorrhagic fever and has features of anaphylaxis. In both dengue and anaphylaxis, immunoglobulin E activates, and released vasoactive mediators (importantly histamine, tryptase and platelet-activating factor) cause, a vascular permeability enabling shock. In dengue, another mechanism, namely antibody-dependent enhancement, due to secondary infection with a heterologous dengue serotype, is associated with release of vasoactive mediators. The homeopathic medicine Apis mellifica indicates plasma leak, shock, and the serous effusion that is noted in dengue patients, and is a suggested prophylactic and therapeutic medicine for dengue shock syndrome.

Platelet-activating Factor Acetyl Hydrolase IB2 Dysregulated Cell Proliferation in Ovarian Cancer

BackgroundOvarian cancer is the world’s largest cause of death for gynaecologic diseases. Platelet-activating factor acetyl hydrolase IB2 (PAF-AH IB2) is an intracellular serine esterase that hydrolyzes platelet-activating factor, a G-protein-like trimer with two catalytic subunits and one regulatory subunit. The deregulatory role of PAF-AHIB2 in the etiology of ovarian cancer is poorly understood. MethodsIn this study, the TCGA exploration and cancer tissue immunohistochemistry were utilized to investigate aberrant overexpression of PAF-AH IB2 in ovarian cancer. PAF-AH IB2 Stable knocking down (KD) ovarian cancer cells were established to investigate the impact on the cell proliferation, migration, and tumorigenicity in vitro. The whole transcription profiling, tyrosine kinase profiling and standard cell functional assays were integrated to explore the biological importance and mechanism of PAF-AH IB2 modulated in ovarian cancer. ResultsInteresting, PAF-AH IB2 was identified significantly overexpression in four subtypes of ovarian cancer. PAF-AHIB2 KD significantly reduced cancer cell proliferation, migration, and tumorigenicity in vitro, activated Caspases and caused cell cycle arrest, and making the cells more sensitive to PAF. Several key regulators of multiple tyrosine kinases-mediated signaling pathway were down-regulated in PAF-AH 1B2 KD cells, revealing a novel interaction network between the growth factor receptors pathway and PAF-AH 1B2 mediated PAF signalling.Conclusions These results discovered an unrevealed role for PAFAH IB2 as a novel potential therapy target and essential signaling mediators in ovarian cancer pathogenesis, as well as new potential preventive and therapeutic strategies to inhibit this enzyme in clinical treatment for ovarian cancer.