Epigenetic and transcriptional regulation of cytokine production by Plasmodium falciparum-exposed monocytes.

Plasmodium falciparum infection causes the most severe form of malaria, where excessive production of proinflammatory cytokines can drive the pathogenesis of the disease. Monocytes play key roles in host defense against malaria through cytokine production and phagocytosis; however, they are also implicated in pathogenesis through excessive proinflammatory cytokine production. Understanding the underlying molecular mechanisms that contribute to inflammatory cytokine production in P. falciparum-exposed monocytes is key towards developing better treatments. Here, we provide molecular evidence that histone 3 lysine 4 (H3K4) methylation is key for inflammatory cytokine production in P. falciparum-exposed monocytes. In an established in vitro system that mimics blood stage infection, elevated proinflammatory TNF and IL-6 cytokine production is correlated with increased mono- and tri-methylated H3K4 levels. Significantly, we demonstrate through utilizing a pharmacological inhibitor of H3K4 methylation that TNF and IL-6 expression can be suppressed in P. falciparum-exposed monocytes. This elucidated epigenetic regulatory mechanism, controlling inflammatory cytokine production, potentially provides new therapeutic options for future malaria treatment.

Signaling pathways underlying TGF-ß mediated suppression of IL-12A gene expression in monocytes.

Transforming growth factor-ß (TGF-ß) is a pleiotropic cytokine essential for multiple biological processes, including the regulation of inflammatory and immune responses. One of the important functions of TGF-ß is the suppression of the proinflammatory cytokine interleukin-12 (IL-12), which is crucial for mounting an anti-tumorigenic response. Although the regulation of the IL-12p40 subunit (encoded by the IL-12B gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by IL-12A gene) subunit regulation is relatively limited. This study investigates the molecular regulation of IL-12A by TGF-ß-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of IL-12A gene expression by TGF-ß, which involves multiple cellular signaling pathways, such as Smad2/3, NF-κB, p38 and JNK1/2. Pharmacological inhibition of NF-κB signaling decreased IL-12A expression, while blocking the Smad2/3 signaling pathway by overexpression of Smad7 and inhibiting JNK1/2 signaling with a pharmacological inhibitor, SP600125, increased its expression. The elucidated signaling pathways that regulate IL-12A gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment.

Targeting transcription factors for therapeutic benefit in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a destructive inflammatory autoimmune disease that causes pain and disability. Many of the currently available drugs for treating RA patients are aimed at halting the progression of the disease and alleviating inflammation. Further, some of these treatment options have drawbacks, including disease recurrence and adverse effects due to long-term use. These inefficiencies have created a need for a different approach to treating RA. Recently, the focus has shifted to direct targeting of transcription factors (TFs), as they play a vital role in the pathogenesis of RA, activating key cytokines, chemokines, adhesion molecules, and enzymes. In light of this, synthetic drugs and natural compounds are being explored to target key TFs or their signaling pathways in RA. This review discusses the role of four key TFs in inflammation, namely NF-κB, STATs, AP-1 and IRFs, and their potential for being targeted to treat RA.

A study on canine dirofilariasis in selected areas of Sri Lanka.

OBJECTIVES: Canine dirofilariasis is a mosquito borne zoonotic filarial parasitic disease caused by Dirofilaria species. In Sri Lanka, human dirofilariasis is endemic and well documented. Even though canine dirofilariasis is an established infection among dog populations in Sri Lanka, the prevalence and risk factors were not documented in Kanthale divisional secretariat, Eastern Province of Sri Lanka. Therefore, the main objective of this study is to determine the prevalence of dirofilariasis and to identify the exposure-related risk factors in dogs using an interviewer administered questionnaire in Kanthale divisional secretariat. RESULTS: Out of 162 blood samples collected from dogs, 47.5% (n = 77/162) were positive for the presence of microfilariae by direct smear. Of 162 samples 58.6% (n = 95/162) were molecularly identified as D. repens. Species-specific primer pair DIR3/DIR4 that amplified 5S rRNA was used. The current study observed a significant association between mongrels and canine dirofilariasis (p = 0.049), where 61.3% (n = 95) out of 155 mongrels showed PCR positivity. This study showed no significant association between the occurrence of dirofilariasis and the age, sex, rearing method, presence or absence of skin rash, and stray or domestic dogs. Dirofilaria immitis was not identified in direct smear test and PCR.

Human Dirofilariasis Caused by Dirofilaria repens in Sri Lanka from 1962 to 2020.

PURPOSE: Sri Lanka has reported the highest prevalence of human dirofilariasis cases in Asia. Thus far, Dirofilaria repens is the only reported Dirofilaria species that affect humans, dogs, and cats in Sri Lanka. Therefore, this systematic review was carried out to analyse the studies performed on dirofilariasis in Sri Lanka. METHODS: Peer-reviewed articles were searched on dirofilariasis published on Google Scholar, PubMed, Cochrane, and ResearchGate from January to March 2021. Articles were selected using inclusion and exclusion criteria. Three reviewers assessed the studies and extracted data independently to minimize the risk of bias. Extracted data were compiled, and then the results were compared and discussed in this systematic review. RESULTS: Twenty-five studies performed in Sri Lanka were analysed, and high prevalence areas, frequent clinical presentations, diagnostic methods, reservoir hosts, and treatment were identified. More than 173 cases of human dirofilariasis caused by D. repens were reported from 1962 to 2020 in 20 districts among 25 investigated. The highest number of cases (n = 80) was recorded during 2010-2012 period. Canine and feline dirofilariasis are reported countrywide, and a large number of potential mosquito breeding sites could be seen in Sri Lanka. CONCLUSIONS: The number of reported cases of human dirofilariasis has been varied from 1962 to 2020. The highest number of cases has reported in 2010-2012, and then the number of cases has dropped. This may be due to underreporting. Thus, awareness of Dirofilaria repens infection in humans, control measures in endemic areas and further research on dirofilariasis in other districts of Sri Lanka are crucial.

Comparison of diagnostic methods and analysis of socio-demographic factors associated with Trichomonas vaginalis infection in Sri Lanka.

BACKGROUND: Trichomonas vaginalis infection is underreported due to nonspecific clinical presentation and the nonavailability of sensitive laboratory diagnostic tests at the clinical setup. Hence, this study was designed to compare the sensitivity and specificity of microscopy and culture methods with polymerase chain reaction (PCR). The socio-demographic factors associated with the infection were explored. METHODS: The study was carried out at the National Sexually Transmitted Diseases and Acquired Immuno Deficiency Syndrome Control Programme in Colombo and Sexually Transmitted Diseases and Acquired Immuno Deficiency Syndrome Control Programme in Kandy. Samples were collected from a total of 385 patients including, 272 females (70.7%) and 113 males (29.3%), and tested using microscopy (wet mount and Giemsa staining), culture, and PCR. Genus-specific primer set (TFR1/TFR2) that amplifies 5.8S rRNA and species-specific primer sets (TV16Sf-2/TV16Sr-2 and TVK3/7) that amplifies 18S rRNA and repetitive DNA, respectively, were used. Patient's socio-demographic and sexual behaviour data were obtained using a standard interviewer-administered questionnaire. Data were analyzed with R statistical software Version 3.6.3. RESULTS: The overall prevalence of trichomoniasis was 4.4% (17/385). Of these, six (1.6%) were positive for microscopic examination, 7 (1.8%) were positive for culture, and 13 (3.4%) for TVK3/7, 15 (3.9%) for TV16Sf/r, and TFR1/2 17 (4.4%) were positive for PCR. Sensitivities of PCR using TFR1/2, TV16Sf/r, and TVK3/7 primer sets were 100%, 88.20%, and 76.50%, respectively, against the expanded gold standard. Trichomoniasis was associated with age above 36 (p = 0.033), not using condoms in last three months (p = 0.016), multiple sex partners (p = 0.001), reason for attendance (p = 0.027), symptomatic nature (p = 0.015), and the presence of other sexually transmitted diseases (p = 0.001). CONCLUSIONS: The study highlighted that age over 36 years, multiple sex partners, not using condoms, reason for attendance, symptomatic nature, and having other sexually transmitted diseases can increase the risk of acquiring trichomoniasis. Furthermore, this study confirmed PCR as highly sensitive and specific diagnostic test for the diagnosis of trichomoniasis in comparison to microscopy and culture methods.