TH9 cells are required for tissue mast cell accumulation during allergic inflammation

BACKGROUND: IL-9 is important for the growth and survival of mast cells. IL-9 is produced by T cells, natural killer T cells, mast cells, eosinophils, and innate lymphoid cells, although the cells required for mast cell accumulation during allergic inflammation remain undefined. OBJECTIVE: We sought to elucidate the role of TH9 cells in promoting mast cell accumulation in models of allergic lung inflammation. METHODS: Adoptive transfer of ovalbumin-specific TH2 and TH9 cells was used to assess the ability of each subset to mediate mast cell accumulation in tissues. Mast cell accumulation was assessed in wild-type mice and mice with PU.1-deficient T cells subjected to acute and chronic models of allergic inflammation. RESULTS: Adoptive transfer experiments demonstrated that recipients of TH9 cells had significantly higher mast cell accumulation and expression of mast cell proteases compared with control or TH2 recipients. Mast cell accumulation was dependent on IL-9, but not IL-13, a cytokine required for many aspects of allergic inflammation. In models of acute and chronic allergic inflammation, decreased IL-9 levels in mice with PU.1-deficient T cells corresponded to diminished tissue mast cell numbers and expression of mast cell proteases. Mice with PU.1-deficient T cells have defects in IL-9 production from CD4(+) T cells, but not natural killer T cells or innate lymphoid cells, suggesting a TH cell-dependent phenotype. Rag1(-/-) mice subjected to a chronic model of allergic inflammation displayed reduced mast cell infiltration comparable with accumulation in mice with PU.1-deficient T cells, emphasizing the importance of IL-9 produced by T cells in mast cell recruitment. CONCLUSION: TH9 cells are a major source of IL-9 in models of allergic inflammation and play an important role in mast cell accumulation and activation

Role of Serum Lactate Dehydrogenase (LDH) and endometrial thickness in the detection of endometrial carcinoma in perimenopausal bleeding

Introduction: Postmenopausal bleeding (PMB) refers to any uterine bleeding in a menopausal patient (other than the expected cyclic bleeding that occurs in patients taking combined (ie, estrogen-progestin), cyclic, postmenopausal hormone therapy. Perimenopausal bleeding (PMB) occurs in approximately 3% of women and it is the usual presenting symptom of endometrial carcinoma in approximately 93% of cases. Objective: To assess the role of serum lactate dehydrogenase (LDH) and endometrial thickness in the detection of endometrial carcinoma in perimenopausal bleeding. Methods: This prospective cross-sectional study was carried out at Obstetrics and Gynecology Department, Rajshahi Medical College Hospital, Rajshahi, Bangladesh from January 2020 to June 2022. This study included 102 women with perimenopausal bleeding admitted to Obstetrics & Gynecology Department at RMCH. All cases were subjected to full history, full clinical examination, transvaginal sonography, serum LDH, and Diagnostic endometrial biopsy was taken for histopathological examination.  Result: In this study, endometrial thickness at 11.5mm cut-off value showed 80.6% sensitivity, 53.7% specificity, PPV 53.7%, NPV 80.5%and diagnostic accuracy 64.4%. It was found that TVS evaluation of endometrial thickness is not sensitive enough to detect cancer of the endometrium and therefore, could not replace the histological evaluation of the endometrial tissue in women with postmenopausal bleeding. LDH level cutoff value of 430 U/L could differentiate malignant from benign lesions with a sensitivity of 80.6%, specificity of 57.4%, PPV of 55.7% and NPV of 81.5% with a diagnostic accuracy of 66.7%. Thus, total serum LDH can be used as a good negative test using the cut-off level (430 U/L). A combination of evaluation of endometrial thickness by TVS (with a specificity of 53.7% and accuracy of 64.4%) and serum LDH (with a specificity of 57.4% and accuracy of 66.7%) increase the specificity to 72.2%. also, increase the accuracy to 67.7%. Conclusion: Measurement of serum LDH is considered another simple method to be combined with TVS if endometrial cancer is suspected. However, further studies are needed using LDH isoenzymes profile and TVS endometrial morphology

Limonene extraction from the zest of Citrus sinensis, Citrus limon, Vitis vinifera and evaluation of its antimicrobial activity

Citrus rinds contain essential oils. One of the major constituents of the essential oils in the zest of different fruits like Citrus sinensis, C. limon, and Vitis vinifera is limonene. In this research, limonene was extracted by hydro-distillation method using Clevenger set up and its antimicrobial activity against certain bacterial and fungal strains was determined by using Kirby Bauer’s disc diffusion method. The primary antimicrobial screening of limonene without dilution exhibited a zone of inhibition (mm) comparable to Ampicillin (20mg/ml) and Amphotericin B (20mg/ml). The effect of pure limonene against all strains used was high as compared to the isolated samples. The MIC values also showed an expected decrease in the zone of inhibition from 1:2 to 1:8 dilutions. Based on this study, the cost-effective isolation of limonene and other essential oils is quite possible

Polyphenol-rich pomegranate fruit extract (POMx) suppresses PMACI-induced expression of pro-inflammatory cytokines by inhibiting the activation of MAP Kinases and NF-κB in human KU812 cells

<p>Abstract</p> <p>Background</p> <p>Mast cells and basophils are multifunctional effector cells and contain plentiful secretary granules in their cytoplasm. These cell types are involved in several inflammatory and immune events and are known to produce an array of mediators including a broad spectrum of cytokines. Pomegranate fruit is rich in anthocyanins and hydrolysable tannins; a group of polyphenolic compounds shown to be potent antioxidant with anti-inflammatory activity. However, no studies have been undertaken to investigate whether a polyphenol-rich pomegranate fruit extract (POMx) inhibits the inflammatory activity of activated human mast cells and basophils. The aim of this study was to examine whether POMx modulates inflammatory reactions using human basophilic cell line KU812.</p> <p>Methods</p> <p>KU812 cells were stimulated with phorbol-12-myristate 13-acetate plus calcium inophore A23187 (PMACI). The inhibitory effect of POMx on pro-inflammatory cytokine gene expression and production by stimulated KU812 cells was measured by quantitative RT-PCR, and cytokine-specific ELISA assays, respectively. Western blotting was used to analyze the effect of POMx on the activation of mitogen-activated protein kinases (MAPKs), and the nuclear factor (NF)-κB in PMACI stimulated KU812 cells. Effect on the activity of NF-κB was determined using Luciferase reporter assay. Significance of differences from control values were analyzed by means of standard statistical methods.</p> <p>Results</p> <p>POMx significantly decreased PMACI stimulated inflammatory gene expression and production of interleukin (IL)-6 and IL-8 in KU812 cells. The inhibitory effect of POMx on the pro-inflammatory cytokines was MAPK subgroups c-jun N-terminal kinase (JNK)- and extracellular-regulated kinase (ERK) dependent. In addition, POMx suppressed the NF-κB activation induced by PMACI by inhibiting IκB-degradation in human basophil cells. POMx also suppressed the powerful induction of NF-κB promoter-mediated luciferase activity in transiently transfected KU812 cells.</p> <p>Conclusion</p> <p>These novel pharmacological actions of POMx provide new suggestion that POMx or POMx-derived compounds may be of therapeutic use for the treatment of inflammatory diseases by suppressing mast cells/basophils activation.</p

The role of SARS-CoV-2 immunosuppression and the therapy used to manage COVID-19 disease in the emergence of opportunistic fungal infections: A review

Since December 2019 SARS-CoV-2 infections have affected millions of people worldwide. Along with the increasing number of COVID-19 patients, the number of cases of opportunistic fungal infections among the COVID-19 patients is also increasing. There have been reports of the cases of aspergillosis and candidiasis in the COVID-19 patients. The COVID-19 patients have also been affected by rare fungal infections such as histoplasmosis, pneumocystosis, mucormycosis and cryptococcosis. These fungal infections are prolonging the stay of COVID-19 patients in hospital. In this study several published case reports, case series, prospective and retrospective studies were investigated to explore and report the updated information regarding candidiasis, crytptococcosis, aspergillosis, mucormycosis, histoplasmosis, and pneumocystosis infections in COVID-19 patients. In this review, the risk factors of these co-infections in COVID-19 patients have been reported. There have been reports that the comorbidities and the treatment with corticoids, monoclonal antibodies, use of mechanical ventilation, and use of antibiotics during COVID-19 management are associated with the emergence of fungal infections in the COVID-19 patients. Hence, this review analyses the role of these therapies and comorbidities in the emergence of these fungal infections among COVID-19 patients. This review will help to comprehend if these fungal infections are the result of the co-morbidities, and treatment protocol followed to manage COVID-19 patients or directly due to the SARS-CoV-2 infection. The analysis of all these factors will help to understand their role in fungal infections among COVID-19 patients which can be valuable to the scientific community

Endonuclease and redox activities of human apurinic/apyrimidinic endonuclease 1 have distinctive and essential functions in IgA class switch recombination

The base excision repair (BER) pathway is an important DNA repair pathway and is essential for immune responses. In fact, it regulates both the antigen-stimulated somatic hypermutation (SHM) process and plays a central function in the process of class switch recombination (CSR). For both processes, a central role for apurinic/apyrimidinic endonuclease 1 (APE1) has been demonstrated. APE1 acts also as a master regulator of gene expression through its redox activity. APE1's redox activity stimulates the DNA-binding activity of several transcription factors, including NF-\u3baB and a few others involved in inflammation and in immune responses. Therefore, it is possible that APE1 has a role in regulating the CSR through its function as a redox coactivator. The present study was undertaken to address this question. Using the CSR-competent mouse B-cell line CH12F3 and a combination of specific inhibitors of APE1's redox (APX3330) and repair (compound 3) activities, APE1-deficient or -reconstituted cell lines expressing redox-deficient or endonuclease-deficient proteins, and APX3330-treated mice, we determined the contributions of both endonuclease and redox functions of APE1 in CSR. We found that APE1's endonuclease activity is essential for IgA-class switch recombination. We provide evidence that the redox function of APE1 appears to play a role in regulating CSR through the interleukin-6 signaling pathway and in proper IgA expression. Our results shed light on APE1's redox function in the control of cancer growth through modulation of the IgA CSR process

Increased Th2 activity and diminished skin barrier function cooperate in allergic skin inflammation

Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt−/−) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt−/− mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD

Haplogroup heterogeneity of LHON patients carrying the m.14484T&#62;C mutation in India

Purpose: To investigate the clinical and mitochondrial DNA (mtDNA) haplogroup background of Indian Leber Hereditary Optic Neuropathy (LHON) patients carrying the m.14484T&#62;C mutation. Methods: Detailed clinical investigation and complete mtDNA sequencing analysis was carried out for eight Indian LHON families with the m.14484T&#62;C mutation. Haplogroup was constructed based on the evolutionarily important mtDNA variants. Results: In the present study, we characterized eight unrelated probands selected from 187 LHON cases. The overall penetrance of the disease was estimated to be 19.75% (16/81) in eight pedigrees with the m.14484T&#62;C mutation and showed substantially higher sex bias (male:female = 13:3). The mtDNA haplogrouping revealed that they belong to diverse haplogroups; i.e. F1c1, M31a, U2a, M*, I1, M6, M3a1 and R30a. Interestingly, we did not find an association of the m.14484T&#62;C mutation with any specific haplogroup within the Indian population. We also did not find any secondary mutation(s) in these pedigrees, which might affect the clinical expression of LHON. Conclusions: Contrary to earlier reports showing preferential association of the m.14484T&#62;C mutation with western Eurasian haplogroup J and increased clinical penetrance when present in J1 subhaplogroup background, the present study shows that m.14484T&#62;C arose independently in a different mtDNA haplogroup and ethnic background in India, which may influence the clinical expression of the disease