Vitamin C Facilitates Demethylation of the <i>Foxp3</i> Enhancer in a Tet-Dependent Manner

Sasidharan Nair, Varun,Song, Mi Hye,Oh, Kwon Ik American Association of Immunologists 2016 Journal of Immunology Vol. No.

<P>Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-beta (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2 2/2 iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2 2/2 mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.</P>

DNA Demethylation of the Foxp3 Enhancer Is Maintained through Modulation of Ten-Eleven-Translocation and DNA Methyltransferases

Nair, Varun Sasidharan,Song, Mi Hye,Ko, Myunggon,Oh, Kwon Ik Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.12

Stable expression of Foxp3 is ensured by demethylation of CpG motifs in the Foxp3 intronic element, the conserved non-coding sequence 2 (CNS2), which persists throughout the lifespan of regulatory T cells (Tregs). However, little is known about the mechanisms on how CNS2 demethylation is sustained. In this study, we found that Ten-Eleven-Translocation (Tet) DNA dioxygenase protects the CpG motifs of CNS2 from re-methylation by DNA methyltransferases (Dnmts) and prevents Tregs from losing Foxp3 expression under inflammatory conditions. Upon stimulation of Tregs by interleukin-6 (IL6), Dnmt1 was recruited to CNS2 and induced methylation, which was inhibited by Tet2 recruited by IL2. Tet2 prevented CNS2 re-methylation by not only the occupancy of the CNS2 locus but also by its enzymatic activity. These results show that the CNS2 methylation status is dynamically regulated by a balance between Tets and Dnmts which influences the expression of Foxp3 in Tregs.

Antifungal activity of violacein purified from a novel strain of Chromobacterium sp. NIIST (MTCC 5522)

Anju Sasidharan,Nishanth Kumar Sasidharan,Dileepkumar Bhaskaran Nair Saraswathy Amma,Radhakrishnan Kokkuvayil Vasu,Anupama Vijaya Nataraja,Krishnakumar Bhaskaran 한국미생물학회 2015 The journal of microbiology Vol.53 No.10

A novel strain of Chromobacterium sp. NIIST (MTCC 5522) producing high level of purple blue bioactive compound violacein was isolated from clay mine acidic sediment. During 24 h aerobic incubation in modified Luria Bertani medium, around 0.6 g crude violacein was produced per gram of dry weight biomass. An inexpensive method for preparing crystalline, pure violacein from crude pigment was developed (12.8 mg violacein/L) and the pure compound was characterized by different spectrometric methods. The violacein prepared was found effective against a number of plant and human pathogenic fungi and yeast species such as Cryptococcus gastricus, Trichophyton rubrum, Fusarium oxysporum, Rhizoctonia solani, Aspergillus flavus, Penicillium expansum, and Candida albicans. The best activity was recorded against Trichophyton rubrum (2 μg/ml), a human pathogen responsible for causing athlete’s foot infection. This is the first report of antifungal activity of purified violacein against pathogenic fungi and yeast.

Shaping Methane Emission Patterns: Megasphaera hexanoica-driven Rumen Microbiome Engineering

Pranav SASIDHARAN NAIR,Byoung-In SANG 한국생물공학회 2023 한국생물공학회 학술대회 Vol.2023 No.10

Validation of Combs prognostic scoring system in Indian recurrent glioma patients treated with re-radiation

Debnarayan Dutta(Debnarayan Dutta ),Meenu Jose(Meenu Jose ),Sruthi Kalavagunta(Sruthi Kalavagunta ),Ajay Sasidharan(Ajay Sasidharan ),Haridas Nair(Haridas Nair ),Annex H. Edappattu(Annex H. Edappattu 대한방사선종양학회 2024 Radiation Oncology Journal Vol.42 No.1

Purpose: Retrospective audit of recurrent glioma patients treated by different fractionation schedules and to validate the modified Combs prognostic score in Indian patient cohort. Materials and Methods: Between Jan 2009 and June 2022, 66 recurrent gliomas patients treated with standard adjuvant treatment—radiation (RT) ± temozolomide (chemotherapy)—and re-treated with RT (± chemotherapy) were categorized as per modified Combs prognostic criteria and outcomes were compared. Results: Sixty-six patients with recurrent gliomas who received reirradiation (re-RT) were audited—53% males; 61% Karnofsky performance status (KPS) ≥80 at time of re-RT; median age 41.5 years (range, 6 to 70 years); 67% <50 years; primary histology low-grade glioma in 33% ; grade III 27%, grade IV 40%; initial median dose of 60 Gy equivalent dose in 2 Gy fractions (EQD2); maximum safe resection at recurrence 41%; mean and median follow-up 78 ± 51 months and 66 months. Mean time interval between RT was 46.4 ± 39 months. Mean planning target volume (PTV) volume in conventional RT (Conv-RT), hypofractionated RT (Hypo-RT), and ultra-hypofractionated RT (UF-RT) was 226.1 ± 140.7 mL, 162.8 ± 123.3 mL, and 143.3 ± 145.8 mL. Mean dose for Conv-RT, Hypo-RT, and UF-RT was 50 Gy (range, 40 to 60), 31 Gy (range, 20 to 40), and 20 Gy (range, 10 to 30). Mean overall survival (OS) in Conv-RT, Hypo-RT, and UF-RT cohort was 18.8 months (range, 2.4 to 76.8); 6.6 months (range, 2 to 17.4), and 13.9 months (range, 3 to 131.9). Median OS as per Combs criteria were 16.6 months (Group a), 24.6 months (Group b), 4.6 months (Group c), and 3 months (Group d). Significant survival benefit was with good KPS score (KPS >80 vs. <80; 20.46 vs. 5.25 months; p < 0.001), patients receiving salvage chemotherapy (20.46 vs. 6.96 months; p = 0.001), and patients received re-RT biological equivalent dose (BED3) >80 Gy (16.62 vs. 5.48 months; p = 0.03). Median overall survival (OS) in our patient cohort and Combs cohort in Group a was 16.6 and 19.5 months; Group b was 24.6 and 11.3 months; Group c was 4.7 and 8.1 months, and Group d was 2 and 5.5 months, respectively. Six months survival in our patient cohort and Combs cohort in Groups a, b, c, d were 100%, 92%, 34%, 17% and 94%, 79%, 70%, 41%, respectively. Twelve months survival in our patient cohort and Combs cohort in Groups a, b, c, d were 88%, 74%, 22%, 0% and 88%, 47%, 22%, 7%, respectively. Conclusion: Modified Combs prognostic factors predicts OS and is applicable in Indian subcontinent patient population.

Enhancing Caproic Acid Production from Crude Glycerol: Cell Immobilization of Caproiciproducens galacitolivoransin an Up-flow Reactor

안예은,( Pranav Sasidharan Nair ),강성철,상병인 한국공업화학회 2024 한국공업화학회 연구논문 초록집 Vol.2024 No.0

Vitamin C enhances the expression of IL17 in a Jmjd2-dependent manner

( Mi Hye Song ),( Varun Sasidharan Nair ),( Kwon Ik Oh ) 생화학분자생물학회 2017 BMB Reports Vol.50 No.1

Previously, we reported that vitamin C facilitates the CpG demethylation of Foxp3 enhancer in CD4⁺Foxp3⁺ regulatory T cells (Tregs) by enhancing the activity of a DNA demethylase ten-eleven-translocation (Tet). However, it is not clear whether vitamin C affects other helper T cell lineages like T helper type 17 (Th17) cells which are related with Tregs. Here, we show that the expression of interleukin-17A (IL17) increases with the treatment of vitamin C but not with other antioxidants. Interestingly, the upregulation of IL17 was not accompanied by DNA demethylation in Il17 promoter and was independent of Tet enzymes. Rather, vitamin C reduced the trimethylation of histone H3 lysine 9 (H3K9me3) in the regulatory elements of the Il17 locus, and the effects of vitamin C were abrogated by knockdown of jumonji-C domain-containing protein 2 (jmjd2). These results suggest that vitamin C can affect the expression of IL17 by modulating the histone demethylase activity. [BMB Reports 2017; 50(1): 49-54]

Immune checkpoint inhibitors: recent progress and potential biomarkers

Pramod Darvin,Salman M. Toor,Varun Sasidharan Nair,Eyad Elkord 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-

Cancer growth and progression are associated with immune suppression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. Monoclonal antibodies that target immune checkpoints provided an immense breakthrough in cancer therapeutics. Among the immune checkpoint inhibitors, PD-1/PD-L1 and CTLA-4 inhibitors showed promising therapeutic outcomes, and some have been approved for certain cancer treatments, while others are under clinical trials. Recent reports have shown that patients with various malignancies benefit from immune checkpoint inhibitor treatment. However, mainstream initiation of immune checkpoint therapy to treat cancers is obstructed by the low response rate and immune-related adverse events in some cancer patients. This has given rise to the need for developing sets of biomarkers that predict the response to immune checkpoint blockade and immune-related adverse events. In this review, we discuss different predictive biomarkers for anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors, including immune cells, PD-L1 overexpression, neoantigens, and genetic and epigenetic signatures. Potential approaches for further developing highly reliable predictive biomarkers should facilitate patient selection for and decision-making related to immune checkpoint inhibitor-based therapies.

Sepsis-induced cardiomyopathy is associated with higher mortality rates in patients with sepsis

Balaram Krishna J Hanumanthu,Anika Sasidharan Nair,Adarsh Katamreddy,Jason S Gilbert,Jee Young You,Obiageli Lynda Offor,Ankit Kushwaha,Ankita Krishnan,Marzio Napolitano,Leonidas Palaidimos,Joaquin Mor 대한중환자의학회 2021 Acute and Critical Care Vol.36 No.3

Background Patients with sepsis are at risk for developing sepsis-induced cardiomyopathy (SIC). Previous studies offer inconsistent results regarding the association of SIC and mortality. This study sought to assess whether SIC is linked to mortality in patients with sepsis and to evaluate predictors of the development of SIC. Methods In this retrospective study, patients admitted to the medical intensive care unit with a diagnosis of sepsis in the absence of acute coronary syndrome were included. SIC was identified using transthoracic echo and was defined by a new onset decline in left ventricular ejection fraction (LVEF) ≤50%, or ≥10% decline in LVEF compared to baseline in patients with a history of heart failure with reduced ejection fraction. Multivariable logistic regression analysis was performed using the R software program. Results Of the 359 patients in the final analysis, 19 (5.3%) had SIC. Eight (42.1%) of the 19 patients in the SIC group and 60 (17.6%) of the 340 patients in the non-SIC group died during hospitalization. SIC was associated with an increased risk for all-cause in-hospital mortality (odds ratio [OR], 4.46; 95% confidence interval [CI], 1.15–18.69; P=0.03). Independent predictors for the development of SIC were albumin level (OR, 0.47; 95% CI, 0.23–0.93; P=0.03) and culture positivity (OR, 8.47; 95% CI, 2.24–55.61; P=0.006). Concomitant right ventricular hypokinesis was noted in 13 (68.4%) of the 19 SIC patients. Conclusions SIC was associated with an increased risk for all-cause in-hospital mortality. Low albumin level and culture positivity were independent predictors of SIC.