This study investigates the endothelial protective activity of flavokawain A (FKA) against

oxidative stress induced by ochratoxin A (OTA), which acts as a mycotoxin, and its primary mecha-
nisms in in vitro models. Reactive oxygen species, in general, regulate oxidative stress that signifi-
cantly contributes to the pathophysiology of endothelial dysfunctions. OTA exerts toxicity through

inflammation and the accumulation of ROS. This research is aimed at exploring the defensive function
of FKA against the endothelial injury triggered by OTA through the Nrf2 pathway regulated by
PI3K/AKT. OTA exposure significantly increased the nuclear translocation of NFκB, whereas we
found a reduction in inflammation via NFκB inhibition with FKA treatment. FKA increased the PI3K
and AKT phosphorylation, which may lead to the stimulation of antioxidative and antiapoptotic
signaling in HUVECs. It also upregulated the phosphorylation of Nrf2 and a concomitant expression
of antioxidant genes, such as HO-1, NQO-1, and γGCLC, depending on the dose under the oxidative
stress triggered by OTA. Knockdown of Nrf2 through small interfering RNA (siRNA) impedes the
protective role of FKA against the endothelial toxicity induced by OTA. In addition, FKA enhanced

Bcl2 activation while suppressing apoptosis marker proteins. Therefore, FKA is regarded as a po-
tential agent against endothelial oxidative stress caused by the deterioration of the endothelium.

The research findings showed that FKA plays a key role in activating the p-PI3K/p-AKT and Nrf2
signaling pathways, while suppressing caspase-dependent apoptosis.

The short non-coding microRNAs (miRNAs) have emerged as reliable modulators of various pathological conditions including autoimmune diseases in mammals. The current study, aims to identify new potential differential expressed miRNAs and their downstream mRNA targets of the autoimmune disease, Multiple sclerosis (MS). The study identifies a new set of miRNA(s) that are probably implicated in MS using computational tools. The study further carried-out different in vivo and in vitro experiments to check these identified miRNAs could be role in as therapeutic and prognostic applications. Preliminary insilico screening revealed that miR-659-3p, miR659-5p, miR-684, miR-3607-3p, miR-3607-5p, miR-3682-3p, miR-3682-5p miR-4647, miR-7188-3p, miR-7188- 5p and miR-7235 are specifically elevated in the secondary lymphoid cells of EAE mice. In addition, expression of the downstream target mRNA of these miRNAs such as FXBO33, SGMS-1, ZDHHC-9, GABRA-3, NRXN-2 were reciprocal to miRNA expression in lymphoid cells. These confirmed by applying the mimic and silencing miRNA models, suggesting new inflammatory target genes of these promising miRNA markers. The in vivo adoptive transfer model revealed that the suppression of miRNA-7188-5p and miR-7235 changed the pattern of astrocytes and CNS pathophysiology. The current study opens a new miRNA and their mRNA targets in MS disease. The absence of miRNA-7188-5p and miR-7235 enhanced the disease alleviation, confirms the regulatory effect of these targets. These optimized results highlights new set of miRNA’s with therapeutic potential in experimental MS. Further studies are required to confirm these miRNA as therapeutic biomarker.

Rheumatoid arthritis (RA) is a chronic autoimmune, multifactorial, inflammatory disorder characterized by hyperplasia and infiltration of inflammatory cells at the synovial lining leading to destruction of cartilage and bone tissues. Pinocembrin (PCB) is a natural flavonoid extracted as a pure molecule from honey, propolis, and some plants. In this study, we evaluated the antiarthritic effect of PCB in adjuvant induced arthritis (AIA) mice. Treating the AIA mouse model with PCB reduced the arthritis symptoms/score, including edema size, extent of hind paw redness, abnormal movement, and holding inability. At the pathological level, PCB significantly decreased the joint erosion and percentages of infiltrated inflammatory cells. Biochemically, PCB interacts with the transcription factor, SRY-related HMG-box 4 (Sox4), and then modulates its dysregulated expression and the expression of Sox4/Stat3 signaling molecules in AIA mice. These molecules include tumor necrosis factor-α, nuclear transcription factor kappaB, and cyclooxygenase-2, besides the microRNAs; miR-132, miR-202-5p, and miR-7235, which are dysregulated in adjuvant-induced arthritis model relative to the control mice. The possible PCB interaction with Sox4 transcriptional protein was confirmed through molecular docking where three hydrogen bonds were formed at ARG and LYS residues at a stable binding energy of -4.72. Taken together, our data demonstrate that PCB could serve as a therapeutic drug in treatment of RA.

Atherosclerosis is a persistent inflammatory disorder specified by the dysfunction of the arteries, the world's leading cause of cardiovascular diseases. We sought to determine the effectiveness of KRL in B[a]P-induced oxidative stress and programmed cell death in endothelial cells. Western blotting, real-time PCR, DCFH2-DA, and TUNEL staining were performed to detect pPI3K, pAKT, Nrf2, HO-1, NQO-1, Bcl2, Bax, and caspase-3 on the HUVECs. Through the pretreatment of KRL, a drastic enhancement was observed in the cell viability of HUVECs, whereas DNA damage and generation of reactive oxygen species induced by B[a]P was suppressed. KRL's potential use as an antioxidant was observed to have a direct correlation with an antioxidant gene's augmented expression and the nuclear translocation activation of Nrf2, even during the event when B[a]P was found to be absent. In addition, this study proved that the signaling cascades of PI3K/AKT mediated Nrf2 translocation. Activation of suppressed nuclear Nrf2 and reduced antioxidant genes across cells interacting with an LY294002 confirmed this phenomenon. In addition, knockdown of Nrf2 by Nrf2-siRNA transfection abolished the protective effects of KRL on HUVECs cells against oxidative damage. Finally, the expression of apoptotic proteins also supported the hypothesis that KRL may inhibit endothelial dysfunction. This study showed that KRL potentially prevents B[a]P-induced redox imbalance in the vascular endothelium by inducing the Nrf2 signaling via the PI3K/AKT pathway.

This paper fosters both uniform spaces and way-below relations with an innovative analysis of their mutual relationships. A new concept of uniform spaces based on a way below relation (LB-fuzzifying uniform space, or LBFU space, for short) will be introduced and investigated. With this aim, first, some fundamental concepts in L-fuzzifying topological spaces will be studied. Then, we shall explore some L-fuzzifying topological spaces induced by an LBFU space. Furthermore, new concepts of the interior, closure, bases, and subbases relative to an LBFU topology will be established. Finally, the continuity of functions between LBFU spaces will be introduced and investigated.

© The Author(s) under exclusive licence to Sociedade Brasileira de Matemática Aplicada e Computacional 2022

In this paper, some lower separation axioms in interval-valued intuitionistic fuzzy topological spaces are proposed. Furthermore, we pay some attention to determining the corresponding variations of them in intuitionistic fuzzy topological spaces. The four different types of the concepts of R◦-ness, T◦-ness, and T1-ness separation axioms are developed and the corresponding R1-ness and T2-ness are defined. Also, some conclusions by establishing some results are drawn and several examples for illustration are provided.