Tumor Necrosis Factor Alpha (TNF-α) is a pleiotropic pro-inflammatory cytokine. It act as central biological regulator in critical immune functions, but its dysregulation has been linked with a ...number of diseases. Inhibition of TNF-α has considerable therapeutic potential for diseases such as cancer, diabetes, and especially autoimmune diseases. Despite the fact that many small molecule inhibitors have been identified against TNF-α, no orally active drug has been reported yet which demand an urgent need of a small molecule drug against TNF-α. This study focuses on the development of ligand-based selective pharmacophore model to perform virtual screening of plant origin natural product database for the identification of potential inhibitors against TNF-α. The resultant hits, identified as actives were evaluated by molecular docking studies to get insight into their potential binding interaction with the target protein. Based on pharmacophore matching, interacting residues, docking score, more affinity towards TNF-α with diverse scaffolds five compounds were selected for in vitro activity study. Experimental validation led to the identification of three chemically diverse potential compounds with the IC
32.5 ± 4.5 µM, 6.5 ± 0.8 µM and 27.4 ± 1.7 µM, respectively.
Coronavirus is an enclosed positive-sense RNA virus with club-like spikes protruding from its surface that causes acute respiratory infections in humans. Because it is considered a member of the ...complex pathogen group, it has been found to infect different host species and cause a variety of diseases. So far, it has been discovered that it may affect the immune, infection, and inflammatory systems, leading to the hypothesis that the immune and inflammatory systems (signaling pathways and components) fail to control infection, opening the door to look for potential targets primarily in these systems. The study's main purpose is to identify highly overexpressed genes and their functional implications as a result of COVID-19 infection, as well as to investigate probable infections, inflammation, and immune systems to better understand the impact of coronavirus infection. We explored the genes and pathways mostly linked with infection, inflammation, and the immune systems using the datasets available for COVID-19 infection gene expression compendium. NFKBIA, FN1, FAP, KANK4, COMP, FAM101B, COL1A2, ANKRD1, TAGLN, SPARC, ADAM19, OLFM4, CXCL10/11, OASL, FOS, APOBEC3A, IFI44L, IFI27, IFIT1, RSAD2, NDUFS1, SRSF6, HECTD1, CBX3, and DDX17 are among the genes that may be impacted by infection, according to our findings. The functional changes are mainly associated with these pathways TNF, cytokine, NF-kB, TLR, TCR, BCR, Foxo, and TGF signaling pathways are among them and there are additional pathways such as hippo signaling, apoptosis, estrogen signaling, regulating pluropotency of stem cells, ErbB, Wnt, p53, cAMP, MAPK, PI3K-AKT, oxidative phosphorylation, protein processing in endoplasmic reticulum, prolactin signaling, adipocytokine, neurotrophine signaling, and longevity regulating pathways. Moreover, we have also explored the potential herbal drug (apigenin, quercetin, and resveratrol) targets for the top-rated genes based on the overall analysis where we observe that quercetin and resveratrol as most effective.
A library of thiosemicarbazide derivatives of isoniazid 3-27, was synthesized and evaluated for their anti-inflammatory and urease inhibition activities, by using in vitro bioassays. Among these ...compounds 9, 10, 12, 21, and 26 were identified as new derivatives. Prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) and infections caused by Helicobacter pylori (ureolytic bacteria), are the two most significant causes of gastric and peptic ulcers. We focused on the identification of the dual inhibitors of inflammation and urease enzyme. Compound 23 was identified as the best dual inhibitor of inflammation (ROS; IC
= 12.3 µg/mL), and urease enzyme inhibition activity (IC
= 22.4 µM). Many of these compounds showed comparable activities to the standard anti-inflammatory drug (ibuprofen, IC
= 11.2 µg/mL) and urease inhibitor (thiourea/acetohydraoxamic acid, IC
= 21.1/20.3 µM). Compound 12 was found to be the most potent urease inhibitor (IC
= 12.3 µM) and good inhibitor of inflammation (IC
= 27.7 µg/mL). Compounds 19, 11, 13, 9, 17, 10, and 16, were also found to be potent inhibitors of urease. Cytotoxicity was also evaluated and all the compounds were found to be non-cytotoxic, except compound 18 and the parent drug isoniazid (IC
= 29.5 and 28.5 µM, respectively).
Scorpion venoms are known to contain over 100,000 biologically active constituents. However, only a few of them have been studied. The major constituents of venom are proteins and peptides, which ...exhibit various biological and pharmacological properties, including anticancer activities. In the current study, the venom of yellow scorpions (Buthus sindicus) found in Sindh, Pakistan, was extracted and evaluated for its anti-cancer and anti-inflammatory activities. The crude venom showed a dose dependent inhibition of phagocyte oxidative burst from human whole blood cells (28.3% inhibition at highest tested concentration of 300 μg/mL). In-vitro cytotoxicity of crude venom was evaluated against human prostrate (PC3), cervical (HeLa) and neuroblastoma (U87-MG) cell lines, along with cytotoxicity against normal human fibroblast (BJ) cells. Crude venom was cytotoxic to all cell lines, with prominent inhibitory effect on PC3 cells. Crude venom was fractionated through RP-UPLC, resulted in fifteen fractions, followed by evaluation of their anticancer potential. Among all, the fraction I significantly (P < 0.001) reduced the cell viability of all three cancer cell lines, and exhibited insignificant cytotoxicity against normal cell line. Furthermore, the apoptotic cell death pathway was evaluated for crude venom, and fraction I, in most sensitive cell line PC3, by using flow-cytometry analysis. Both crude venom and its fraction I caused a mitochondrial-mediated apoptosis in prostate cancer cells (PC3). To the best of our knowledge, this is the first report of the anticancer and anti-inflammatory activity of venom of Pakistani yellow scorpions. Results indicate their therapeutic potential, and a case for further purification and validation studies.
Ultraviolet-A (UVA) radiation is a major contributor to reactive oxygen species (ROS), reactive nitrite species (RNS), inflammation, and DNA damage, which causes photoaging and photocarcinogenesis. ...This study aimed to evaluate the UVA protective potential of lipophilic chain conjugated thiourea-substituted aryl group molecules against UVA-induced cellular damages in human dermal fibroblasts (BJ cell line). We tested a series of nineteen (19) molecules for UVA photoprotection, from which 2',5'-dichlorophenyl-substituted molecule DD-04 showed remarkable UVA protection properties compared to the reference (benzophenone). The results indicate that DD-04 significantly reduced intracellular ROS and nitric oxide (NO) as compared to the UVA-irradiated control (p < 0.001). Moreover, the compound DD-04 showed anti-inflammatory activity as it significantly reduced the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) pro-inflammatory cytokines produced by THP-1 (human monocytic) cells (p < 0.05). DNA damage was also prevented by DD-04 treatment in the presence of UVA. It was observed that DD-04 significantly reduced the number of cyclobutane pyrimidine dimers (CPDs) when compared to the UVA-irradiated control (p < 0.001). Finally, the DNA strand breaks were checked and a single intact DNA band was seen upon treatment with DD-04 in the presence of UVA. In conclusion, DD-04 can be considered a potential candidate UVA filter due to its photoprotective potential.
Sulfamethazine (SMZ) (1) is an antibacterial sulfa drug which suppresses the synthesis of dihydrofolic acid. It is used for the treatment of infections in livestock; such as gastrointestinal, and ...respiratory tract infections. During the current study, synthesis, characterization, and evaluation of immunomodulatory activities of derivatives of sulfamethazine (SMZ) (3-39) was carried out. These derivatives were synthesized by the reaction of sulfamethazine with a range of acid chlorides. All the compounds were characterized by using modern spectroscopic techniques, such as 1H-, and 13C-NMR, EI-MS, and HRFAB-MS. Compounds 3-10, 14, and 15 were identified as new compounds. Immunomodulatory effect of compounds 3-39 on different parameters of innate immune response was evaluated, including the production of Reactive Oxygen Species (ROS) from human whole blood and isolated polymorphonuclear neutrophils (PMNs), nitric oxide (NO), and pro-inflammatory cytokine TNF-α. All the new compounds, except 14 and 15, showed a significant anti-inflammatory activity. Compounds 3-39 were also evaluated for their anti-bacterial activity and cytotoxicity (3T3 mouse fibroblast cell lines). All the compounds were found to be non-cytotoxic against normal cell lines.
In search of anti-inflammatory compounds, novel scaffolds containing isonicotinoyl motif were synthesized via an efficient strategy. The compounds were screened for their in vitro anti-inflammatory ...activity. Remarkably high activities were observed for isonicotinates
-
and
-
. The compound
exhibits an exceptional IC
value (1.42 ± 0.1 µg/mL) with 95.9% inhibition at 25 µg/mL, which is eight folds better than the standard drug ibuprofen (11.2 ± 1.9 µg/mL). To gain an insight into the mode of action of anti-inflammatory compounds, molecular docking studies were also performed. Decisively, further development and fine tuning of these isonicotinates based scaffolds for the treatment of various aberrations is still a wide-open field of research.
Two new ursane-type triterpenoids, named Polyanside A (
) and B (
), along with eleven known compounds (
-
), were isolated and elucidated from
(Benth.) Prance. The structures of these compounds were ...elucidated based on chemical evidence and multiple spectroscopic data. Isolated compounds were evaluated for anti-cancer, anti-inflammatory activities, and cytotoxicity on a normal human cell line (BJ). None of them showed activity and cytotoxicity. The hexane fraction was analyzed by GC-MS, resulting in the identification of forty-one compounds. This is the first comprehensive study on the phytochemistry of
.
Natural products have served as primary remedies since ancient times due to their cultural acceptance and outstanding biodiversity. To investigate whether
L. modulates an inflammatory process, we ...carried out bioassay-guided isolation where the extracts and isolated compounds were tested for their modulatory effects on several inflammatory indicators, such as nitric oxide (NO), reactive oxygen species (ROS), proinflammatory cytokine; tumour necrosis factor (TNF-
), as well as the proliferation of the lymphocyte T-cells. The aqueous ethanolic extract of the plant inhibited the intracellular ROS production, NO generation, and T-cell proliferation. The aqueous ethanolic crude extract was partitioned by liquid-liquid fractionation using
-hexane (
-C
H
), dichloromethane (DCM), ethyl acetate (EtOAc),
-butanol (
-BuOH), and water (H
O). The DCM and
-BuOH extracts showed the highest activity against most inflammatory indicators and were further purified to obtain compounds
-
. The structures of 3,5-dihydroxy-4',7-dimethoxyflavone (
) and 3,5-dihydroxy-4-methoxybenzoic acid methyl ester (
) from the DCM extracts; and kaempferol (
), and 3-hydroxy-4-methoxy-(
)-cinnamic acid (
) from the
-BuOH extract were elucidated by different spectroscopic tools, including MS, NMR, UV, and IR. Compound
inhibited the production of ROS and TNF-
, whereas compound
showed inhibitory activity against all the tested mediators. A better understanding of the potential aspect of
L. derivatives as anti-inflammatory agents could open the door for the development of advanced anti-inflammatory entities.
The protein constituent of honey exhibits therapeutic activities in inflammation, and parasitic infections. The biological activities of honey depend on multiple factors such as types of flora, ...honeybee species, and geographical region. The immunomodulatory activities of proteins of honey of many floral types have not been performed so far. In this study, the proteins composition in seven types of honeys of different flora (Acacia, Thyme, Pine, Khairpur, Chinaberry, Gum tree and Citrus honeys), and geographical regions was determined using gel filtration chromatography (GFC), and their anti-inflammatory activity was studied by determining the inhibition of reactive oxygen species (ROS) in zymogen activated human polymorph nuclear leucocytes (PMNLs). The analysis showed that natural honeys differ in their proteins composition, containing 3–6 proteins fractions. The concentration dependent inhibition of ROS production was observed with precipitated as well as fractionated honey proteins (IC
50
0.6–18 ng/mL). The crude proteins of acacia honey exhibited IC
50
of 11.3 ng/mL, thyme 5.3 ng/mL, pine 3.1 ng/mL, Khairpur 7.5 ng/mL, and Chinaberry 16.5 ng/mL. Different GFC fractions of honey samples under study also showed significantly low IC
50
values in the range of 0.2–9.8 ng/mL. The results of this study show, for the first time, that protein fractions of natural honeys of different botanical flora possess varying yet high potential to suppress ROS production in macrophages, suggesting their tissue protective role by alleviating oxidative stress.
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