scholarly journals In Silico Drug Repurposing for Anti-Inflammatory Therapy: Virtual Search for Dual Inhibitors of Caspase-1 and TNF-Alpha

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1832
Author(s):  
Alejandro Speck-Planche ◽  
Valeria V. Kleandrova ◽  
Marcus T. Scotti

Inflammation involves a complex biological response of the body tissues to damaging stimuli. When dysregulated, inflammation led by biomolecular mediators such as caspase-1 and tumor necrosis factor-alpha (TNF-alpha) can play a detrimental role in the progression of different medical conditions such as cancer, neurological disorders, autoimmune diseases, and cytokine storms caused by viral infections such as COVID-19. Computational approaches can accelerate the search for dual-target drugs able to simultaneously inhibit the aforementioned proteins, enabling the discovery of wide-spectrum anti-inflammatory agents. This work reports the first multicondition model based on quantitative structure–activity relationships and a multilayer perceptron neural network (mtc-QSAR-MLP) for the virtual screening of agency-regulated chemicals as versatile anti-inflammatory therapeutics. The mtc-QSAR-MLP model displayed accuracy higher than 88%, and was interpreted from a physicochemical and structural point of view. When using the mtc-QSAR-MLP model as a virtual screening tool, we could identify several agency-regulated chemicals as dual inhibitors of caspase-1 and TNF-alpha, and the experimental information later retrieved from the scientific literature converged with our computational results. This study supports the capabilities of our mtc-QSAR-MLP model in anti-inflammatory therapy with direct applications to current health issues such as the COVID-19 pandemic.

2021 ◽  
Vol 9 (A) ◽  
pp. 1031-1036
Author(s):  
Yuyun Yueniwati ◽  
Mokhammad Fahmi Rizki Syaban ◽  
Nabila Erina Erwan ◽  
Gumilar Fardhani Ami Putra ◽  
Agung Dwi Krisnayana

BACKGROUND: Diabetes mellitus contributes to the delayed healing of wounds causes disturbance of inflammatory cytokine. Tumour necrosis factor alpha (TNF-alpha) and Vascular Endothelial Growth Factor Receptor (VEGFR) both have a role in the persistent inflammation associated with diabetic wounds. Ficus religiosa has developed a reputation as a traditional wound healer among some java people in Indonesia. AIM: Our study aims to discover the molecular interaction between the active constituents of F. religiosa with TNF-alpha and VEGFR. MATERIALS AND METHODS: This research was conducted in computerized molecular docking using Protein database, Pymol, Discovery studio, and Pyrex software. A thorough literature search was conducted to identify the potential compound and molecular target for diabetic wounds. Analysis of its anti-inflammatory properties was also carried out using a passonline webserver. Pharmacokinetic analysis was performed using the Lipinski Rule of Five websites and the PreADMET website. RESULTS: Each of the study’s active compounds has a good pharmacokinetic profile. The predictions of the compound’s structure indicate that it has a strong anti-inflammatory impact. Lupenyl acetate and Lanosterol bind more strongly to the TNF-alpha than the natural ligand, but Piperine binds more strongly to VEGFR. CONCLUSIONS: Lupenyl acetate, Lanosterol, and Piperine compounds have anti-inflammatory effects through inhibition of TNF-alpha and VEGFR. In addition, this compound has potential to become a drug because it has good pharmacokinetics. Future studies are required to determine the effectiveness and toxicity of Lupenyl acetate, Lanosterol, and Piperine as potential treatment in diabetic wounds.


2014 ◽  
Vol 124 (1) ◽  
pp. 46-48 ◽  
Author(s):  
Barabara Rybacka-Chabros ◽  
Aldona Pietrzak ◽  
Paweł Chabros ◽  
Janusz Milanowski

AbstractIntroduction. Anti-inflammatory, separate from anti-thrombotic activity of low molecular weight heparin, is still not well documented. Aim. We estimated the influence of enoxaparin on serum levels of tumor necrosis factor alpha, as the pro-inflammatory cytokine, and interleukin-12, as the heparin-binding, anti-inflammatory cytokine, in patients with exacerbations of chronic obstructive pulmonary disease. Material and methods. Seventy-three consecutive patients (48 males, 25 females) aged 56-75 years without thromboembolic history, were enrolled into the study. They were randomized to group who received enoxaparin in one daily dose 40 mg, or to group who did not receive it. Patients receiving oral anti-coagulants were excluded from the study. Using ELISA approach, we evaluated serum levels of tumor necrosis factor-alpha and interleukin-12 at the following periods: before the first dose of enoxaparin, after 7 days of treatment and 14 days of treatment. Serum level of the C-reactive protein was evaluated simultaneously. Results. In enoxaparin recipients statistically significant (p<0.01) decreasing of TNF-alpha serum levels (from 168.33 pg/ml in admission, to 85.67 pg/ml in the end of study) to compare enoxaparine non-recipients, was observed. Interleukin-12 serum levels were significantly higher in enoxaparine recipients both after 7 days (67.46 pg/ml) and 14 days (89.32 pg/ml) of the study (p<0.05). C-reactive proteins serum levels were significantly higher in enoxaparine non-recipients than recipients (p<0.05) in all study period. Conclusions. Enoxaparin in daily dose 40 mg, significantly depressed serum levels of TNF-alpha and promote serum levels of interleukin-12. Enoxaparin administration may be beneficial for the patients with COPD exacerbation during the first 14 days of treatment


2018 ◽  
Vol 2 (2) ◽  
pp. 01-04
Author(s):  
Ganesh Chandra Jagetia

Inflammation is an all-pervasive phenomenon and it is triggered as a countermeasure against pathogenic attack, harmful stimuli and damage to the body tissues. Generally, inflammation peters out once its cause gets terminated. However, persistence of (chronic) inflammation is harbinger of almost all diseases, which that inflammation needs to be tamed to ward off against its harmful effects. The natural products may be good candidates to suppress inflammation. Hesperidin, a bioflavonoid consumed regularly by humans is attributed to possess several medicinal properties including free radical scavenging and anti-inflammatory. This review mainly dwells on its anti-inflammatory property in various study systems. The regular use of hesperidin may be encouraged to stall inflammation related health disorders in humans.


Author(s):  
Seigo Nagashima ◽  
Monalisa C. Mendes ◽  
Ana Paula C. Martins ◽  
Nicolas H. Borges ◽  
Thiago M. Godoy ◽  
...  

ABSTRACTObjectiveEndothelial cells that are close to the alveolar-capillary exchange membranes can be activated by SARS-CoV-2 infection leading to cytokine release and macrophage activation syndrome. This could trigger endothelial dysfunction, pyroptosis, and immunothrombosis, which are the vascular changes commonly referred to as COVID-19 endotheliopathy. Thus, this study aimed to identify tissue biomarkers associated with endothelial activation/dysfunction and the pyroptosis pathway in the lung and myocardial samples of COVID-19 patients and to compare them to pandemic Influenza A virus H1N1 subtype – 2009 and Control cases.Approach and ResultsPost-mortem lung (COVID-19 group=6 cases; H1N1 group=10 cases, and Control group=11 cases) and myocardial samples (COVID-19=2 cases and control=1 case) were analyzed using immunohistochemistry and the following monoclonal primary antibodies: anti-CD163, anti-interleukin-6 (IL-6), anti-tumor necrosis factor-alpha (TNF-alpha), anti-intercellular adhesion molecule-1 (ICAM-1), and anti-caspase-1. From the result, IL-6, TNF-alpha, ICAM-1, and caspase-1 showed higher tissue expression in the COVID-19 group than in the H1N1 and control groups.ConclusionOur results demonstrated the presence of endotheliopathy and suggest the participation of the pyroptosis pathway in both the pulmonary and myocardial samples. These conditions might lead to systemic immunothrombotic events that could impair the efforts of clinical staff to avoid fatal outcomes. One of the goals of health professionals should be to identify the high-risk of immunothrombosis patients early to block endotheliopathy and its consequences.


2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Daniela Assimiti

Abstract Objectives Introduction: Inflammation is a complex biological response of the body tissues to foreign particles or pathogens.Research shows that an alkaline state maintained by the cells is healthier while an acidic pH increases the risk for numerous problems including chronic inflammation. The usual adverse effects of the anti-inflammatory drugs, necessitate the search for novel compounds of herbal origin. Red beetroot (Beta vulgaris rubra), is a vegetable plant known to possess various beneficial properties and is considered as a promising therapeutic tool in a range of clinical pathologies associated with oxidative stress and inflammation due to the betalain pigments contained. The present study refers to three cases suggesting options in which beetroot might be used to handle in different situations of inflammation. Methods Case description: Raw beetroot was administered as a common, affordable, safe to use natural remedies and a possible alternative to the common pharmaceutical over-the-counter anti-inflammatory drugs. Its efficiency was evaluated in few particular situations involving inflammation, as : episodes of gingivitis and toothache, migraine headaches, or as part of a more elaborate plan to recover from Bell's palsy. All three cases are individuals in the age range 50–65. Results Eating raw beetroot and chewing thoroughly proved to be an efficient way to alleviate symptoms of gingivitis (probably linked to tooth infection). Gum inflammation was fully resolved within a week. In another case, it helped reduce deep pulsating headache and recurrent pain which prevented sleep as well as ease of the tension, thus headache was ameliorated within 30 min and good night rest could be resumed. Another challenge was given to help accelerate recovering from Bell's palsy condition (this time, under a more elaborate plan which included also vitamin B12 supplements and massage therapy) and the complete recovery and returning to normal function could be obtained within 8 weeks instead of 3–6 months. Conclusions Beetroot proved to be a potential highly effective anti-inflammatory remedy, easy accessible and safe to use. Further investigations would be essential in order to validate the bioactive components involved, its efficiency in other forms of inflammation and implications for clinical practice, as well as defining the best way to use it. Funding Sources No.


2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
José Christian Machado Ximenes ◽  
Kelly Rose Tavares Neves ◽  
Luzia Kalyne A. M. Leal ◽  
Marta Regina Santos do Carmo ◽  
Gerly Anne de Castro Brito ◽  
...  

Parkinson’s disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson’s disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were observed not only in the CA1 and CA3 subfields of the hippocampus, but also in the temporal cortex. In conclusion, we showed that VA partly reversed the behavioral, neurochemical, histological, and immunohistochemical alterations observed in the untreated 6-OHDA-lesioned animals. These effects are probably related to the drug anti-inflammatory activity and strongly suggest that VA is a potential candidate to be included in translational studies for the treatment of neurodegenerative diseases as PD.


2021 ◽  
Author(s):  
Vanessa D’Antongiovanni ◽  
Carolina Pellegrini ◽  
Laura Benvenuti ◽  
Matteo Fornai ◽  
Clelia Di Salvo ◽  
...  

Abstract The pharmacological blockade of P2X4 receptors has shown potential benefits in the management of several immune/inflammatory diseases. However, data regarding the involvement of P2X4 receptors in the pathophysiological mechanisms of action in intestinal inflammation are not well defined. We aimed to evaluate the anti-inflammatory effects of two novel and selective P2X4 receptor antagonists, NC-2600 and NP-1815-PX, and characterize the molecular mechanisms of their action in a murine model of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis. These two drugs and dexamethasone (DEX) were administered orally for 6 days, immediately after the manifestation of DNBS. The body weight decrease, resulting from colitis, was attenuated by NC-2600 and NP-1815-PX, but not DEX. However, all three drugs attenuated the increase in spleen weight and ameliorated macroscopic and microscopic colonic tissue damage. Furthermore, all three compounds decreased tissue IL-1β levels and caspase-1 expression and activity. Colonic tissue increase of tumor necrosis factor was downregulated by DEX, while both NC-2600 and NP-1815-PX were ineffective The reduction of occludin associated with colitis was ameliorated by NC-2600 and NP-1815-PX, but not DEX. In THP-1 cells, lipopolysaccharide and ATP upregulated IL-1β release and NLRP3, caspase-1, caspase-5 and caspase-8 activity, but not of caspase-4. These changes were prevented by NC-2600 and NP-1815-PX treatment. For the first time, the above findings show that the selective inhibition of P2X4 receptors represents a viable approach to manage bowel inflammation via the inhibition of NLRP3 inflammasome signaling pathways.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 408
Author(s):  
Eui Jin Kim ◽  
Ji Bin Seo ◽  
Jae Sik Yu ◽  
Seoyoung Lee ◽  
Jae Sung Lim ◽  
...  

Inflammation is a defense mechanism that protects the body from infections. However, chronic inflammation causes damage to body tissues. Thus, controlling inflammation and investigating anti-inflammatory mechanisms are keys to preventing and treating inflammatory diseases, such as sepsis and rheumatoid arthritis. In continuation with our work related to the discovery of bioactive natural products, a polyphenol, catechin-7,4′-O-digallate (CDG), was isolated from Woodfordia uniflora, which has been used as a sedative and remedy for skin infections in the Dhofar region of Oman. Thus far, no study has reported the anti-inflammatory compounds derived from W. uniflora and the mechanisms underlying their action. To investigate the effects of CDG on the regulation of inflammation, we measured the reduction in nitric oxide (NO) production following CDG treatment in immortalized mouse Kupffer cells (ImKCs). CDG treatment inhibited NO production through the downregulation of inducible nitric oxide synthase expression in lipopolysaccharide (LPS)-stimulated ImKCs. The anti-inflammatory effects of CDG were mediated via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, an important inflammatory-response-associated signaling pathway. Moreover, CDG treatment has regulated the expression of pro-inflammatory cytokines, such as IL-6 and IL-1β. These results suggested the anti-inflammatory action of CDG in LPS-stimulated ImKCs.


2019 ◽  
Vol 11 (4) ◽  
pp. 277-284
Author(s):  
Vitrianingsih Vitrianingsih ◽  
Sitti Khadijah

Studi memperkirakan emesis gravidarum terjadi pada 50-90% kehamilan. Mual muntah pada kehamilan memberikan dampak yang signifikan bagi tubuh dimana ibu menjadi lemah, pucat dan cairan tubuh berkurang sehingga darah menjadi kental (hemokonsentrasi). Keadaan ini dapat memperlambat peredaran darah dan berakibat pada kurangnya suplay oksigen serta makanan ke jaringan sehingga dapat membahayakan kesehatan ibu dan janin. Salah satu terapi yang aman dan dapat dilakukan untuk mengurangi keluahan mual muntah pada ibu hamil adalah pemberian aromaterapi lemon. Penelitian bertujuan untuk mengetahui efektifitas aroma terapi lemon untuk menangani emesis gravidarum. Penelitian ini menggunakan rancangan Quasi experiment  dengan  one group pre-post test design. Populasi penelitian adalah ibu hamil yang mengalami emesis gravidarum di Kecamatan Berbah, Sleman. Jumlah sampel 20 ibu hamil trimester pertama yang diambil dengan teknik purposive sampling. Pengukuran mual muntah dilakukan debelum dan setelah  pemberian aromaterapi lemon menggunakan Indeks Rhodes. Analisa data menggunakan uji Paired t-test. Hasil penelitian didapatkan rata-rata skor mual muntah sebelum pemberian aromaterapi lemon berdasarkan Indeks Rhodes pada Ibu Hamil dengan emesis gravidarum yaitu 22,1 dan terjadi penurunan skor setelah pemberian aromaterapi lemon menjadi 19,8. Ada pengaruh pemberian aromaterapi lemon dengan pengurangan mual muntah pada ibu hamil (p-value = 0.017). Berdasarkan hasil penelitian dapat disimpulkan pemberian aromaterapi lemon efektif untuk mengurangi emesis gravidarum pada ibu hamil trimester pertama.  Kata kunci: aromaterapi lemon, emesis gravidarum THE EFFECTIVENESS OF LEMON AROMATHERAPY FOR HANDLING EMESIS GRAVIDARUM   ABSTRACT Studies estimate that nausea and vomiting (emesis gravidarum) occur in 50 – 90% of pregnancies. Nausea and vomiting of pregnancy have a significant impact on the body in which it makes a mother becomes weak, pale, and decreasing body fluid so that the blood becomes thick (hemoconcentration). This situation can slow down blood circulation and inflict the lack of oxygen and food supplies to the body tissues so that it can endanger the health of the mother and fetus. One of the therapies that is safe and can be conducted to reduce nausea and vomiting of pregnancy is by giving the lemon aromatherapy treatment. The research aims to determine the effectiveness of the aroma of lemon therapy to deal with emesis gravidarum. This study applied quasi-experimental research with one group pretest-posttest design. The population of this study was pregnant women who experienced emesis gravidarum. Furthermore, samples were 20 mothers from Berbah, Sleman taken by using a purposive sampling technique. Nausea and vomiting were assessed between before and after giving lemon aromatherapy using the Rhodes Index. The data were analyzed using the paired t-test. The mean score of nausea and vomiting before giving lemon aromatherapy on mother with emesis gravidarum based on the Rhodes Index was 22.1. However, it decreased after given lemon aromatherapy treatment to 19.8. Therefore, there was an effect on giving lemon aromatherapy treatment toward the decrease of nausea and vomiting for pregnant women (p-value = 0.017). Lemon aromatherapy is effective to reduce emesis gravidarum.  Keywords: lemon aromatherapy, emesis gravidarum


Author(s):  
A. E. Chernikova ◽  
Yu. P. Potekhina

Introduction. An osteopathic examination determines the rate, the amplitude and the strength of the main rhythms (cardiac, respiratory and cranial). However, there are relatively few studies in the available literature dedicated to the influence of osteopathic correction (OC) on the characteristics of these rhythms.Goal of research — to study the influence of OC on the rate characteristics of various rhythms of the human body.Materials and methods. 88 adult osteopathic patients aged from 18 to 81 years were examined, among them 30 men and 58 women. All patients received general osteopathic examination. The rate of the cranial rhythm (RCR), respiratory rate (RR) heart rate (HR), the mobility of the nervous processes (MNP) and the connective tissue mobility (CTM) were assessed before and after the OC session.Results. Since age varied greatly in the examined group, a correlation analysis of age-related changes of the assessed rhythms was carried out. Only the CTM correlated with age (r=–0,28; p<0,05) in a statistically significant way. The rank dispersion analysis of Kruskal–Wallis also showed statistically significant difference in this indicator in different age groups (p=0,043). With the increase of years, the CTM decreases gradually. After the OC, the CTM, increased in a statistically significant way (p<0,0001). The RCR varied from 5 to 12 cycles/min in the examined group, which corresponded to the norm. After the OC, the RCR has increased in a statistically significant way (p<0,0001), the MNP has also increased (p<0,0001). The initial heart rate in the subjects varied from 56 to 94 beats/min, and in 15 % it exceeded the norm. After the OC the heart rate corresponded to the norm in all patients. The heart rate and the respiratory rate significantly decreased after the OC (р<0,0001).Conclusion. The described biorhythm changes after the OC session may be indicative of the improvement of the nervous regulation, of the normalization of the autonomic balance, of the improvement of the biomechanical properties of body tissues and of the increase of their mobility. The assessed parameters can be measured quickly without any additional equipment and can be used in order to study the results of the OC.


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