Exploring the potential of Andrographis paniculata for developing novel HDAC inhibitors: an in silico approach.

Cancer is one of the dreaded diseases of the twentieth century, emerging the major global causes of human morbidity. Cancer research in the last 15 years has provided unprecedented information on the role of epigenetics in cancer initiation and progression. Histone deacetylases (HDACs) are recognized as important epigenetic markers in cancer, whose overexpression leads to increased metastasis and angiogenesis. In the current study, thirty-four (34) compounds from Andrographis paniculata were screened for the identification of potential candidate drugs, targeting three Class I HDACs (Histone deacetylases), namely HDAC1 (PDB id 5ICN), HDAC3 (PDB id 4A69) and HDAC8 (PDB id 5FCW) through computer-assisted drug discovery study. Results showed that some of the phytochemicals chosen for this study exhibited significant drug-like properties. In silico molecular docking study further revealed that out of 34 compounds, the flavonoid Andrographidine E had the highest binding affinities towards HDAC1 (-9.261 Kcal mol-1) and 3 (-9.554 Kcal mol-1) when compared with the control drug Givinostat (-8.789 and -9.448 Kcal mol-1). The diterpenoid Andrographiside displayed the highest binding affinity (-9.588 Kcal mol-1) to HDAC8 compared to Givinostat (-8.947 Kcal mol-1). Statistical analysis using Principal Component Analysis tool revealed that all 34 phytocompounds could be clustered in four statistical groups. Most of them showed high or comparable inhibitory potentials towards HDAC target protein. Finally, the stability of top-ranked complexes (Andrographidine E-HDAC1 and HDAC3; Andrographiside-HDAC8) at the physiological condition was validated by Molecular Dynamic Simulation and MM-PBSA study.Communicated by Ramaswamy H. Sarma.

A Case of Multiple Vein Thrombosis Following Pacemaker Implantation.

Pacemakers are implanted as part of the treatment process of conditions including symptomatic bradycardia and certain types of heart block. One complication associated with pacemaker implantation is upper extremity deep venous thrombosis (UEDVT), which can subsequently lead to pulmonary embolism, limb loss, or death. We present the case of an 88-year-old male who developed UEDVT in his left subclavian, axillary, brachial, and basilic veins shortly after dual chamber pacemaker implantation for treating symptomatic heart block. The patient received anticoagulation with intravenous heparin while inpatient but was switched to oral apixaban prior to discharge. This case highlights the importance of detecting and treating UEDVT in patients who recently underwent pacemaker placement.

Relationship Between Reception of Low-Dose Computed Tomography Screening, Tobacco Cessation Attempt, and Reception of Pneumococcal Vaccine.

The stage at diagnosis is the single most important predictor of lung cancer outcome. Therefore, detecting lung cancer early is of utmost importance. Low-dose computed tomography (LDCT) has proven beneficial in the early detection and mortality reduction of lung cancer. Despite this, very few of the high-risk population get annual LDCT done. Patients' attitudes towards tobacco usage and preventive care can be a factor in getting LDCT. We analyzed the relationship between the willingness to undergo LDCT and a person's readiness to try tobacco cessation medication or get the pneumococcal vaccine. We also analyzed the relationship between patients who had tobacco cessation counseling and their willingness to get LDCT and pneumococcal vaccine. Medical records of high-risk patients seen in the East Tennessee State University (ETSU) clinics between January 1, 2016, and November 30, 2020, were analyzed retrospectively. In the data obtained, a total of 2,834 patients were current smokers and were included in the research. The study subjects were assessed in two ways, which from here on will be referred to as method one and method two. In the first method, patients who underwent LDCT were assessed, and the outcome investigated was tobacco cessation counseling, tobacco cessation medication prescription, and pneumococcal vaccination. In the second method, patients who had tobacco cessation counseling were assessed, and the outcome evaluated was LDCT, tobacco cessation medication prescription, and pneumococcal vaccination.  In the first method, out of 2,834 total population, 570 had undergone at least one LDCT screening during the study period. Of the 570 patients who underwent LDCT, 22.8% tried one of the tobacco cessation medications at least once during the study period (vs. 9.8% in patients who did not get the LDCT). Also, 71.5% of patients who had LDCT received at least one dose of pneumonia vaccine (vs. 35.5% in patients who did not get the LDCT). In the second method, 1,673 out of 2,834 patients received at least one tobacco cessation counseling, and out of those, 27.5% had LDCT screening (vs. 9.5% among those who never received counseling). Also, 54.9% received a pneumococcal vaccine (vs. 45.1% among those who did not receive counseling). The study demonstrates a relationship between getting LDCT and getting a pneumococcal vaccine or tobacco cessation medications. It also reveals that tobacco cessation counseling increases the odds of getting LDCT, tobacco cessation medications, and pneumococcal vaccine.

Manipulation of DXP pathway for andrographolide production in callus cultures of Andrographis paniculata.

MAIN CONCLUSION: Greening of in vitro callus cultures and andrographolide over-accumulation was achieved by manipulating light exposure and media composition, when the biosynthetic cascade was channeled through the DXP pathway. Andrographolide, the primary biologically active compound of Andrographis paniculata, is produced through coordinated action of two pathways, the classical cytosolic mevalonate pathway and the alternative plastidial non-mevalonate pathway (Deoxy-xylulose Phosphate pathway). In vitro callus cultures of A. paniculata are useful sources of production, as well as, manipulation of andrographolide, and the present study was designed to explore the strategy of pathway inhibition for its overproduction. When the cytosolic mevalonate pathway blocker, lovastatin, was applied to callus cultures of A. paniculata, andrographolide production was enhanced in comparison to untreated control. In contrast, treatment of the callus tissue with the DXP-pathway blocker, fosmidomycin, led to depletion in andrographolide production. The present study also showed that silver nitrate, a potent elicitor of andrographolide production in in vitro callus culture, when added in combination with the pathway inhibitors resulted in alterations in andrographolide production. The highest andrographolide production was obtained in callus treated with a combination of silver nitrate and lovastatin, indicating a predominant role of the plastidial DXP pathway in andrographolide biosynthesis. A positive co-relation with chlorophyll content and andrographolide production in in vitro callus cultures (untreated and treated) observed also supported the above assumption. It could be inferred from this study that greening of callus tissue through organellar organization was a potent strategy for enhancing andrographolide accumulation in callus tissues of A. paniculata.

Involvement of intracellular signaling cascades in inflammatory responses in human intestinal epithelial cells following Vibrio cholerae infection.

Vibrio cholerae, the etiological agent of cholera, leads to the induction of host cell nuclear responses and the activation of proinflammatory cytokines in the cultured intestinal epithelial cells. However, the host cell signaling pathway leading to proinflammatory response is not explored. In this study, we demonstrated that V. cholerae infection on intestinal epithelial cells results in the activation of extracellular signal-regulated kinases1/2(ERK1/2) and p38 of the mitogen activated protein kinase (MAPK) family. V. cholerae induced intracellular pathways in Int407 cells leading to the activation of protein kinase A (PKA) and protein tyrosine kinase (PTK) in upstream of MAPK and nuclear factor-kappaB (NF-kappaB) pathway. Inhibitor study of Ca(2+) and phospholipase-gamma (PLC-gamma) pathway suggested the possible involvement of Ca(2+) signaling in the V. cholerae pathogenesis. V. cholerae culture supernatants as also insertional mutants of ctxA, toxR and toxT genes modulate the activation of MAPK and NF-kappaB signaling pathways. MAPK and NF-kappaB signaling pathway activation were also modulated by adherence and motility of V. cholerae. Studies with inhibitor of NF-kappaB, MAPK, PTK, PKA, PKC, Ca(2+) and PLC pathways showed differential cytokine secretion in Int407 following V. cholerae infection. Therefore V. cholerae mediated induction of nuclear responses through signal transduction pathway and subsequent activation of proinflammatory cytokines in Int407 modulated by V. cholerae secretory factors, virulence, adhesion/motility which might explain some of its reactogenic mechanisms.