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Biomedical subjects

Ravi Shankar

Publications and source records attributed to Ravi Shankar.

28 records · Page 2Linked to original sources
PubMed2003

Prostaglandin E2 mediates growth arrest in NFS-60 cells by down-regulating interleukin-6 receptor expression.

Interleukin-6 (IL-6), a potent myeloid mitogen, and the immunosuppressive prostanoid prostaglandin E2 (PGE2) are elevated following thermal injury and sepsis. We have previously demonstrated that bone marrow myeloid commitment shifts toward monocytopoiesis and away from granulocytopoiesis during thermal injury and sepsis and that PGE2 plays a central role in this alteration. Here we investigated whether PGE2 can modulate IL-6-stimulated growth in the promyelocytic cell line, NFS-60, by down-regulating IL-6 receptor (IL-6r) expression. Exposure of NFS-60 cells to PGE2 suppressed IL-6-stimulated proliferation as well as IL-6r expression. Receptor down-regulation is functionally significant since IL-6-induced signal transduction through activators of transcription (STAT)-3 is also decreased. Down-regulation of IL-6r correlated with the ability of PGE2 to arrest cells in the G0/G1 phase of the cell cycle. PGE2 appears to signal through EP2 receptors. Butaprost (EP2 agonist) but not sulprostone (EP3 agonist) inhibited IL-6-stimulated proliferation. In addition, an EP2 antagonist (AH6809) alleviated the anti-proliferative effects of PGE2. NFS-60 cells express predominantly EP2 and EP4 receptors. While PGE2 down-regulated both the IL-6r protein and mRNA expression, it had no influence on EP2 or EP4 mRNA expression. The present study demonstrates that PGE2 is a potent down-regulator of IL-6r expression and thus may provide a mechanistic explanation for the granulocytopenia seen in thermal injury and sepsis.

Animals↗
PubMed2002

Handling of low-density lipoprotein by the renal tubule: release of fragments due to incomplete degradation.

Because the mechanism by which lipoproteins are processed and modified in the renal tubule in patients with nephrosis is not completely understood, we studied the handling of low-density lipoprotein (LDL) in perfused rat kidneys made permeable by protamine. Protamine pretreatment increased the clearance of 125(I) LDL 25-fold compared to controls, thereby simulating a proteinuric kidney. Similar studies were also conducted in kidneys of rats made proteinuric by the induction of passive Heymann nephritis. Of the perfused iodinated LDL, 5% was localized in the cortex and lesser amounts in the medulla and urine. In the cortex and medulla, iodinated LDL was present mainly in the intact form (90%); just 10% was present in the degraded form. Using horseradish peroxidase conjugated to LDL, we demonstrated specific staining in the proximal tubules, suggesting that specific LDL receptors were present in that location. Although LDL in the tissue was present mostly in the intact form, it was 95% degraded in urine, and the degradation was inhibited by chloroquine, indicating that the lysosomes were the site of LDL metabolism. Gel chromatography and electrophoresis of iodinated LDL in the urine showed the presence of fragments in the range of 5 to 15 kD. We conclude that renal degradation of LDL is incomplete and that the incompletely degraded fragments released into the urine may be toxic to the kidney by virtue of their lipid side-chains.

Animals↗
PubMed2002

Lead exposure enhances virus multiplication and pathogenesis in mice.

Suppression of the immune system by environmental xenobiotics may cause increased susceptibility of the host towards a variety of microbial pathogens an result in a life-threatening state. We investigated whether lead exposure would enhance susceptibility to Semliki Forest Virus (SFV). Mice orally exposed to lead acetate (62.5, 125, 250 or 500 mg/kg bw) exhibited increased mortality and decreased mean survival time compared to untreated animals on challenge with SFV. The mortality was associated with enhancement of high virus titer and earlier appearance of virus in lead-exposed mice. Histopathological studies observed enhancement of viral pathogenesis in a dose dependent pattern in the lead-dosed group challenged with SFV. The results indicate that exposure to lead enhanced susceptibility to viral infection. Environmental metal contamination and subsequent infection by pathogenic microbes points necessitate studies on the interaction of environmental pollutants on the immune system.

Alphavirus Infections↗
PubMed1999

Reactions of Dimethyl Sulfite with Diorganotin Oxides. One-Pot Synthesis of Methoxydiorganotin Methanesulfonates through the Arbuzov Rearrangement, Spectroscopic Characterization of These Compounds and Their Derivatives, and X-ray Crystal Structures of n-Bu(2)Sn(X)OS(O)(2)Me (X = acac, bzbz, OH).

One-pot reactions of diorganotin oxides, R(2)SnO, with dimethyl sulfite under reflux conditions (125-127 degrees C) proceed via the Arbuzov rearrangement at the sulfur center, yielding the corresponding methoxydiorganotin methanesulfonates, R(2)Sn(OMe)OS(O)(2)Me [R = n-Pr (1), n-Bu (2), i-Bu (3), c-Hx (4)], as white, hygroscopic solids. These compounds react with beta-diketones [acetylacetone (Hacac), benzoylacetone (Hbzac), and dibenzoylmethane (Hbzbz)] to afford mixed-ligand organotin derivatives, R(2)Sn(X)OS(O)(2)Me [X = acac, R = n-Pr (5), n-Bu (6); X = bzac, R = n-Pr (7), n-Bu (8); X = bzbz, R = n-Pr (9), n-Bu (10), i-Bu (11)]. Selective hydrolysis of the Sn-OMe bond in 1-3 occurs, resulting in the isolation of (&mgr;-hydroxo)diorganotin methanesulfonates, R(2)Sn(OH)OS(O)(2)Me [R = n-Pr (12), n-Bu (13), i-Bu (14)]. All the compounds are characterized by elemental analyses and IR, multinuclear ((1)H, (13)C, and (119)Sn) NMR, and mass spectra. Unequivocal evidence of the presence of the methanesulfonate group is provided by the X-ray crystal structures of 6, 10, and 13. [For 6: trigonal space group R&thremacr; (No. 148), a = 28.664(1) Å, c = 13.056(1)Å, Z = 18. For 10: triclinic space group P&onemacr; (No. 2), a = 13.056(3) Å, b = 14.062(3) Å, c = 16.282(3) Å, Z = 4. For 13: triclinic space group P&onemacr; (No. 2), a = 9.089(2) Å, b = 12.040(2) Å, c =13.894(2) Å, Z = 2]. For 6 and 10, the solid-state structural analyses reveal dimeric structures with a bridging bidentate methanesulfonate group forming a centrosymmetric eight-membered ring. Compound 13 possesses a polymeric sheet structure with repeating 20-membered macrocycles (including two four-membered [Sn(OH)](2) rings) by virtue of the bridging bidentate methanesulfonate groups. A search for a possible pathway to give Arbuzov-rearranged products 1-4 leads us to speculate that there is an initial catalytic transformation of dimethyl sulfite to methyl methanesulfonate via intermediate compounds, Bu(2)Sn(OMe)(2) (A) and [Bu(2)SnOMe](2)O (B). A and B subsequently react with methyl methanesulfonate to give 1-4.

Journal Article↗
PubMedDate not supplied

New perspectives for a new century: implications of pathogen responses for the future of antimicrobial therapy.

Although the discovery of new classes of antibiotics has lagged behind in the last three decades, the incidence of life-threatening nosocomial infections that are resistant to multiple antibacterial agents has increased steadily. Recent advances in bacterial pathogenicity through the identification of a number of virulence factors and the bacterial genetics behind it have opened the way to a clearer understanding of the pathogen-host relationship. Bacteria communicate with each other through specific signaling chemicals to act as a community rather than individual cells to achieve a critical density or a "quorum." Establishment of quorum is the initiating signal for turning on a variety of virulence factors essential for the pathogenicity and dissemination of pathogens through the host. Pathogenic bacteria use a variety of biochemical mediators, collectively called "virulence factors," to invade and attack host tissues and to avoid detection and elimination by the host immune system. Delineating the specific responses the host immune system elicits in response to specific virulence factors and quorum-sensing molecules is essential to the development of new diagnostic methods for early detection of an infection and the prognosis to a given antibacterial therapy. Identification of inhibitors of virulence factors will represent new antimicrobial therapeutic modalities, and this can be used synergistically with current antibiotic therapy because they act through independent prokaryotic pathways to inhibit bacterial growth and survival.

Anti-Bacterial Agents↗
PubMedDate not supplied

A novel antibacterial gene transfer treatment for multidrug-resistant Acinetobacter baumannii-induced burn sepsis.

Sepsis caused by multidrug-resistant bacterial infections in critically injured patients has become a major clinical problem. Recently, Acinetobacter baumannii (AB) wound infections, especially in our critically injured soldiers fighting in Iraq and Afghanistan, is posing a major clinical problem and an economic burden. ConjuGon, Inc., has developed a novel antibacterial therapeutic technology using bacterial conjugation. The donor cells are attenuated Escherichia coli carrying a conjugative plasmid. The expression of bactericidal genes cloned on the plasmid is tightly repressed in the donor cells but becomes de-repressed once mobilized into a pathogen and disrupts protein synthesis. Here, we tested the efficacy of this novel conjugation technology to control and eradicate a drug-resistant clinical isolate of AB wound infection both in vitro and in a murine burn sepsis model. C57Blk/6J mice were divided into burn (B) and burn sepsis (BS) groups. All animals received a 12% TBSA dorsal scald full-thickness burn. The BS group was inoculated with multidrug-resistant AB (1 x 10(5) colony-forming units [CFU]) at the burn wound site. BS animals were either untreated or treated with increasing concentrations (10(3) - 19(10) CFU) of attenuated donor E. coli encoding bactericidal proteins. The survival rate was monitored for 10 days. The ability of donor cells to significantly diminish AB levels in the burn wound 24 hours after injury was determined by quantitative cultures. Donor cells were highly effective in killing AB in vitro. In the burn sepsis model, 90% B group animals survived, and 40% to 50% BS animals survived with no treatment in 5 to 6 days. Treatment with donor cells at 10(10) to 10(6) provided significant survival advantage (P < .05). Quantitative cultures of burn wounds revealed that AB numbers increased from 3 x 10(4) CFU to 7.8 +/- 4.4 x 10(9) CFU in 24 hours in the untreated group. Single treatment with donor cells (10(10) CFU) significantly reduced AB in the burn wound to less than the levels seeded into the wound (1.23 +/- 0.5 x 10(4) CFU; P < .05). Taken together, these results indicate that this novel technology is an efficient method to control drug-resistant AB burn wound infections and prevent their systemic spread.

Acinetobacter baumannii↗
PubMedDate not supplied

Immunologic responses to critical injury and sepsis.

Almost 2 million patients are admitted to hospitals in the United States each year for treatment of traumatic injuries, and these patients are at increased risk of late infections and complications of systemic inflammation as a result of injury. Host response to injury involves a general activation of multiple systems in defending the organism from hemorrhagic or infectious death. Clinicians have the capability to support the critically injured through their traumatic insult with surgery and improved critical care, but the inflammatory response generated by such injuries creates new challenges in the management of these patients. It has long been known that local tissue injury induces systemic changes in the traumatized patient that are often maladaptive. This article reviews the effects of injury on the function of immune system cells and highlights some of the clinical sequelae of this deranged inflammatory-immune interaction.

Antibody Formation↗