191 research outputs found
Heme-oxygenase-1 Induction Improves Type-1 Cardiorenal Syndrome Only In Mice With Impaired AngII-induced Lymphocyte Activation (SCID Mice)
No full textRational: The absence of lymphocyte activity protects SCID mice from AngII-induced hypertension facilitating blood pressure-induced sodium excretion, possibly via the stimulation of eNOS- and COX-2-dependent pathways. Type-1 cardiorenal syndrome (CRS-1), characterized by acute kidney dysfunction secondary to deterioration in cardiac function, is caused by renal arteriolar vasoconstriction, mediated by the activation of renin-angiotensin and sympathetic nervous systems (RAAS, SNS). Heme Oxygenase-1 (HO-1) induction improves renal function, but not renal vasoconstriction, in AngII-induced hypertension, and causes the desensitization of vascular smooth muscle to phenylephrine.
Objectives: We evaluated whether AngII resistant SCID mice develop CRS-1 as occurs in control mice, and the differential effects of HO1 induction on renal hemodynamics in CRS-1.
Methods: Post ischemic heart failure was induced in C57 and SCID mice by left anterior coronary artery ligation. Mice were divided in 4 groups: sham, myocardial infarction (MI), MI treated with cobalt protoporphyrin (CoPP), an inducer of HO-1, in the presence and absence of HO activity inhibitor, stannous mesoporphyrin (SnMP). All mice underwent echocardiography (ejection fraction, EF) and renal echoDoppler (arterial pulsatility index, K-PI) examination 30 days after surgery.
Results: EF was significantly reduced both in control and SCID mice after MI (C57: sham 0.60±0.07, MI 0.45±0.04, p<0.05; SCID: sham 0.60±0.06, MI: 0.46±0.1, p<0.01). K-PI was significantly increased in MI groups compared to sham groups (C57: sham 0.98±0.05, MI 1.12±0.11, p<0.05; SCID: sham 0.72±0.08, MI 1.37±0.37, p<0.05). HO1 induction improved renal vasoconstriction only in SCID mice (SCID K-PI: MI+CoPP 0.9±0.19 p<0.5çC57 K-PI: MI+CoPP 1.05±0.15, n.s.). In SCID mice SnMP reversed the effect of CoPP on renal vasoconstriction.
Conclusion: CRS-1 is similar in SCID and control mice and is associated with increased renal arterial resistance. HO-1 induction improves renal vasoconstriction only in SCID (AngII resistant) mice with CRS-1, suggesting that increased HO-1 activity cannot protect the kidney from AngII-induced lymphocyte activation, but only from SNS-induced vasoconstriction.
Author Disclosures: P. Pesce: None. D. Sacerdoti: None. S.R. Monu: None. K. Sodhi: None. M. Boldrin: None. N.G. Abraham: None.
Key Words: Angiotensin II • Renal circulation • Heart failur
Redox-Responsive Nanocapsules for the Spatiotemporal Release of Miltefosine in Lysosome: Protection against Leishmania
No full textLeishmaniasis, a vector-borne disease, is caused by intracellular parasite Leishmania donovani. Unlike most intracellular pathogens, Leishmania donovani are lodged in parasitophorous vacuoles and replicate within the phagolysosomes in macrophages. Effective vaccines against this disease are still under development, while the efficacy of the available drugs is being questioned owing to the toxicity for nonspecific distribution in human physiology and the reported drug-resistance developed by Leishmania donovani. Thus, a stimuli-responsive nanocarrier that allows specific localization and release of the drug in the lysosome has been highly sought after for addressing two crucial issues, lower drug toxicity and a higher drug efficacy. We report here a unique lysosome targeting polymeric nanocapsules, formed via inverse mini-emulsion technique, for stimuli-responsive release of the drug miltefosine in the lysosome of macrophage RAW 264.7 cell line. A benign polymeric backbone, with a disulfide bonding susceptible to an oxidative cleavage, is utilized for the organelle-specific release of miltefosine. Oxidative rupture of the disulfide bond is induced by intracellular glutathione (GSH) as an endogenous stimulus. Such a stimuli-responsive release of the drug miltefosine in the lysosome of macrophage RAW 264.7 cell line over a few hours helped in achieving an improved drug efficacy by 200 times as compared to pure miltefosine. Such a drug formulation could contribute to a new line of treatment for leishmaniasis.A. Das acknowledges SERB (India) Grants (CRG/2020/000492 and JCB/2017/000004) and DBT Grant (BT/PR22251/NNT/28/1274/2017) for supporting this research. N. Mukherjee acknowledges SERB (India) Grant PDF/2016/001437 and K. Das acknowledges the grant EMR/2015/001674 for supporting this research. Financial support from DST (DST/INSPIRE/03/2017/002477) is acknowledged by R.T. This manuscript bears CSMCRI registration no 7/2021.Pramanik, SK (corresponding author), CSIR Cent Salt & Marine Chem Res Inst, Bhavnagar 364002, Gujarat, India.
Mukherjee, N (corresponding author), CSIR Indian Inst Chem Biol, Canc Biol & Inflammatory Disorder Div, Kolkata 700032, India.
Chattopadhy, S (corresponding author), BITS Pilani, Pilani 403726, Goa, India.
Das, A (corresponding author), Indian Inst Sci Educ & Res Kolkata, Mohanpur 741246, W Bengal, India.
[email protected]; [email protected]; [email protected]
Recommended from our members
Identifying HIV-1 host cell factors by genome-scale RNAi screening.
No full textAdvances in the application of RNA interference (RNAi) have facilitated the establishment of systematic cell-based loss-of-function screening platforms. Widespread implementation of this technology has enabled genome-wide genetic analysis of a diverse array of cellular phenotypes, including the identification of host cell factors involved in viral replication. Four recent studies employed whole-genome RNAi technologies to elucidate cellular genes important for the replication of HIV-1. While these four genome-scale screens shared a common objective, they differ in their scope and experimental design. In this review we explore alternative strategies for developing RNAi screens, and discuss potential pitfalls of the technology. Important technical considerations include the choice of silencing reagents, experimental systems, assay readout and analysis methods. We focus on experimental and computational parameters that can impact the outcome of high-throughput genetic screens, and provide guidelines for the development of reliable cell-based RNAi screens
Nanocapsules with stimuli-responsive moieties for controlled release employing light and enzymatic triggers
No full textThe development of stimuli-responsive nanomaterials, that possess tailored functional properties for the release of specific compounds, is of particular interest. To this extent, controlling the release of molecules at the desired target is an important parameter to regulate chemical and/or biological reactions at a more profound level in a wide variety of applications. In the present work, we report on the development of dual-responsive thiourethane-urethane nanocapsules synthesizedviaan interfacial polymerization reaction executed at the droplet interface using the inverse miniemulsion technique. Evidenceviamorphological and controlled release investigations indicate that our nanocapsules are able to encapsulate hydrophilic compounds with high efficiency in their aqueous core and allow for its selective release upon exposure to UV light and the enzyme esterase. Moreover, we demonstrate the efficient encapsulation of the fragrance molecule geranyl acetate and the anticancer drug doxorubicin. For the latter, we demonstrate its apoptotic effect after being released in MCF 7 breast cancer cells. Overall, these nanocapsules can be used for a wide variety of applications where a selective release of the payload is desired.S. S. is an SB PhD Fellow at the FWO (Research Foundation Flanders). S. K. P. acknowledges BOF funding from Hasselt University. This work is supported by Hasselt University and the Research Foundation Flanders (FWO Vlaanderen; Hercules project AUHL/15/2 - GOH3816N). The authors are thankful to Prof. M. Van Bael for access to the DLS device.Pramanik, SK; Ethirajan, A (corresponding author), Hasselt Univ, Inst Mat Res IMO, Wetenschapspk 1 & Agoralaan D, B-3590 Diepenbeek, Belgium; IMEC, Associated Lab IMOMEC, Wetenschapspk 1, B-3590 Diepenbeek, Belgium;
CSIR Cent Salt & Marine Chem Res Inst, Bhavnagar 364002, Gujarat, India.
[email protected]; [email protected]
Retrovirology / HIV-1 protease cleaves the serine-threonine kinases RIPK1 and RIPK2
No full textBackground: HIV-1 protease (PR) is essential for viral infectivity as it cleaves Gag and Gag-Pol polyprotein precursors during viral maturation. Recent evidence suggests that cellular proteins can also be cleaved by PR, perhaps representing an important viral strategy to counter host defense mechanisms. Receptor-interacting protein kinase 1 (RIPK1) and RIPK2 belong to a family of serine/threonine kinases with conserved domain architecture and important functions in apoptosis, necrosis and innate immunity. Results: We found that RIPK1 and RIPK2 but not other members of the RIP kinase family are cleaved by HIV-1 PR. In RIPK1, we identified a putative PR cleavage site; a mutation at this site rendered RIPK1 resistant to PR cleavage. RIPK1 and RIPK2 were cleaved during HIV-1 infection of T cell lines or primary activated CD4+ T cells. Interfering with the viral life cycle at different stages by the addition of specific inhibitors against RT, integrase, or PR, completely prevented RIPK1 and RIPK2 cleavage. Cleavage of RIPK1 disrupted RIPK1/RIPK3 complex formation and RIPK1-mediated induction of NF-kB. Conclusions: These findings indicate that RIPK1 and RIPK2 are targets of HIV-1 PR activity during infection, and their inactivation may contribute to modulation of cell death and host defense pathways by HIV-1
Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure
No full textAntiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid viral rebound from latently infected CD4+ T cells, showing that control of viral replication alone does not fully restore immune function, nor does it eradicate viral reservoirs. With a better understanding of factors and mechanisms that promote viral latency, current approaches are primarily focused on the permanent silencing of latently infected cells (“block and lock”) or reactivating HIV-1 gene expression in latently infected cells, in combination with immune restoration strategies to eliminate HIV infected cells from the host (“shock and kill”). In this review, we provide a summary of the current, most promising approaches for HIV-1 cure strategies, including an analysis of both latency-promoting agents (LPA) and latency-reversing agents (LRA) that have shown promise in vitro, ex vivo, and in human clinical trials to reduce the HIV-1 reservoir
Determination of the weakest branch in a radial distribution network using local voltage stability indicator at the proximity of the voltage collapse point
No full text- …
