The Role of Integrin α<Subscript>4</Subscript>β<Subscript>7</Subscript> in HIV Pathogenesis and Treatment

Purpose of Review

Acute HIV infection is characterized by high-level viral replication throughout the body’s lymphoid system, particularly in gut-associated lymphoid tissues resulting in damage to structural components of gut tissue. This damage is irreversible and believed to contribute to the development of immune deficiencies. Antiretroviral therapy (ART) does not restore gut structure and function. Studies in macaques point to an alternative treatment strategy that may ameliorate gut damage. Integrin α₄β₇ mediates the homing of lymphocytes to gut tissues. Vedolizumab, a monoclonal antibody (mAb) antagonist of α₄β₇, has demonstrated efficacy and has been approved for the treatment of inflammatory bowel disease in humans. Here, we describe our current knowledge, and the gaps in our understanding, of the role of α₄β₇ in HIV pathogenesis and treatment.

Recent Findings

When administered to macaques prior to infection, a nonhuman primate analogue of vedolizumab prevents transmission of SIV. In combination with ART, this mAb facilitates durable virologic control following treatment interruption.

Summary

Targeting α₄β₇ represents a novel therapeutic approach to prevent and treat HIV infection.

     

Interaction of Afobazole with σ<Subscript>1</Subscript>-Receptors

The capacity of living systems to perceive low-intensity stimuli sometimes inducing protective reactions is still little studied. Incubation of neurons under conditions increasing the content of cAMP and Ca²⁺ increases the amplitude of their responses to lidocaine (10⁻³ M). After cell preconditioning with low concentrations of lidocaine (10⁻¹⁵ M) under these conditions, the protective effects of “ineffective” concentrations were detected, because the response amplitude did not decrease. It was hypothesized that the basic amplitude responses retrieved by lidocaine in a concentration of 10⁻³ M are memory traces about the effects of this compound in subthreshold concentrations. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 147, No. 1, pp. 43-46, January, 2009     

Role of Intracellular Calcium and Cyclic Nucleotides in Realization of Cardioprotective Effects of δ<Subscript>1</Subscript>- and κ<Subscript>1</Subscript>-Opioid Receptor Agonists

The role of cyclic nucleotides (cAMP, cGMP) and Ca²⁺-ATPase of the sarcoplasmic reticulum in the mechanism of cardioprotective effects of selective δ₁- and κ₁-opioid receptor agonists DPDPE and U-50488 was studied under conditions of global ischemia and reperfusion of isolated and perfused rat heart. Activation of both types of opioid receptors 2-fold reduced the reperfusion release of creatine phosphokinase. The cardioprotective effect of U-50488 was paralleled by a 2-fold decrease in cAMP content in the myocardium, while DPDPE did not modify the content of cAMP throughout the experiment. None of these substances changed the content of cGMP in the myocardium. The cardioprotective effect of DPDPE was not observed after inhibition of sarcoplasmic reticulum Ca²⁺-ATPase with cyclopiazonic acid. The cardioprotective effect of U-50488 was associated with reduction of cAMP level in the myocardium, while the cytoprotective effect of DPDPE was mediated by opioidergic modulation of Ca²⁺ transport at the level of the sarcoplasmic reticulum.     

A Singular Role of I<Subscript>K1</Subscript> Promoting the Development of Cardiac Automaticity during Cardiomyocyte Differentiation by I<Subscript>K1</Subscript><Emphasis Type="Bold">–</Emphasis>Induced Activation of Pacemaker Current

The inward rectifier potassium current (I_K1) is generally thought to suppress cardiac automaticity by hyperpolarizing membrane potential (MP). We recently observed that I_K1 could promote the spontaneously-firing automaticity induced by upregulation of pacemaker funny current (I_f) in adult ventricular cardiomyocytes (CMs). However, the intriguing ability of I_K1 to activate I_f and thereby promote automaticity has not been explored. In this study, we combined mathematical and experimental assays and found that only I_K1 and I_f, at a proper-ratio of densities, were sufficient to generate rhythmic MP-oscillations even in unexcitable cells (i.e. HEK293T cells and undifferentiated mouse embryonic stem cells [ESCs]). We termed this effect I_K1-induced I_f activation. Consistent with previous findings, our electrophysiological recordings observed that around 50% of mouse (m) and human (h) ESC-differentiated CMs could spontaneously fire action potentials (APs). We found that spontaneously-firing ESC-CMs displayed more hyperpolarized maximum diastolic potential and more outward I_K1 current than quiescent-yet-excitable m/hESC-CMs. Rather than classical depolarization pacing, quiescent mESC-CMs were able to fire APs spontaneously with an electrode-injected small outward-current that hyperpolarizes MP. The automaticity to spontaneously fire APs was also promoted in quiescent hESC-CMs by an I_K1-specific agonist zacopride. In addition, we found that the number of spontaneously-firing m/hESC-CMs was significantly decreased when I_f was acutely upregulated by Ad-CGI-HCN infection. Our study reveals a novel role of I_K1 promoting the development of cardiac automaticity in m/hESC-CMs through a mechanism of I_K1-induced I_f activation and demonstrates a synergistic interaction between I_K1 and I_f that regulates cardiac automaticity.     

Histochemical study of mast cells from the thymus of mice receiving ACTH<Subscript>1–24</Subscript>

Synthetic ACTH_1–24 analogue administered in a daily dose of 0.01 mg/kg decreased the number and size of mast cells and increased intracellular serotonin concentration. ACTH_1–24 induced degranulation of young mast cells and release of undersulfated heparin. Correlation analysis showed that hormonal imbalance produced by ACTH_1–24 was accompanied by redistribution of bioamines. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 138, No. 7, pp. 107–110, July, 2004     

The differential contribution of dopamine D<Subscript>1</Subscript> and D<Subscript>2</Subscript> receptors to μ-opioidergic immunomodulation

Activation of μ-opioid receptors (μ-OR) by the highly selective agonist DAGO (100 μg/kg) significantly increased the immune response in CBA mice. This effect of the μ agonist was prevented by prior blockade of dopamine D₂ receptors with haloperidol (2 mg/kg). In contrast, the selective D₁ receptor antagonist SCH 23390 (1 mg/kg) had no effect on the nature of the immune reaction in response to antigen (sheep erythrocytes, 5·10⁸ cells). However, blockade of both types of dopamine receptor led to the same effect-immunosuppression. These data lead to the suggestion that D₁ and D₂ receptors make different contributions to modulating immunogenesis on activation of μ-OR. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 92, No. 5, pp. 546–551, May, 2006.     

Effect of IFN-α on CC1<Subscript>4</Subscript>-Induced Fibrosis of the Liver and Immune Status in Mice of Different Age

In young, adult, and old mice fibrosis was induced by administration of CC1₄ and treated with IFN-α. Liver fibrosis was evaluated by morphometry of argyrophilic fibers, immune status by the splenocyte proliferative response. Minimum immunosuppression and maximum antifibrotic effect were observed in young mice, while adult mice exhibited pronounced immunotoxicity and weak response to interferon therapy.__________Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 139, No. 3, pp. 303–306, March, 2005     

Opioid Peptide Deltorphin II Simulates the Cardioprotective Effect of Ischemic Preconditioning: Role of δ<Subscript>2</Subscript>-Opioid Receptors,Protein Kinase C,and K<Subscript>ATP</Subscript> Channels

The cardioprotective properties of a δ₂-opioid receptor agonist deltorphin II were studied in rats with coronary occlusion and reperfusion. Opioid receptor ligands and inhibitors (glybenclamide, chelerythrine, and 5-hydroxydecanoate) were injected intravenously before ischemia and reperfusion. A δ₂-opioid receptor agonist deltorphin II signifi cantly decreased the infarction zone/risk zone index. This effect was abolished by naltrexone, naloxone methiodide, and δ₂-opioid receptor antagonist naltriben, but not by a δ₁-opioid receptor antagonist BNTX. The infarct-limiting effect of deltorphin II was not observed after inhibition of protein kinase C or blockade of mitochondrial K_ATP channels.     

Effects of α<Subscript>1</Subscript>-acid glycoprotein on hemostasis in experimental septic peritonitis

Pathogenesis of hemostasis disorders in septic peritonitis and the possibility of their correction with acute phase protein (α₁-acid glycoprotein; two doses of 150 mg/kg) were experimentally studied on outbred albino rats. Platelets count in the peripheral blood and their adhesion to endothelium did not change during peritonitis, while aggregation activity increased due to increased rate and shorter time of aggregation, which was associated with the development of hypercoagulation involving the intrinsic and common coagulation pathways and reduction of antithrombin activity. α₁-Acid glycoprotein increased platelet count above the normal level, normalized aggregation rate, some blood clotting parameters, and antithrombin activity. Hence, α₁-acid glycoprotein is a polyfunctional protein modulating all pathogenetic components in the development of blood clotting disorders during septic peritonitis. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 8, pp. 143–145, August, 2007     

Cardioprotective effect of κ<Subscript>1</Subscript>-opioid receptor activation and role of cAMP in its realization

The cardioprotective and antiarrhythmic effects of a selective κ₁-opioid receptor agonist U-50,488 were studied during experimental 45-min total ischemia and 30-min reperfusion of isolated rat heart. The opioid had no effect on the incidence and type of reperfusion arrhythmias. U-50,488 in a concentration of 0.1 μM inhibited reperfusion-induced release of creatine phosphokinase and decreased cAMP concentration in the myocardium by 2 times. These parameters remained unchanged after treatment with U-50,488 in a concentration of 1 μM. The cardioprotective effect of U-50,488 was probably associated with a decrease in cAMP concentration in heart cells. U-50,488 in a concentration of 1 μM produced no cardioprotective effect, which can be explained by its interaction with an unknown non-opioid receptor in cardiomyocytes. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 1, pp. 28–31, January, 2007     

Effect of an α<Subscript>1</Subscript>-adrenergic blocker on plasticity elicited by motor training

Recovery of motor function elicited by motor training after cortical lesions in rats is enhanced by norepinephrine (neurotransmitter mediating α₁-adrenergic function) and downregulated by α₁-adrenergic antagonists. In spite of this, α₁-adrenergic antagonists are used to treat elderly patients with hypertension and prostate hyperplasia in stroke settings. The purpose of this study was to determine the effects of a single oral dose of the α₁-adrenergic antagonist prazosin on training-dependent plasticity in intact humans, a function thought to contribute to recovery of motor function after cortical lesions. We report that prazosin decreased the ability of motor training to elicit training-dependent plasticity relative to a drug-free condition. These data suggest caution when using α₁-adrenergic blockers in rehabilitative clinical settings following brain lesions. Electronic Publication     

Renal β<Subscript>2</Subscript>-adrenoceptor Modulates the Lipopolysaccharide Transport System in Sepsis-induced Acute Renal Failure

The aim of this study was to define the contribution of renal β₂-adrenoceptor (β₂-AR) system to regulation of the lipopolysaccharide (LPS) transport system in the kidney of endotoxin-induced septic rats. Seven-week-old Wistar rats (n = 6/groups) pre-treated with the β₂-AR antagonist (ICI118,551: 3.14 μg/kg) or saline were injected with LPS (10 mg/kg i.p.) or saline, and then 24 hours later, renal function, β₂-AR signaling proteins, innate immune proteins, and cytokines were assayed. The injection of LPS depressed creatinine clearance rate (Ccr) associated with the reduction of renal Gsα and cAMP levels by a single dose of ICI118,551. On the other hand, renal CD14, toll-like receptor 4(TLR4), and tumour necrosis factor (TNF)-α protein expressions were significantly increased (P < 0.05) by the combination of LPS and ICI118,551. The reduction of Ccr by LPS plus ICI118,551 suggests a possibility that renal specific up-regulation of the CD14-TLR4-TNF-α signaling cascade by β₂-AR inhibition might be involved in sepsis-induced ARF.     

β<Subscript>III</Subscript>-tubulin at the invasive margin of colorectal cancer: possible link to invasion

Cell locomotion, including cancer cell invasion, is closely associated with the dynamics of cytoskeletal structures. Previous in vitro studies indicated that tubulin isotype composition may affect polymerization properties and dynamics of microtubules. Colorectal cancer is a good model for studying tumour invasion because of the easily detectable invasive front. Hence, we investigated the localization of β_III-tubulin in colorectal cancer specimens. Immunohistochemical staining for β_III-tubulin was evident in cancer cells apparently budding from adjacent malignant cells with a higher differentiation and negative staining. An association between β_III-tubulin immunoreactivity and tumour budding grade was demonstrated. To the best of our knowledge, this is the first report documenting a preferential localization of β_III-tubulin in the invading epithelium. From this finding arises the possibility that changes in tubulin isotypes could modulate the invading activity of cancer cells. Further investigations are needed to determine whether our findings have clinical implications.     

Arg25Pro polymorphism of transforming growth factor-β<Subscript>1</Subscript> and its role in the pathogenesis of essential hypertension in Russian population of the Central Chernozem Region

We studied the relationship between Arg25Pro polymorphism of TGFb1 gene and predisposition to essential hypertension in the Russian population of Central Chernozem Region (n=402). An association was found between 25Pro allele and 25ArgPro genotype with low risk of essential hypertension in male individuals. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 7, pp. 72–74, July, 2007     

Estimation of<Emphasis Type="Italic"> V̇</Emphasis>O<Subscript>2max</Subscript> from the ratio between HR<Subscript>max </Subscript>and HR<Subscript>rest</Subscript> – the Heart Rate Ratio Method

The effects of ̇raining and/or ageing upon maximal oxygen uptake (O_2max) and heart rate values at rest (HR_rest) and maximal exercise (HR_max), respectively, suggest a relationship between O_2max and the HR_max-to-HR_rest ratio which may be of use for indirect testing of O_2max. Fick principle calculations supplemented by literature data on maximum-to-rest ratios for stroke volume and the arterio-venous O₂ difference suggest that the conversion factor between mass-specific O_2max (ml·min^–1·kg^–1) and HR_max·HR_rest ^–1 is ~15. In the study we experimentally examined this relationship and evaluated its potential for prediction of O_2max. O_2max was measured in 46 well-trained men (age 21–51 years) during a treadmill protocol. A subgroup (n=10) demonstrated that the proportionality factor between HR_max·HR_rest ^–1 and mass-specific O_2max was 15.3 (0.7) ml·min^–1·kg^–1. Using this value, O_2max in the remaining 36 individuals could be estimated with an SEE of 0.21 l·min^–1 or 2.7 ml·min^–1·kg^–1 (~4.5%). This compares favourably with other common indirect tests. When replacing measured HR_max with an age-predicted one, SEE was 0.37 l·min^–1 and 4.7 ml·min^–1·kg^–1 (~7.8%), which is still comparable with other indirect tests. We conclude that the HR_max-to-HR_rest ratio may provide a tool for estimation of O_2max in well-trained men. The applicability of the test principle in relation to other groups will have to await direct validation. O_2max can be estimated indirectly from the measured HR_max-to-HR_rest ratio with an accuracy that compares favourably with that of other common indirect tests. The results also suggest that the test may be of use for O_2max estimation based on resting measurements alone.An erratum to this article can be found at     

Overshoot in <Emphasis Type="Italic">V̇</Emphasis>O<Subscript>2</Subscript> following the onset of moderate-intensity cycle exercise in trained cyclists

We have previously observed that following the onset of moderate intensity cycle ergometry, the pulmonary O₂ uptake (O₂) in trained cyclists often does not increase towards its steady-state value with the typical mono-exponential characteristics; rather, there is a transient overshoot. The purpose of this study was to systematically examine this phenomenon by comparing the O₂responses to two moderate-intensity work rates and one high-intensity work rate in trained and untrained subjects. Following a ramp exercise test to the limit of tolerance for the determination of the gas exchange threshold (GET) and O_2peak, seven trained cyclists [mean (SD); O_2peak 66.6 (2.5) ml·kg^–1·min^–1] and eight sedentary subjects [O_2peak 42.9 (5.1) ml·kg^–1·min^–1] completed six step transitions from baseline cycling to work rates requiring 60% and 80% GET and three step transitions from baseline cycling to a work rate requiring 50% of the difference between GET and O_2peak (50%). O₂ was measured breath-by-breath and modelled using standard techniques. The sedentary subjects did not overshoot the steady-state O₂ at any intensity. At 60% GET, six of the seven cyclists overshot the steady-state O₂ [by an integral volume of 164 (44) ml between ~45 and 125 s]. At 80% GET, four of the seven cyclists overshot the steady-state O₂ [by an integral volume of 185 (92) ml between ~55 and 140 s]. None of the cyclists showed an overshoot at 50%. These results indicate that trained cyclists evidence an overshoot in O₂ before steady-state is reached in the transition to moderate-intensity exercise. The mechanism(s) responsible for this effect remains to be elucidated, as does whether the overshoot confers any functional or performance benefit to the trained cyclist.     

Negative regulation of caspase-3 expression in the neonatal cerebral cortex by α<Subscript>2A</Subscript>-adrenoceptors

Antisense oligonucleotide to α_2A-adrenoceptors increased the levels of mRNA (reverse polymerase chain reaction) and protein for a key executioner protease of apoptosis caspase-3 (immunoblotting assay) in the cerebral cortex of newborn rats. The relationship between the observed effect and low expression of α₂-adrenoceptors was confirmed by the possibility of correcting this phenomenon by clonidine (stimulator of α₂-adrenoceptors). __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 3, pp. 244–246, March, 2007     

15-Deoxy-Δ<Superscript>12,14</Superscript>-Prostaglandin J<Subscript>2</Subscript> and Curcumin Modulate the Expression of Toll-like Receptors 4 and 9 in Autoimmune T Lymphocyte

Introduction

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model for multiple sclerosis (MS). We have shown earlier that 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) and curcumin ameliorate EAE by modulating inflammatory signaling pathways in T lymphocytes. Toll-like receptors (TLRs), expressed primarily in innate immune cells, play critical roles in the pathogenesis of EAE. T lymphocytes also express TLRs and function as costimulatory receptors to upregulate proliferation and cytokine production in response to specific agonists.

Discussion

In this study, we show that naïve CD4⁺ and CD8⁺ T cells express detectable levels of TLR4 and TLR9 and that increase after the induction of EAE in SJL/J and C57BL/6 mice by immunization with PLPp139–151 and MOGp35–55 antigen, respectively. It is interesting to note that in vivo treatment with 15d-PGJ2 or curcumin results in a significant decrease in TLR4 and TLR9 expression in CD4⁺ and CD8⁺ T cells in association with the amelioration of EAE.

Conclusion

Although the exact mechanisms are not known, the modulation of TLR expression in T lymphocytes by 15d-PGJ₂ and curcumin suggests new therapeutic targets in the treatment of T cell-mediated autoimmune diseases.

     

Effects of α<Subscript>1</Subscript>-acid glycoprotein on free radical oxidation processes in experimental liver failure

The effects of α₁-acid glycoprotein (2 intraperitoneal injections in a total dose of 300 mg/kg) on free radical oxidation during liver failure were studied in 53 outbred rats. On day 3 of liver failure, glycoprotein reduced plasma concentrations of free radical oxidation products, elevated the antioxidant potential of the plasma and liver and kidney homogenates, and restored functional reserve and capacity of leukocytes to generation of oxygen radicals. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 7, pp. 29–31, July, 2007