scholarly journals Pathways of Renal Involvement in COVID-19 Infection

Author(s):  
Catherin Ouseph ◽  
Praful Patil

The causative agent of the highly infectious pandemic COVID-19 is SARS-CoV-2. According to WHO, as of August 18th 2020, the number of confirmed cases was and confirmed deaths was 771,635 from 216 countries. The most affected organ system in COVID-19 is the respiratory system. Later studies proved that the virus caused multiorgan infections. Several studies shows that SARS-CoV-2 causes damage to the renal system and; critically ill patients with associated renal damage show a higher mortality rate as compared to those patients with an unaffected renal system .This review article aims at updating the knowledge about associated kidney failure in covid-19 cases and its impact on the morbidity and mortality. The virus damages the renal system through two different mechanisms: Direct and Indirect pathway. The direct pathway explains how the virus damages the renal system by directly acting upon the target cells in the kidney.SARS-CoV-2 gains its entry by binding to the ACE2 receptors on the target cell. The SARS-CoV-2 progresses its journey and extensively spread the infection, damaging the kidneys leading to the failure of the renal system. The indirect pathway of damage speaks about the secondary damage caused to the renal system due to cytokine release syndrome caused by SARS-CoV-2.This pathway also points out the formation of microthrombi in the glomerular capillaries and also kidney hypoperfusion. AKI in covid-19 patients can occur secondary to multiorgan failure. This review aims to build a foundation concerning the direct pathway and indirect pathway by means of which SARS-Cov-2 infects the kidneys by summarizing the numerous researches carried out till date to update the knowledge gained thus far to aid in building better protocols for covid-19 management and decrease morbidity caused due to renal damage.

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4596
Author(s):  
Joseph Kauer ◽  
Fabian Vogt ◽  
Ilona Hagelstein ◽  
Sebastian Hörner ◽  
Melanie Märklin ◽  
...  

T cell-recruiting bispecific antibodies (bsAbs) are successfully used for the treatment of cancer. However, effective treatment with bsAbs is so far hampered by severe side effects, i.e., potentially life-threatening cytokine release syndrome. Off-target T cell activation due to binding of bispecific CD3 antibodies to T cells in the absence of target cells may contribute to excessive cytokine release. We report here, in an in vitro setting, that off-target T cell activation is induced by bsAbs with high CD3 binding affinity and increased by endothelial- or lymphoid cells that act as stimulating bystander cells. Blocking antibodies directed against the adhesion molecules CD18/CD54 or CD2/CD58 markedly reduced this type of off-target T cell activation. CD18 blockade—in contrast to CD2—did not affect the therapeutic activity of various bsAbs. Since CD18 antibodies have been shown to be safely applicable in patients, blockade of this integrin holds promise as a potential target for the prevention of unwanted off-target T cell activation and allows the application of truly effective bsAb doses.


2021 ◽  
Vol 92 (8) ◽  
pp. A6.1-A6
Author(s):  
Akshay Nair ◽  
Adeel Razi ◽  
Sarah Gregory ◽  
Robb Rutledge ◽  
Geraint Rees ◽  
...  

BackgroundThe gating of movement in humans is thought to depend on activity within the cortico-striato-thalamic loops. Within these loops, emerging from the cells of the striatum, run two opponent pathways the direct and indirect pathway. Both are complex and polysynaptic but the overall effect of activity within these pathways is to encourage and inhibit movement respectively. In Huntingtons disease (HD), the preferential early loss of striatal neurons forming the indirect pathway is thought to lead to disinhibition that gives rise to the characteristic motor features of the condition. But early HD is also specifically associated with apathy, a failure to engage in goal-directed movement. We hypothesised that in HD, motor signs and apathy may be selectively correlated with indirect and direct pathway dysfunction respectively.MethodsUsing a novel technique for estimating dynamic effective connectivity of the basal ganglia, we tested both of these hypotheses in vivo for the first time in a large cohort of patients with prodromal HD (n = 94). We used spectral dynamic casual modelling of resting state fMRI data to model effective connectivity in a model of these cortico-striatal pathways. We used an advanced approach at the group level by combining Parametric Empirical Bayes and Bayesian Model Reduction procedure to generate large number of competing models and compare them by using Bayesian model comparison.ResultsWith this fully Bayesian approach, associations between clinical measures and connectivity parameters emerge de novo from the data. We found very strong evidence (posterior probability > 0.99) to support both of our hypotheses. Firstly, more severe motor signs in HD were associated with altered connectivity in the indirect pathway and by comparison, loss of goal-direct behaviour or apathy, was associated with changes in the direct pathway component of our model.ConclusionsThe empirical evidence we provide here is the first in vivo demonstration that imbalanced basal ganglia connectivity may play an important role in the pathogenesis of some of commonest and disabling features of HD and may have important implications for therapeutics.


Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 414
Author(s):  
Elizaveta A. Dutysheva ◽  
Marina A. Mikeladze ◽  
Maria A. Trestsova ◽  
Nikolay D. Aksenov ◽  
Irina A. Utepova ◽  
...  

Traumatic brain injury (TBI) often causes massive brain cell death accompanied by the accumulation of toxic factors in interstitial and cerebrospinal fluids. The persistence of the damaged brain area is not transient and may occur within days and weeks. Chaperone Hsp70 is known for its cytoprotective and antiapoptotic activity, and thus, a therapeutic approach based on chemically induced Hsp70 expression may become a promising approach to lower post-traumatic complications. To simulate the processes of secondary damage, we used an animal model of TBI and a cell model based on the cultivation of target cells in the presence of cerebrospinal fluid (CSF) from injured rats. Here we present a novel low molecular weight substance, PQ-29, which induces the synthesis of Hsp70 and empowers the resistance of rat C6 glioma cells to the cytotoxic effect of rat cerebrospinal fluid taken from rats subjected to TBI. In an animal model of TBI, PQ-29 elevated the Hsp70 level in brain cells and significantly slowed the process of the apoptosis in acceptor cells in response to cerebrospinal fluid action. The compound was also shown to rescue the motor function of traumatized rats, thus proving its potential application in rehabilitation therapy after TBI.


2020 ◽  
pp. 108886832096189
Author(s):  
Rebecca M. Walsh ◽  
Amanda L. Forest

Garnering support for distressing experiences is highly important, yet notoriously challenging. We examine whether expressing positive thoughts and feelings when seeking support for negative events can help people elicit support, and we present a theoretical process model that explains why it might do so. The model includes three support-eliciting pathways through which expressing positivity could increase support: by strengthening providers’ prorelational motives, increasing providers’ positive mood, and enhancing providers’ expected support effectiveness. It also includes a support-suppressing pathway through which expressing positivity could decrease support: by undermining providers’ appraisals of support seekers’ needs. After presenting the model and providing evidence for each indirect pathway, we review research regarding the direct pathway. We then consider various types of positivity, discuss possible moderators, and identify directions for future research. Our model highlights support seekers’ underemphasized role in shaping support receipt and provides a novel perspective on positive expressivity’s potential value in distress-related contexts.


1992 ◽  
Vol 83 (6) ◽  
pp. 677-682
Author(s):  
R. F. G. J. King ◽  
M. Madan ◽  
D. Alexander ◽  
A. Boyd ◽  
K. Ibrahim ◽  
...  

1. This study was designed to test the hypothesis that three-carbon intermediates can be used in the ‘indirect’ pathway of glycogen synthesis in human liver (i.e. a route additional to the use of glucose by the ‘direct’ pathway). 2. After an overnight fast, 13 patients were given an infusion of 20% (w/v) glucose before elective abdominal operation. All received a 2.5 g bolus of 2220 kBq of selectively 3H- and 14C-labelled glucose before removal of a 1 g biopsy of liver. 3H and 14C were determined in purified glycogen as well as in glucose and lactate from samples of peripheral blood. 3. The ratio and specific activities of 3H and 14C in glycogen were found to be significantly lower than those in administered glucose. By calculation, 7–74% of glycogen repletion occurred by indirect pathways and not all of this was from the glucose supplied. 4. This study suggests that the operation of a direct pathway in man is not exclusive and that significant repletion of hepatic glycogen occurs by an indirect route.


1999 ◽  
Vol 277 (5) ◽  
pp. E815-E823 ◽  
Author(s):  
F. Fery ◽  
L. Plat ◽  
E. O. Balasse

The effects of fasting on the pathways of insulin-stimulated glucose disposal were explored in three groups of seven normal subjects. Group 1 was submitted to a euglycemic hyperinsulinemic clamp (∼100 μU/ml) after both a 12-h and a 4-day fast. The combined use of [3-3H]- and [U-14C]glucose allowed us to demonstrate that fasting inhibits, by ∼50%, glucose disposal, glycolysis, glucose oxidation, and glycogen synthesis via the direct pathway. In group 2, in which the clamp glucose disposal during fasting was restored by hyperglycemia (155 ± 15 mg/dl), fasting stimulated glycogen synthesis (+29 ± 2%) and inhibited glycolysis (−32 ± 3%) but only in its oxidative component (−40 ± 3%). Results were similar in group 3 in which the clamp glucose disposal was restored by a pharmacological elevation of insulin (∼2,800 μU/ml), but in this case, both glycogen synthesis and nonoxidative glycolysis participated in the rise in nonoxidative glucose disposal. In all groups, the reduction in total carbohydrate oxidation (indirect calorimetry) induced by fasting markedly exceeded the reduction in circulating glucose oxidation, suggesting that fasting also inhibits intracellular glycogen oxidation. Thus prior fasting favors glycogen retention by three mechanisms: 1) stimulation of glycogen synthesis via the direct pathway; 2) preferential inhibition of oxidative rather than nonoxidative glycolysis, thus allowing carbon conservation for glycogen synthesis via the indirect pathway; and 3) suppression of intracellular glycogen oxidation.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1397-1397 ◽  
Author(s):  
Rayne H. Rouce ◽  
Takuya Sekine ◽  
Gerrit Weber ◽  
Claude Chew ◽  
Katayoun Rezvani ◽  
...  

Abstract Background Natural killer (NK) cells are a key component of innate immunity, with the potential to recognize and kill transformed malignant cells without prior sensitization. A balance between activating and inhibitory signals from cell surface receptors determines NK cell cytotoxicity and cytokine release. Therapeutic approaches to augmenting NK cell function are being explored in various malignancies. Little is known about NK phenotype and function in patients with childhood acute lymphoblastic leukemia (ALL), the most common childhood cancer. Here we describe an inhibitory phenotype and impaired cytolytic function in NK cells from pediatric ALL patients at diagnosis, compared with healthy pediatric controls. Restoring NK function may be a useful therapeutic approach in ALL. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 25 patients with newly diagnosed B-ALL, age 1-16 years, and 7 healthy controls, age 2-13 years, in order to compare NK cell frequency, immunophenotype, and functional activity. NK frequency was assessed by flow cytometric staining for CD56+CD3- cells. NK phenotype was assessed by surface expression of activating receptors NKp30, NKp44, NKp46 and NKG2D and inhibitory receptors KIR2DL1/S1, KIR2DL2/S2, KIR3DL1 and NKG2A. Functional activity was determined by incubation of NKs with target cells, followed by flow cytometric measurement of degranulation (surface CD107a) and cytokine release (intracellular IFNg and TNFa). Targets included the MHC class I deficient K562 cell line and, where available, autologous ALL blasts. Results ALL patients demonstrated significantly lower absolute NK cell counts compared with healthy controls (mean absolute count 168 vs. 406 cells/uL, p = 0.0002). They also exhibited significantly fewer NK cells expressing the activating marker NKp46 (mean absolute count 70 vs. 165, p = 0.016); and a significantly higher percentage of cells expressing the inhibitory marker NKG2A (mean 20.5% vs. 1.95% in controls, p = 0.012) (Fig 1A). In co-culture assays with K562 target cells, ALL patients' NK cells demonstrated inferior degranulation and cytokine release compared to healthy controls (representative data in Fig 1B; mean IFNγ production of 1.2% vs. 4.8%, p = 0.02; mean TNFα production of 1.8% vs. 3.8%, p = 0.06; and mean surface CD107a of 5.4% vs. 15.1%, p = 0.08). ALL samples (n = 3) demonstrated little to no cytokine release when incubated with autologous blasts compared with the response elicited by PMA-ionomycin (representative data in Fig 1C; mean CD107a 0.92% vs. 7.85%, p = 0.04; mean IFNγ 0.26% vs 40.47%, p = 0.10; mean TNFα 0.2% vs 41%, p = 0.008). Conclusion At diagnosis, pediatric ALL patients exhibit a lower frequency of NK cells, an inhibitory phenotype, and decreased cytolytic activity compared to healthy pediatric controls, particularly against autologous leukemic blasts. These results suggest that augmentation of the NK response may be useful therapeutically to improve outcomes in childhood ALL. Disclosures: No relevant conflicts of interest to declare.


2015 ◽  
Vol 112 (36) ◽  
pp. 11383-11388 ◽  
Author(s):  
Takashi Yamaguchi ◽  
Akihiro Goto ◽  
Ichiro Nakahara ◽  
Satoshi Yawata ◽  
Takatoshi Hikida ◽  
...  

The nucleus accumbens (NAc) serves as a key neural substrate for aversive learning and consists of two distinct subpopulations of medium-sized spiny neurons (MSNs). The MSNs of the direct pathway (dMSNs) and the indirect pathway (iMSNs) predominantly express dopamine (DA) D1 and D2 receptors, respectively, and are positively and negatively modulated by DA transmitters via Gs- and Gi-coupled cAMP-dependent protein kinase A (PKA) signaling cascades, respectively. In this investigation, we addressed how intracellular PKA signaling is involved in aversive learning in a cell type-specific manner. When the transmission of either dMSNs or iMSNs was unilaterally blocked by pathway-specific expression of transmission-blocking tetanus toxin, infusion of PKA inhibitors into the intact side of the NAc core abolished passive avoidance learning toward an electric shock in the indirect pathway-blocked mice, but not in the direct pathway-blocked mice. We then examined temporal changes in PKA activity in dMSNs and iMSNs in behaving mice by monitoring Förster resonance energy transfer responses of the PKA biosensor with the aid of microendoscopy. PKA activity was increased in iMSNs and decreased in dMSNs in both aversive memory formation and retrieval. Importantly, the increased PKA activity in iMSNs disappeared when aversive memory was prevented by keeping mice in the conditioning apparatus. Furthermore, the increase in PKA activity in iMSNs by aversive stimuli reflected facilitation of aversive memory retention. These results indicate that PKA signaling in iMSNs plays a critical role in both aversive memory formation and retention.


2009 ◽  
Vol 9 ◽  
pp. 1321-1344 ◽  
Author(s):  
César Quiroz ◽  
Rafael Luján ◽  
Motokazu Uchigashima ◽  
Ana Patrícia Simoes ◽  
Talia N. Lerner ◽  
...  

Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1and D2receptors, respectively. Adenosine A2Areceptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2Areceptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2Areceptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2Areceptors could provide a new target for the treatment of neuropsychiatric disorders.


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