scholarly journals New Insights in the Pathogenesis of Cisplatin-Induced Nephrotoxicity

2019 ◽  
Vol 0 (0) ◽  
Author(s):  
Bojana Djokovic ◽  
Marina Gazdic Jankovic ◽  
C. Randall Harrell ◽  
Crissy Fellabaum ◽  
Nebojsa Arsenijevic ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
High Dose ◽  
Salt Wasting ◽  
New Therapeutic Approaches ◽  
Forced Diuresis ◽  
Proximal Tubular Epithelial Cells ◽  
Urinary Concentrating Ability

Abstract Cisplatin (cis-diamminedichloroplatinum II) is a widely used chemotherapeutic agent. However, efficacy and clinical utility of this drug is significantly limited by severe side effects such as nephrotoxicity which develops due to renal accumulation and bio-transformation in proximal tubular epithelial cells. Cisplatin-induced nephrotoxicity can be manifested as acute kidney injury (AKI), or as different types of tubulopathies, salt wasting, loss of urinary concentrating ability, and magnesium wasting. The attenuation of cisplatin-caused AKI is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis. However, mannitol treatment causes over-diuresis and consequent dehydration, indicating an urgent need for the clinical use of newly designed, safe and efficacious renoprotective drug, as an additive therapy for high dose cisplatin-treated patients. Accordingly, we emphasized current knowledge regarding molecular mechanisms responsible for cisplatin-caused nephrotoxicity and we described in detail the main clinical manifestations of cisplatin-induced renal dysfunction in order to pave the way for the design of new therapeutic approaches that can minimize detrimental effects of cisplatin in the kidneys. Having in mind that most of cisplatin-induced cytotoxic effects against renal cells are, at the same time, involved in anti-tumor activity of cisplatin, new nephroprotective therapeutic strategies have to prevent renal injury and inflammation without affecting cisplatin-induced toxicity against malignant cells.

scholarly journals Lyme Neuroborreliosis: Mechanisms of B. burgdorferi Infection of the Nervous System

2021 ◽  
Vol 11 (6) ◽  
pp. 789
Author(s):  
Lenzie Ford ◽  
Danielle M. Tufts
Keyword(s):  
United States ◽  
Nervous System ◽  
Antibiotic Treatment ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
The United States ◽  
Sensu Stricto ◽  
Lyme Neuroborreliosis

Lyme borreliosis is the most prevalent tick-borne disease in the United States, infecting ~476,000 people annually. Borrelia spp. spirochetal bacteria are the causative agents of Lyme disease in humans and are transmitted by Ixodes spp ticks. Clinical manifestations vary depending on which Borrelia genospecies infects the patient and may be a consequence of distinct organotropism between species. In the US, B. burgdorferi sensu stricto is the most commonly reported genospecies and infection can manifest as mild to severe symptoms. Different genotypes of B. burgdorferi sensu stricto may be responsible for causing varying degrees of clinical manifestations. While the majority of Lyme borreliae-infected patients fully recover with antibiotic treatment, approximately 15% of infected individuals experience long-term neurological and psychological symptoms that are unresponsive to antibiotics. Currently, long-term antibiotic treatment remains the only FDA-approved option for those suffering from these chronic effects. Here, we discuss the current knowledge pertaining to B. burgdorferi sensu stricto infection in the central nervous system (CNS), termed Lyme neuroborreliosis (LNB), within North America and specifically the United States. We explore the molecular mechanisms of spirochete entry into the brain and the role B. burgdorferi sensu stricto genotypes play in CNS infectivity. Understanding infectivity can provide therapeutic targets for LNB treatment and offer public health understanding of the B. burgdorferi sensu stricto genotypes that cause long-lasting symptoms.

scholarly journals Moderate aging does not exacerbate cisplatin-induced kidney injury or fibrosis despite altered inflammatory cytokine expression and immune cell infiltration

2019 ◽  
Vol 316 (1) ◽  
pp. F162-F172 ◽  
Author(s):  
Cierra N. Sharp ◽  
Mark Doll ◽  
Tess V. Dupre ◽  
Levi J. Beverly ◽  
Leah J. Siskind
Keyword(s):  
Acute Kidney Injury ◽  
Risk Factor ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Current Knowledge ◽  
Kidney Injury ◽  
Cell Infiltration ◽  
High Dose ◽  
Immune Cell Infiltration ◽  
Old Mice

Aging is a risk factor for certain forms of kidney injury due to normal physiological changes, but the role of aging in cisplatin-induced kidney injury is not well defined in humans or animal models of the disease. To improve on current knowledge in this field, we treated 8- and 40-wk-old FVB/n mice with one high dose of cisplatin as a model of acute kidney injury or with repeated low doses of cisplatin (7 mg/kg cisplatin once a week for 4 wk) as a clinically relevant model of chronic kidney disease to determine if aging exacerbates cisplatin-induced kidney injury. Levels of acute kidney injury were comparable in 8- and 40-wk-old mice. In 40-wk-old mice, fibrotic markers were elevated basally, but treatment with cisplatin did not exacerbate fibrosis. We concluded that this may be the result of a decreased inflammatory response in 40-wk-old cisplatin-treated mice compared with 8-wk-old mice. Despite a decreased inflammatory response, the level of immune cell infiltration was greater in 40-wk-old cisplatin-treated mice than 8-wk-old mice. Our data highlight the importance of examining age as a risk factor for cisplatin-induced kidney injury.

Rare Ginsenoside 20(R)-Rg3 Inhibits D-Galactose-Induced Liver and Kidney Injury by Regulating Oxidative Stress-Induced Apoptosis

2020 ◽  
Vol 48 (05) ◽  
pp. 1141-1157 ◽  
Author(s):  
Wei Li ◽  
Jian-Qiang Wang ◽  
Yan-Dan Zhou ◽  
Jin-Gang Hou ◽  
Ying Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Treated Group ◽  
High Dose ◽  
Lipid Peroxidation Product ◽  
Stress Injury ◽  
Beneficial Effects ◽  
Liver And Kidney ◽  
Induced Apoptosis

Oxidative stress is considered as a major factor in aging and exacerbates aging process through a variety of molecular mechanisms. D-galactose, a normal reducing sugar with high dose can cause the accumulation of reactive oxygen species (ROS) or stimulate free radical production indirectly by the formation of advanced glycation end products in tissues, finally resulting in oxidative stress. 20(R)-ginsenoside Rg3 (20(R)-Rg3), a major and representative component isolated from red ginseng (Panax ginseng C.A Meyer), has been shown to observably have an anti-oxidative effect. We thereby investigated the beneficial effects of 20(R)-Rg3 on D-galactose-induced oxidative stress injury and its underlying mechanisms. Our results showed that continuous injection of D-galactose with 800[Formula: see text]mg/kg/day for 8 weeks increased the levels of alanine aminotransferase (ALT) and blood urea nitrogen (BUN). However, such increases were attenuated by the treatment of 20(R)-Rg3 for 4 weeks. Meanwhile, 20(R)-Rg3 markedly inhibited D-galactose-caused oxidative stress in liver and kidney. The anti-oxidants, including catalase (CAT) and superoxide dismutase (SOD), were elevated in the mice from 20(R)-Rg3-treated group compared with that from D-galactose group. In contrast, a significant decrease in levels of cytochrome P450 E1 (CYP2E1) and the lipid peroxidation product malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were observed in the 20(R)-Rg3-treated group. These effects were associated with a significant increase of AGEs. More importantly, 20(R)-Rg3 effectively attenuated D-galactose induced apoptosis in liver and kidney via restoring the upstream PI3K/AKT signaling pathway. Taken together, our study suggests that 20(R)-Rg3 may be a novel and promising anti-oxidative therapeutic agent to prevent aging-related injuries in liver and kidney.

scholarly journals Pathophysiology and Clinical Manifestations of COVID-19-Related Acute Kidney Injury—The Current State of Knowledge and Future Perspectives

2021 ◽  
Vol 22 (13) ◽  
pp. 7082
Author(s):  
Iwona Smarz-Widelska ◽  
Ewelina Grywalska ◽  
Izabela Morawska ◽  
Alicja Forma ◽  
Adam Michalski ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Treatment Strategies ◽  
Kidney Injury ◽  
Vast Number ◽  
Efficient Management ◽  
Current State ◽  
Post Mortem Findings

The continually evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in a vast number of either acute or chronic medical impairments of a pathophysiology that is not yet fully understood. SARS-CoV-2 tropism for the organs is associated with bilateral organ cross-talks as well as targeted dysfunctions, among which acute kidney injury (AKI) seems to be highly prevalent in infected patients. The need for efficient management of COVID-related AKI patients is an aspect that is still being investigated by nephrologists; however, another reason for concern is a disturbingly high proportion of various types of kidney dysfunctions in patients who have recovered from COVID-19. Even though the clinical picture of AKI and COVID-related AKI seems to be quite similar, it must be considered that regarding the latter, little is known about both the optimal management and long-term consequences. These discrepancies raise an urgent need for further research aimed at evaluating the molecular mechanisms associated with SARS-CoV-2-induced kidney damage as well as standardized management of COVID-related AKI patients. The following review presents a comprehensive and most-recent insight into the pathophysiology, clinical manifestations, recommended patient management, treatment strategies, and post-mortem findings in patients with COVID-related AKI.

scholarly journals Rhabdomyolisys as a Cause of Acute Renal Injury

2018 ◽  
Vol 45 (2) ◽  
pp. 49-54
Author(s):  
M. Nikolova ◽  
N. Guerguinova ◽  
T. Tsocheva ◽  
D. Vasilieou ◽  
M. Hristova ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Injury ◽  
Current Knowledge ◽  
Cell Damage ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Acute Renal Injury ◽  
Striate Muscle Cell ◽  
Muscle Groups ◽  
Substantial Morbidity

Abstract Rhabdomyolysis (RM) is defined as striate muscle-cell damage with disintegration of skeletal muscles and release of intracellular constituents to the circulation, with or without subsequent kidney injury. RM is one of the leading causes of acute kidney injury and is associated with substantial morbidity. The major signs of acute kidney injury in rhabdomyolysis are: pain, weakness and swelling of the injured muscle or muscle groups and myoglobinuria with reddish discoloration of the urine and decrease in urine output to anuria. The authors describe three cases of rhabdomyolysis with acute renal injury and discuss the current knowledge on the etiopathogenesis, clinical manifestations, diagnosis and treatment of this condition.

scholarly journals Toxicological Assessment of Venlafaxine: Acute and Subchronic Toxicity Study in Rats

2018 ◽  
Vol 37 (4) ◽  
pp. 327-334 ◽  
Author(s):  
Melad G. Paulis ◽  
Essam M. Hafez ◽  
Nashwa F. El-Tahawy ◽  
Mohmed K. M. Aly
Keyword(s):  
Psychiatric Treatment ◽  
Histopathological Examination ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Toxic Effects ◽  
High Dose ◽  
Toxicological Assessment ◽  
Liver And Kidney ◽  
Glutamyl Transferase ◽  
Therapeutic Doses

Antidepressants are the most commonly prescribed drugs for psychiatric treatment, and venlafaxine (VEN) is one of the most popular options. Venlafaxine is a nontricyclic dual-acting serotonin–norepinephrine reuptake inhibitor. Although an increased incidence of acute toxicity and addiction has been reported, controlled studies examining its toxic effects on different organs are still lacking. This study investigated the possible toxic effects of VEN on the liver, kidney, and gastric tissues. Three groups of rats were administered saline, a single LD50 dose (350 mg/kg), or 100 mg/kg VEN daily, followed by increases in the dose of 50 mg/kg every 10 days for 30 days (about 10 times the therapeutic doses). The following parameters of liver and kidney injury were then assayed: alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, prothrombin time, partial thromboplastin time, blood urea nitrogen, and serum creatinine. A histopathological examination was then conducted. Both acute and subchronic administration of VEN produced multiple clinical manifestations in the experimental animals, including seizures, coma, and even death. Moreover, the liver and renal function tests indicated injury in these tissues. Furthermore, the histopathological examination showed signs of organ toxicity after both acute and chronic VEN exposure. This study has shown that VEN has harmful effects on the liver, kidney, and stomach in either a single high dose (LD50) or repeated exposure to 10 times the therapeutic doses. As a result, strategies to increase awareness of these effects among physicians and the public are needed because this drug may be addictive.

scholarly journals New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Eva Sticova ◽  
Milan Jirsa ◽  
Joanna Pawłowska
Keyword(s):  
Intrahepatic Cholestasis ◽  
Bile Salts ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Clinical Manifestations ◽  
Bile Secretion ◽  
Drug Induced ◽  
Benign Recurrent Intrahepatic Cholestasis ◽  
End Stage

Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)—with onset in early infancy and progression to end-stage liver disease—to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles ofATP8B1,ABCB11,ABCB4,TJP2,andNR1H4have been described. In addition to familial intrahepatic cholestasis, partial defects inATP8B1,ABCB11,andABCB4predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

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