Al-Shaimaa F. Ahmed

Objective: Numerous studies suggest that oxindole-based derivatives exert neuroprotective activity on neurons. However, these studies used in-vitro evaluation methods and were not evaluated in vivo . Thus, this study aimed to test and assess the neuroprotective effect of a synthetic compound (OP1) by Knoevenagel condensation of cinnamaldehyde and oxindole. Methods: In this study, we used a model of global cerebral ischemia to evaluate the neuroprotective effects of OP1. This was achieved by measuring the behavioral outcomes and infarct volume. Results: The results showed that OP1 resulted in a significant improvement in open field, beam walk, and tape removal tests compared with ischemic rats. Also, OP1 reduced the infarct size after induction of ischemia. Conclusion: OP1 shows a promising neuroprotective effect against cerebral ischemia.

Sepsis is a life-threatening organ dysfunction associated with a robust systemic inflammatory and immune response to infection. Its pathological consequences lead to multiple organ deficits. Klotho was initially introduced as an antiaging molecule. Its deficiency significantly reduces lifespan, and its overexpression protects against organ injury. It reduces oxidative stress and apoptosis and has anti-inflammatory and antifibrotic properties. In this review, we discuss the underlying mechanisms of sepsis-related klotho down-regulation and the protective role of klotho in sepsis. In developing sepsis-induced multiple organ damage, klotho can modulate multiple downstream signals including nuclear factor-kappa β, mitogen activated protein kinase, and apoptosis. Multiple studies show klotho's protective effects in sepsis through activation of nuclear factor erythroid-related factor 2, Forkhead transcription factor O, and restoration of internal antioxidant activity. The proposed protective action of klotho is a promising therapeutic strategy for managing sepsis and ameliorating its related organ damage.

Sepsis is characterized by massive inflammatory and oxidative stress responses. The imbalance between oxidant and antioxidant activities during sepsis contributes to hyperinflammation, oxidation, endothelin system activation, and apoptosis, key elements of multiorgan failure. The current study investigated the role of tempol attenuating sepsis-induced acute cardiorenal injuries through modulation of Klotho. We used a cecal ligation and puncture (CLP) model of sepsis. Survival rate, histopathological assessment, and cardiorenal functions were analyzed. Oxidant and antioxidant activities, IL-6, and lactate were measured. The expression of tumor necrosis factor- α (TNF-α), p38-mitogen activating protein kinase (p38-MAPK), klotho, and caspase-3 were evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of IL-6 and lactate, an imbalance in oxidant/antioxidant activities, elevated expression of TNF-α, p38, caspase-3, and reduced expression of klotho. Tempol improved survival, reduced inflammatory and oxidative stress parameters, improved cardiorenal functions, elevated the tissue contents of reduced glutathione (GSH) and superoxide dismutase (SOD), raised the expression of klotho protein and reduced the expression of p38, TNF- α and caspase-3. Tempol is a promising agent against sepsis-induced organ damage. This was evident in its cardiorenal protective effect, up-regulation of klotho, suppression of inflammation, oxidation, and apoptosis, and enhancement of the antioxidant status.

Sepsis‐induced organ failure is a major health problem, characterised by massive inflammatory and oxidative stress responses. Endothelin‐1 (ET‐1) is one of the peptides expressed during septicemia with proapoptotic, proinflammatory, and oxidant effects. ET‐1 plays a role in heart and kidney injuries in sepsis. Accordingly, the current study was conducted to investigate, on a mechanistic basis, whether inhibition of ET‐1 signalling either by blocking its receptors or inhibiting its formation attenuates sepsis‐induced acute cardiorenal injuries. To analyse the role of ET‐1 in sepsis, we used a cecal ligation and puncture (CLP) model of sepsis. The animals were divided into five groups: CLP non‐treated group, CLP‐treated groups with bosentan, ambrisentan, and phosphoramidon (30, 5, and 0.5 mg/kg, respectively), and sham‐operated group. In addition to the same set of groups, survival analysis was assigned Survival rate, histopathological assessment, and cardiorenal functions were analysed. Oxidant and antioxidant activities, ET‐1, IL‐6, and lactate were measured. The expression of TNF‐α, p38, Klotho, and caspase‐3 was evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of ET‐1, IL‐6, and lactate, as well as an imbalance in oxidant/antioxidant activities, elevated expression of TNF‐α, p38, caspase‐3 and reduced expression of klotho. Bosentan, ambrisentan, or phosphoramidon improved survival, reduced the levels of inflammatory and oxidative stress parameters, improved cardiorenal functions and structure, elevated the tissue contents of GSH and SOD, raised the expression of klotho protein, and reduced the cardiorenal expression of p38, TNF‐α and caspase‐3. Endothelin receptor antagonists (ERAs); bosentan and ambrisentan, or endothelin converting enzyme inhibitor (ECE‐i) phosphoramidon, are promising agents against sepsis‐induced organ damage. This was evident in their cardiorenal protective effects, up‐regulation of klotho, suppression of inflammation, oxidation, apoptosis, and enhancement of the antioxidant status.

The journal retracts the article, “Omega-3 Self-Nanoemulsion Role in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats”

Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction, and cell death causing sepsis‐associated encephalopathy (SAE). These pathological consequences lead to short‐ and long‐term neurobehavioural deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioural impairments. In this review, we discuss the underlying mechanisms of sepsis‐induced brain injury with a focus on the latest progress regarding neuroprotective effects of SIRT1 (silent mating type information regulation‐2 homologue‐1). SIRT1 is an NAD⁺‐dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF‐κB, HMGB, AMPK, PGC1α and FoxO), which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective effects of SIRT1 in neuroinflammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.

Sepsis is a life-threatening organ dysfunction that results from dysregulated host response to infection. Multiple organ system dysfunction syndromes are prevalent among septic patients and are essential hallmarks of sepsis diagnosis. These syndromes involve failure of the pulmonary, hepatic, circulatory, renal, gastrointestinal and central nervous systems. Neurological dysfunction is part of this syndrome and has gained research attention recently [1]. Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction and cell death causing sepsis-associated encephalopathy (SAE). These pathological consequences lead to short- and long-term neurobehavioral deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioral impairments. In this review, we discuss the underlying mechanisms of sepsis-induced brain injury with a focus on the latest progress regarding neuroprotective effects of SIRT1 (silent mating type information regulation-2 homologue-1). SIRT1 is an NAD+-dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF-κB, HMGB, AMPK, PGC1α and FoxO) which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective effects of SIRT1 in neuroinflammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.