Adjunct antiseizure effect of clotrimazole in a rotenone corneal kindling mouse model of mitochondrial drug-resistant epilepsy.

This study aimed to investigate the therapeutic potential of clotrimazole, an inhibitor of the transient receptor potential cation channel, for treating mitochondrial drug-resistant epilepsy and to understand its underlying neurochemical mechanisms. Adult albino mice underwent rotenone-corneal kindling, receiving daily electric shocks (15 mA, 20 V, 6-Hz for 3 s) through a corneal electrode, to induce mitochondrial drug-resistant epilepsy. The onset of drug resistance was confirmed by the significant (p < 0.05) lack of seizure control with standard antiseizure medications including levetiracetam (40 mg/kg), valproate (250 mg/kg), phenytoin (35 mg/kg), lamotrigine (15 mg/kg), and carbamazepine (40 mg/kg). Drug-resistant mice were then classified into one vehicle-treated group and three groups treated with varying doses of clotrimazole (40, 80, and 160 mg/kg orally). Neurochemical analysis of the seizurogenic hippocampus and cerebral cortex was conducted using high-performance liquid chromatography with an electrochemical detector. Administration of clotrimazole alongside standard antiseizure medications led to a significant decrease (p < 0.05) in seizure scores suggesting the restoration of antiseizure effects. Neurochemicals, including tryptophan, serotonin, kynurenine, serine, taurine, gamma-aminobutyric acid, and glutamate, were significantly restored post-clotrimazole treatment. Overall, the present study underscores the adjunct antiseizure effect of clotrimazole in a rotenone corneal kindling mouse model of mitochondrial drug-resistant epilepsy, emphasising its role in neurochemical restoration.

Regulation of the Endogenous Opiate Signaling Pathway against Oxidative Stress and Inflammation: A Considerable Approach for Exploring Preclinical Treatment of Parkinson's Disease.

INTRODUCTION: Oxidative stress and inflammation are major factors contributing to the progressive death of dopaminergic neurons in Parkinson's disease (PD). Recent studies have demonstrated that morphine's biosynthetic pathway, coupled with nitric oxide (NO) release, is evolutionarily conserved throughout animals and humans. Moreover, dopamine is a key precursor for morphine biosynthesis. METHOD: The present study evaluated a series of preclinical experiments to evaluate the effects of low-level morphine treatment upon neuro-immune tissues exposed to rotenone and 6-OHDA as models of PD, followed by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay and cell/tissue computer-assisted imaging analyses to assess cell/neuronal viability. RESULTS: Morphine at normal physiological concentrations (i.e., 10-6 M and 10-7 M) provided neuroprotection, as it significantly inhibited rotenone and 6-OHDA dopaminergic insults; thereby, reducing and/or forestalling cell death in invertebrate ganglia and human nerve cells. To ensure that morphine caused this neuroprotective effect, naloxone, a potent opiate receptor antagonist, was employed and the results showed that it blocked morphine's neuroprotective effects. Additionally, co-incubation of NO synthase inhibitor L-NAME also blocked morphine's neuroprotective effects against rotenone and 6-OHDA insults. CONCLUSIONS: Taken together, the present preclinical study showed that while morphine can attenuate lipopolysaccharide-induced inflammation and cell death, both naloxone and L-NAME can abolish this effect. Preincubation of morphine precursors (i.e., L-3,4-dihydroxyphenylalanine, reticuline, and trihexyphenidyl [THP] at physiological concentrations) mimics the observed morphine effect. However, high concentrations of THP, a precursor of the morphine biosynthetic pathway, induced cell death, indicating the physiological importance of morphine biosynthesis in neural tissues. Thus, understanding the morphine biosynthetic pathway coupled with a NO signaling mechanism as a molecular target for neuroprotection against oxidative stress and inflammation in other preclinical models of PD is warranted.

Effects of fluoride on oxidative DNA damage, nitric oxide level, lipid peroxidation and cholinesterase enzyme activity in a rotenone-induced experimental Parkinson's model.

OBJECTIVE: Environmental toxins are known to be one of the important factors in the development of Parkinson's disease (PD). This study was designed to investigate the possible contribution of fluoride (F) exposure to oxidative stress and neurodegeneration in rats with PD induced by rotenone (ROT). MATERIALS AND METHODS: A total of 72 Wistar albino male rats were used in the experiment and 9 groups were formed with 8 animals in each group. ROT (2 mg/kg) was administered subcutaneously (sc) for 28 days. Different doses of sodium fluoride (NaF) (25, 50 and 100 ug/mL) were given orally (po) for 4 weeks. Malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), oxidative DNA damage (8-OHdG) and cholinesterase (AChE/BChE) enzyme activities were evaluated in serum and brain tissue homogenates. RESULTS: Rats treated with ROT and NaF had significant increases in serum and brain MDA, NO content, and decreases in GSH. In addition, the combination of ROT and NaF triggered oxidative DNA damage and resulted in increased AChE/BChE activity. CONCLUSIONS: Findings suggest that NaF and ROT may interact synergistically leading to oxidative damage and neuronal cell loss. As a result, we believe that exposure to pesticides in combination with NaF is one of the environmental factors that should not be ignored in the etiology of neurological diseases such as PD in populations in areas with endemic fluorosis.

Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein.

Parkinson´s disease (PD) pathology progresses throughout the nervous system. Whereas motor symptoms are always present, there is a high variability in the prevalence of non-motor symptoms. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed-alpha-synuclein (ASYN) on the endogenous ASYN. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology in vivo and in vitro and compared the effect of endocytosed-ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type and ASYN-KO mice. Our results show that, in vivo, pathology progression did not occur in the absence of endogenous ASYN. Remarkably, the damage caused by endocytosed-ASYN, rotenone or paraquat was independent from endogenous ASYN and related to the alteration of the host´s mitochondrial membrane potential. Dopaminergic neurons were very sensitive to these noxae compared to other neuronal subtypes. These results suggest that ASYN-mitochondrial interactions play a major role in initiating the pathological process in the host neuron and endogenous ASYN is essential for the transsynaptical transmission of the pathology. Our results also suggest that protecting mitochondrial function is a valid primary therapeutic target.

Bioinformatics guided rotenone adjuvant kindling in mice as a new animal model of drug-resistant epilepsy.

Drug-resistant epilepsy results from multiple mechanisms which are difficult to fully acquire in animal models. Technological advances, that allow transformation of big data into novel therapies, are now assisting in identification a disease targets for animal modeling. Our goal was to transform the available genomic and proteomic data related to drug-resistant epilepsy into ubiquitous disease target using system biology and network pharmacology approaches, followed by animal modeling and assess its validity. We used a dataset of 42 antiseizure drugs, 175 drug targets, and 601 epilepsy-gene associations to create interactome of 543 diseased proteins linked to drug-resistant epilepsy. DIAMOnD algorithm and DAVID web-services were used to identify 35 disease pathways whereby mitochondrial complex-I was selected for animal modeling. Albino mice were treated with specific inhibitor of mitochondrial complex-I (i.e., rotenone 2.5 mg/kg, i.p on daily basis) along with chemical and electric kindling stimulus for 35 days and 15 days, respectively. According to our results, the rotenone kindling model with inhibited complex-I activity showed significant (P < 0.001) resistance to lamotrigine (15 mg/kg), levetiracetam (40 mg/kg), carbamazepine (40 mg/kg), zonisamide (100 mg/kg), gabapentin (224 mg/kg), pregabalin (30 mg/kg), phenytoin (35 mg/kg), topiramate (300 mg/kg), valproate (200 mg/kg), and drug combinations at doses that had significantly (P < 0.001) controlled seizure severity in lamotrigine-pentylenetetrazole and corneal kindling models. In conclusion, lamotrigine kindling model is more advantageous than earlier described lamotrigine and corneal kindling models which respond to drug combinations. As a result, pre-clinical drug screening through rotenone kindling may uncover broad spectrum drugs with novel antiseizure mechanisms which is a pressing issue to deal with drug-resistant epilepsy.

Neuroprotective effects of linagliptin in a rotenone-induced rat model of Parkinson's disease.

The present study investigates the antiParkinsonian activity of dipeptidyl peptidase-4 (DPP-IV) inhibitor, linagliptin. The experimental Parkinson's disease (PD) was induced by administration of rotenone at a dose of 1.5 mg/kg at alternate day subcutaneously for 21 days. Standard drug (levodopa-200 mg/kg and carbidopa-50 mg/kg) and treatment drug (linagliptin-5 mg/kg, 10 mg/kg, and 20mg/kg) were administered orally daily 1 h before rotenone administration. In a rat rotenone model, linagliptin improved muscle coordination, motor performance, and corrected akinesia. Pretreatment with linagliptin showed significant higher levels of superoxide dismutase, catalase, and glutathione in brain homogenate of animals. Linagliptin significantly elevated the levels of striatal DA and active glucagon-like peptide 1 in brain homogenate of animals. Furthermore, linagliptin amended alterations induced by rotenone in the thiobarbituric acid reactive substances and inflammatory marker such as tumor necrosis factor-α level. The results of the present study indicate the neuroprotective potential of linagliptin for the management of PD might be due to remarkable improvement in motor functions, antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective mechanisms.

Pharmacological basis and new insights of deguelin concerning its anticancer effects.

Deguelin is a rotenoid of the flavonoid family, which can be extracted from Lonchocarpus, Derris, or Tephrosia. It possesses the inhibition of cancer cell proliferation by inducing apoptosis through regulating the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, the NF-κB signaling pathway, the Wnt signaling pathway, the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway and epidermal growth factor receptor (EGFR) signaling, activating the p38 mitogen-activated protein kinase (MAPK) pathway, repression of Bmi1, targeting cyclooxygenase-2 (COX-2), targeting galectin-1, promotion of glycogen synthase kinase-3ß (GSK3ß)/FBW7-mediated Mcl-1 destabilization and targeting mitochondria via down-regulating Hexokinases II-mediated glycolysis, PUMA-mediation, which are some crucial molecules which modulate closely cancer cell growth and metastasis. Deguelin inhibits tumor cell propagation and malignant transformation through targeting angiogenesis, targeting lymphangiogenesis, targeting focal adhesion kinase (FAK), inhibiting the CtsZ/FAK signaling pathway, targeting epithelial-mesenchymal transition (EMT), the NF-κB signaling pathway, regulating NIMA-related kinase 2 (NEK2). In addition, deguelin possesses other biological activities, such as targeting cell cycle arrest, modulation of autophagy, inhibition of hedgehog pathway, inducing differentiation of mutated NPM1 acute myeloid leukemia etc. Therefore, deguelin is a promising chemopreventive agent for cancer therapy.

FBXO22, ubiquitination degradation of PHLPP1, ameliorates rotenone induced neurotoxicity by activating AKT pathway.

Parkinson's disease (PD) is a neurodegenerative disease caused by the lacking of dopaminergic neurons. Many reports have illustrated that rotenone is applied to establish the experimental model of PD, which simulates PD-like symptoms. FBXO22 is a poorly understood protein that may be involved in neurological disorders. However, little is known about FBXO22 in PD. In this study, first, SH-SY5Y cells were treated with rotenone to construct PD model in vitro. It was discovered that the FBXO22 expression was down-regulated following rotenone treatment. Additionally, overexpression of FBXO22 reduced rotenone treatment-mediated cell apoptosis in SH-SY5Y cells. In view of the ubiquitination effect of FBXO22, our study uncovered that FBXO22 bound with and degraded PHLPP1 by ubiquitination. Next, the effects of PHLPP1 on AKT pathway in PD were further explored. It was demonstrated that PHLPP1 inactivated AKT pathway through down-regulating the pAKT/AKT and pmTOR/mTOR levels. Through rescue assays, the results showed that PHLPP1 overexpression partially reversed the reduction of rotenone induced neurotoxicity caused by FBXO22 overexpression. Finally, we found that overexpression of FBXO22 alleviated rotenone-induced PD symptoms in rat model. Moreover, it was discovered that l-dopa treatment could not affect the FBXO22 expression in PD. In conclusion, findings from our work proved that FBXO22 degraded PHLPP1 by ubiquitination to ameliorate rotenone induced neurotoxicity, which attributed to activate AKT pathway. This work suggested that FBXO22 may be an effective biological marker for PD treatment.

Deguelin targets multiple oncogenic signaling pathways to combat human malignancies.

Cancer is an anomalous growth and differentiation of cells known to be governed by oncogenic factors. Plant-based natural metabolites have been well recognized to possess chemopreventive properties. Deguelin, a natural rotenoid, is among the class of bioactive phytoconstituents from a diverse range of plants with potential antineoplastic effects in different cancer subtypes. However, the precise mechanisms of how deguelin inhibits tumor progression remains elusive. Deguelin has shown promising results in targeting the hallmarks of tumor progression via inducing tumor apoptosis, cell cycle arrest, and inhibition of angiogenesis and metastasis. Based on initial scientific excerpts, deguelin has been reported to inhibit tumor growth via different signaling pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase, serine/threonine protein kinase B (also known as Akt), mammalian target of rapamycin, nuclear factor-κB, matrix metalloproteinase (MMP)-2, MMP-9 and caspase-3, caspase-8, and caspase-9. This review summarizes the mechanistic insights of antineoplastic action of deguelin to gain a clear understanding of its therapeutic effects in cancer. The anticancer potential of deguelin with respect to its efficacy in targeting tumorigenesis via nanotechnological approaches is also investigated. The initial scientific findings have presented deguelin as a promising antitumorigenic agent which can be used for monotherapy as well as synergistically to augment efficacy of chemotherapeutic treatment regimes.

Disruption of neocortical synchronisation during slow-wave sleep in the rotenone model of Parkinson's disease.

Parkinson's disease motor dysfunctions are associated with improperly organised neural oscillatory activity. The presence of such disruption at the early stages of the disease in which altered sleep is one of the main features could be a relevant predictive feature. Based on this, we aimed to investigate the neocortical synchronisation dynamics during slow-wave sleep (SWS) in the rotenone model of Parkinson's disease. After rotenone administration within the substantia nigra pars compacta, one group of male Wistar rats underwent sleep-wake recording. Considering the association between SWS oscillatory activity and memory consolidation, another group of rats underwent a memory test. The fine temporal structure of synchronisation dynamics was evaluated by a recently developed technique called first return map. We observed that rotenone administration decreased the time spent in SWS and altered the power spectrum within different frequency bands, whilst it increased the transition rate from a synchronised to desynchronised state. This neurotoxin also increased the probability of longer and decreased the probability of shorter desynchronisation events. At the same time, we observed impairment in object recognition memory. These findings depict an electrophysiological fingerprint represented by a disruption in the typical oscillatory activity within the neocortex at the early stages of Parkinson's disease, concomitant with a decrease in the time spent in SWS and impairment in recognition memory.

Rotenone restrains colon cancer cell viability, motility and epithelial­mesenchymal transition and tumorigenesis in nude mice via the PI3K/AKT pathway.

Rotenone, a natural hydrophobic pesticide, has been reported to display anticancer activity in a variety of cancer cells. However, the mechanism of rotenone on colon cancer (CC) cell migration, invasion and metastasis is still unknown. In the present study, the cytotoxicity of rotenone on CC cells were detected by the Cell Counting Kit­8 assay and confirmed by clone formation assay. The effects of rotenone on CC cell invasion and migration activity were determined in vitro by Transwell invasion and wound healing assays, respectively. In addition, to reveal whether rotenone affected the epithelial­mesenchymal­transition (EMT) process, reverse transcription­quantitative PCR, western blotting and immunofluorescence assays were used to detect the expression of EMT markers. The expression levels of the key markers of the PI3K/AKT pathway after rotenone treatment alone or in combination with a PI3K/AKT signaling activator in CC were also detected by western blotting. Finally, the in vivo antitumor effects of rotenone were evaluated in a subcutaneous xenotransplant tumor model treated with an intraperitoneal injection of rotenone. The results of the present study demonstrated that rotenone treatment induced CC cell cytotoxicity and greater effects were observed with increasing concentrations and inhibited cell proliferation compared with untreated cells. In vitro cell function assays revealed that rotenone inhibited CC cell migration, invasion and EMT compared with untreated cells. Mechanically, the phosphorylation levels of AKT and mTOR were downregulated in rotenone­treated CC cells compared with untreated cells. Additionally, AKT and mTOR phosphorylation levels were increased by the PI3K/AKT signaling activator insulin­like growth factor 1 (IGF­1), which was reversed by rotenone treatment. The cell function assays confirmed that the IGF­1­activated cell proliferation, migration and invasion were decreased by rotenone treatment. These results indicated that rotenone affected CC cell proliferation and metastatic capabilities by inhibiting the PI3K/AKT/mTOR signaling pathway. In addition, rotenone inhibited tumor growth and metastatic capability of CC, which was confirmed in a xenograft mouse model. In conclusion, the present study revealed that rotenone inhibited CC cell viability, motility, EMT and metastasis in vitro and in vivo by inhibiting the PI3K/AKT/mTOR signaling pathway.

Rotenone protects against ß-cell apoptosis and attenuates type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is caused by pancreatic ß-cell dysfunction and apoptosis, with consequent severe insulin deficiency. Thus, ß-cell protection may be a primary target in the treatment of T1DM. Evidence has demonstrated that defective mitochondrial function plays an important role in pancreatic ß-cell dysfunction and apoptosis; however, the fundamental effect of mitochondrial complex I action on ß-cells and T1DM remains unclear. In the current study, the pancreas protective effect of complex I inhibitor rotenone (ROT) and its potential mechanism were assessed in a streptozotocin (STZ)-induced mouse model of T1DM and in cultured mouse pancreatic ß-cell line, Min6. ROT treatment exerted a hypoglycemic effect, restored the insulin level, and decreased inflammation and cell apoptosis in the pancreas. In vitro experiments also showed that ROT decreased STZ- and inflammatory cytokines-induced ß-cell apoptosis. These protective effects were accompanied by attenuation of reactive oxygen species, increased mitochondrial membrane potential, and upregulation of transcriptional coactivator PPARα coactivator 1α (PGC-1α)-controlled mitochondrial biogenesis. These findings suggest that mitochondrial complex I inhibition may represent a promising strategy for ß-cell protection in T1DM.

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential.

Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt-inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial-to-mesenchymal transition; angiogenesis-related pathways; and the phosphoinositide 3-kinase/Akt, Wnt, epidermal growth factor receptor, c-Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.

Rotenone Protects Against Acetaminophen-Induced Kidney Injury by Attenuating Oxidative Stress and Inflammation.

BACKGROUND/AIMS: In clinic, excessive acetaminophen (APAP) can cause kidney damage with uncertain mechanisms. Recently, accumulating evidence demonstrated a pathogenic role of mitochondrial dysfunction in the kidney injury. Thus, in this study, rotenone, a mitochondrial complex I inhibitor, was applied to the mice with APAP-induced acute kidney injury to evaluate the effect of mitochondrial complex I inhibition on APAP nephrotoxicity. METHODS: After 3 days of rotenone pretreatment, mice were administered with APAP (300mg/kg) by intraperitoneal injection for 24 h. Then the kidney injury, inflammation, and oxidative stress were evaluated. RESULTS: APAP significantly enhanced the BUN, serum creatine, and cystatin C levels in line with a moderate alteration of renal morphology. Strikingly, rotenone treatment normalized BUN, serum creatinine, and cystatin C levels, as well as the kidney morphology. Meanwhile, APAP enhanced tubular injury markers of NGAL and KIM-1 by 347- and 5-fold at mRNA levels, respectively. By Western blotting, we confirmed a 15-fold increment of NGAL in APAP-exposed kidneys. Importantly, rotenone treatment largely normalized NGAL and KIM-1 levels and attenuated inflammatory response in APAP-treated mice. Similarly, rotenone treatment enhanced the expressions of SOD1-3 compared with APAP group in line with a significant suppression of kidney MDA content. Finally, we observed that inhibition of mitochondrial complex III failed to protect against APAP-induced nephrotoxicity. CONCLUSION: Mitochondrial complex I inhibitor rotenone protected kidneys against APAP-induced injury possibly via the inhibition of mitochondrial oxidative stress and inflammation.

The Natural Rotenoid Deguelin Ameliorates Diabetic Neuropathy by Decreasing Oxidative Stress and Plasma Glucose Levels in Rats via the Nrf2 Signalling Pathway.

BACKGROUND/AIMS: Deguelin is a natural rotenoid that shows anti-inflammatory and antimicrobial activities. Rotenoids prevent oxidative damage and potentiate natural antioxidant activity in diabetic conditions, suggesting utility in treating diabetes and its complications. Here, we evaluate the potential efficacy of deguelin against diabetic neuropathy (DN). METHODS: DN was induced by streptozotocin followed by daily treatment with deguelin (4, 6 or 8 mg/kg) for 14 days. Blood glucose was measured, neurobehavioral tests for nociception and motor coordination were performed, and neuron conduction velocities were analysed electrophysiologically. We also assessed (Na+-K+) ATPase activity, performed a reactive oxygen species assay, measured the levels of various markers of oxidative stress, and of hydrogen sulphide (H2S) in dorsal root ganglion (DRG) neurons, conducted immunoblotting studies for proteins and ELISA for inflammatory cytokines. RESULTS: Deguelin significantly suppressed mechanical and thermal hyperalgesia, as well as cold allodynia, and partially restored the conduction velocities of neurons in DN rats. Significantly decreased expression levels of capspase-3 in DRG neurons, and increased (Na+-K+) ATPase activity in sciatic nerves, were observed. In addition, deguelin decreased glucose levels, attenuated oxidative stress and neuroinflammation, and elevated levels of H2S, nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1, suggesting a disease-attenuating effect of deguelin in DN rats. To shed light on the underlying mechanism of action of deguelin, insulin- and dimethyl fumarate (BG-12)-treated groups were also included. Insulin suppressed glucose levels and BG-12 produced effects on Nrf2 levels similar to 8 mg/kg deguelin, confirming involvement of the Nrf2 pathway in the beneficial effects of deguelin against DN. CONCLUSIONS: Deguelin attenuated DN by decreasing oxidative stress and plasma glucose levels via the Nrf2 signalling pathway.

Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells.

A hallmark of advanced prostate cancer (PC) is the concomitant loss of PTEN and p53 function. To selectively eliminate such cells, we screened cytotoxic compounds on Pten-/-;Trp53-/- fibroblasts and their Pten-WT reference. Highly selective killing of Pten-null cells can be achieved by deguelin, a natural insecticide. Deguelin eliminates Pten-deficient cells through inhibition of mitochondrial complex I (CI). Five hundred-fold higher drug doses are needed to obtain the same killing of Pten-WT cells, even though deguelin blocks their electron transport chain equally well. Selectivity arises because mitochondria of Pten-null cells consume ATP through complex V, instead of producing it. The resulting glucose dependency can be exploited to selectively kill Pten-null cells with clinically relevant CI inhibitors, especially if they are lipophilic. In vivo, deguelin suppressed disease in our genetically engineered mouse model for metastatic PC. Our data thus introduce a vulnerability for highly selective targeting of incurable PC with inhibitors of CI.

Tephrosin attenuates sepsis induced acute lung injury in rats by impeding expression of ICAM-1 and MIP-2.

Acute lung injury (ALI), a devastating form of respiratory infections, is characterized by increased edema, release of cytokines, weakened arterial oxygenation and infiltration of neutrophils and lymphocytes. The objective of the research envisaged was to reveal protective effects of tephrosin (TP) in ALI. In the present investigation, sepsis was triggered in rats by cecal ligation and puncture (CLP) method, and TP was administered intraperitonially. Five groups - Group A (control), Group B (Sham group) Group C (infected and untreated), and Group D and E (infected and treated with 25 and 50 mg/kg TP respectively) - of ten rats each, were used for the investigation. Evaluation parameters included measurement of arterial oxygenation, lung water content, protein determination, cytokine determination, neutrophil and lymphocyte count in the bronchoalveolar lavage fluid (BALF). As indicated by histopathological examination, the lung injury score was maximum in group C, but indicated reduction in group D and E. Intracellular adhesion molecule (ICAM)-1 and macrophage inflammatory protein-2 (MIP-2) are known to be important mediators responsible for ALI. Reduction in the ICAM-1 and MIP-2 expression was found to reduce after treatment with TP. In comparison to group D, group E reflected higher magnitude of ICAM-1 and MIP-2 suppression due to administration of higher TP dose. Compared to Group A and B, Group E indicated slightly higher expression of ICAM-1 and MIP-2. The research envisaged thus supports that TP attenuates ICAM-1 and MIP-2 expression in sepsis induced ALI rat model.

The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury.

Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS. In vivo treatment with an inhibitor of MCJ expression protects liver from acetaminophen-induced liver injury at a time when N-acetylcysteine, the standard therapy, has no efficacy. We also show elevated levels of MCJ in the liver of patients with acetaminophen overdose. We suggest that MCJ may represent a therapeutic target to prevent and rescue liver injury caused by acetaminophen.

Deguelin Attenuates Allergic Airway Inflammation via Inhibition of NF-κb Pathway in Mice.

Asthma is a chronic respiratory disease characterized by airway inflammation and remodeling, resulting in a substantial economic burden on both patients and society. Deguelin, a constituent of the Leguminosae family, exhibits anti-proliferative and anti-inflammatory activities in cancer mice models via inhibiting phosphatidylinositol 3-kinases and the NF-κB pathway. We demonstrated that deguelin effectively reduced OVA-induced inflammatory cell recruitment, decreased lung tissue inflammation and mucus production, suppressed airway hyperresponsiveness, and inhibited serum immunoglobulin and Th2 cytokine levels in a dose-dependent manner in asthmatic mice. In addition, we found that deguelin reduced inflammatory gene expressions both in vivo and in vitro, which were closely associated with activation of the NF-κB signaling pathway. Thus, we further explored the underlying mechanisms of deguelin in normal human bronchial epithelial cells (BEAS-2B). Our results suggested that deguelin inhibited NF-κB binding activity by enhancing the ability of IκBα to maintain NF-κB in an inactive form in the cytoplasm and preventing the TNF-α induced translocation of p65 to the nucleus. In conclusion, our research indicates that deguelin attenuates allergic airway inflammation via inhibition of NF-κB pathway in mice model and may act as a potential therapeutic agent for patients with allergic airway inflammation.