Understanding neuropsychiatric symptoms in Alzheimer's disease: challenges and advances in diagnosis and treatment.

Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) affect up to 97% of AD patients, with an estimated 80% of current AD patients experiencing these symptoms. Common AD-associated NPS include depression, anxiety, agitation, aggression, and apathy. The severity of NPS in AD is typically linked to the disease's progression and the extent of cognitive decline. Additionally, these symptoms are responsible for a significant increase in morbidity, mortality, caregiver burden, earlier nursing home placement, and greater healthcare expenditure. Despite their high prevalence and significant impact, there is a notable lack of clinical research on NPS in AD. In this article, we explore and analyze the prevalence, symptom manifestations, challenges in diagnosis, and treatment options of NPS associated with AD. Our literature review reveals that distinguishing and accurately diagnosing the NPS associated with AD remains a challenging task in clinical settings. It is often difficult to discern whether NPS are secondary to pathophysiological changes from AD or are comorbid psychiatric conditions. Furthermore, the availability of effective pharmaceutical interventions, as well as non-pharmacotherapies for NPS in AD, remains limited. By highlighting the advance and challenges in diagnosis and treatment of AD-associated NPS, we aspire to offer new insights into the complexity of identifying and treating these symptoms within the context of AD, and contribute to a deeper understanding of the multifaceted nature of NPS in AD.

Activation of a novel α2AAR-spinophilin-cofilin axis determines the effect of α2 adrenergic drugs on fear memory reconsolidation.

Posttraumatic stress disorder (PTSD) after the pandemic has emerged as a major neuropsychiatric component of post-acute COVID-19 syndrome, yet the current pharmacotherapy for PTSD is limited. The use of adrenergic drugs to treat PTSD has been suggested; however, it is hindered by conflicting clinical results and a lack of mechanistic understanding of drug actions. Our studies, using both genetically modified mice and human induced pluripotent stem cell-derived neurons, reveal a novel α2A adrenergic receptor (α2AAR)-spinophilin-cofilin axis in the hippocampus that is critical for regulation of contextual fear memory reconsolidation. In addition, we have found that two α2 ligands, clonidine and guanfacine, exhibit differential abilities in activating this signaling axis to disrupt fear memory reconsolidation. Stimulation of α2AAR with clonidine, but not guanfacine, promotes the interaction of the actin binding protein cofilin with the receptor and with the dendritic spine scaffolding protein spinophilin to induce cofilin activation at the synapse. Spinophilin-dependent regulation of cofilin is required for clonidine-induced disruption of contextual fear memory reconsolidation. Our results inform the interpretation of differential clinical observations of these two drugs on PTSD and suggest that clonidine could provide immediate treatment for PTSD symptoms related to the current pandemic. Furthermore, our study indicates that modulation of dendritic spine morphology may represent an effective strategy for the development of new pharmacotherapies for PTSD.

ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors.

Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient-derived xenografts, we show that ARID1A-mutant tumors were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was sensitive to combination therapies with EZH2 and PI3K inhibitors in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K and revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.

Cymbopogon schoenanthus (Ethkher) ameliorates cadmium induced toxicity in swiss albino mice.

Cadmium is among the toxic and hazardous metal widely dispersed in the environment in high levels. Current studies have provided new insights into antioxidant properties of bioflavonoid which have emerged as probable therapeutic and nutraceutical agents. The present study is geared to investigate the possible role of Cymbopogon schoenanthus (L.) Spreng. (or Ethkher) on heavy metal cadmium (Cd) induced oxidative stress in mice. Mice were randomly divided into four groups and treated for 15 days as follows: group 1: normal control-treated (saline); group 2: Ethkher leaves extract-treated (100 mg/kg); group 3: cadmium chloride (CdCl2) treated; group 4: CdCl2 plus Ethkher leaves extract. The results showed a significant reduction in hemoglobin, RBC and hematocrit in cadmium-treated mice as compared to control. Exposure to Cd caused a significant increase in the number of white blood cells (P < 0.05) indicating the occurrence of systemic inflammation. The results of this study also revealed that the mice intoxicated with Cd showed a significant increase in bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGTP) activities. Cd intoxication leads to suppression in humoral immunity. However, pretreatment with Ethkher extract reversed almost all the abnormalities in the blood parameters showing noteworthy protection against cadmium induced toxicity in mice. The outcome of the present study revealed that the Ethkher possessed significant immunomodulatory activity and had a preventive effect on the hematological alterations in Cd intoxicated mice.

Immunosuppressant drug tacrolimus induced mitochondrial nephrotoxicity, modified PCNA and Bcl-2 expression attenuated by Ocimum basilicum L. in CD1 mice.

Tacrolimus (TAC) is used sporadically as an immunosuppressive agent for organ transplantation, but its clinical used is limited due to its marked nephrotoxicity. Ocimum basilicum L. (Lamiaceae) (OB) had been shown to possess antioxidant, anti-inflammatory and nephroprotective activity, and effective at improving renal inflammation and glomerular. In our study, we aim to evaluate the efficacy of the OB against TAC-induced mitochondrial nephrotoxicity in CD1 mice. Mice were randomly divided into four groups. Group 1 (control group); administered orally with normal saline (1 mL/kg) for two weeks; Group 2 (OB extract treated-group) (500 mg/kg b.wt) gavaged once/day for two weeks; Group 3 (TAC-treated group) (3 mg/kg b.wt, administered ip once a day for two weeks); and Group 4; (TAC plus OB extract treated-group). Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. The OB extract was high in phenolic content (50.3 mg/g of gallic acid equivalent), total flavonoids (14.5 mg/g CE equivalent). The potential antioxidant efficacy of the extract (IC50) was 24.5 µg/mL. OB pretreatment significantly improved the TAC-induced changes in biochemical markers of nephrotoxicity for instance blood urea nitrogen (BUN), creatinine, total protein, and albumin (P < 0.01, when compared with TAC treated group). Also, it significantly restored the increase activities of TBARS, protein carbonyl (PC) (P < 0.001, when compared to healthy control group) and decreased activities of nonprotein thiol (NP-SH) levels, Mn-superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPx) antioxidants of mitochondria. The nephroprotective efficacy of the OB leaves extract was further evident by histopathological analysis together with the PCNA-ir and Bcl2. The upshot of the present study revealed that the OB possessed significant antioxidant and nephroprotective activity and had a preventive effect on the biochemical alterations and histological changes in TAC-treated mice.

Ischemic preconditioning attenuates acute lung injury after partial liver transplantation.

Pulmonary complications frequently occur after liver transplantation and are often life-threatening. Thus, we investigated whether hepatic ischemic preconditioning (IP) attenuates acute lung injury (ALI) after small-for-size liver transplantation. Rat livers were explanted after 9-min ischemia plus 5-min reperfusion, reduced to 50% of original size ex vivo, and implanted into recipients with approximately twice the donor body weight, resulting in quarter-size liver grafts (QSG). After QSG transplantation, hepatic Toll-like receptor 4 (TLR4) and tumor necrosis factor-α (TNFα ) expression increased markedly and high mobility group box-1 (HMGB1), an endogenous damage-associated molecular pattern molecule (DAMP), was released from QSG into the blood. IP blunted TLR4 and TNFα expression and HMGB1 release from QSG. In the lungs of QSG recipients without IP treatment, nuclear factor-κB (NF-κB) activation and intercellular adhesion molecule (ICAM)-1 expression increased; alveolar septal walls thickened with increased cellularity as neutrophils, monocytes/macrophage and T lymphocytes infiltrated into alveolar septa and alveolar spaces; and pulmonary cleaved caspase-8 and -3 and TUNEL-positive cells increased. In contrast, in the lungs of recipients of ischemic-preconditioned QSG, NF-κB activation and ICAM-1 expression were blunted; leukocyte infiltration was decreased; and alveolar septal wall thickening, caspase activation, and cell apoptosis were attenuated. IP did not increase heat-shock proteins in the lungs of QSG recipients. In conclusion, toxic cytokine and HMGB1 released from failing small-for-size grafts leads to pulmonary adhesion molecule expression, leukocyte infiltration and injury. IP prevents DAMP release and toxic cytokine formation in small-for-size grafts, thereby attenuating ALI.

Ecological variations and role of heat shock protein in Artemisia judaica L. in response to temperature regimes of Tabuk, Saudi Arabia.

Artemisia judaica L. (Compositae) are shrubby herbs growing wildly in Tabuk region and distributed in the desert regions. This region is characterized by extremely variable environmental conditions where the temperature varies from extreme low to extreme high. These temperature regimes have a profound effect on morphology, growth physiology and biochemistry of the plants. The plant samples were collected from Tabuk-Jordan road (760 m above sea level) in the month of January, April, July and October 2013 to evaluate the effect of temperature dynamics on A. judaica L. in four different seasons. Physiological, biochemical alterations and heat shock proteins (HSPs) were studied during these seasons in order to evaluate the environmental adaptation and stress tolerance in response to temperature variations. Plant growth parameters showed a significant increase in height, fresh and dry matter accumulation, total chlorophyll, nitrogen, phosphorus, potassium, artemisinin and leaf relative water contents investigated in the month of April and October. Growth of plant was suppressed and an active role of carbonic anhydrase (CA), catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) was observed to cope with the extreme low temperature in January and extreme high temperature in July 2013. However, the plants collected in October and April did not show a statistical difference. Inductions in the expression of HSP90 were recorded in all the plants collected during April and October 2013 with no statistically significant difference. Therefore, based on the results it is recommended that during April and October the environmental conditions are best suitable for growth, development and medicinal use of Artemisia.

8-pCPT-cGMP prevents mitochondrial depolarization and improves the outcome of steatotic partial liver transplantation.

Permeant cGMP analogs prevent the mitochondria permeability transition (MPT) in vitro. In this study, we explored whether 8-pCPT-cGMP prevents the MPT and decreases post-transplant damage to fatty partial liver grafts (FPG) in vivo. Rats were fed a control or high-fat, high-fructose diet for 2-week. Lean and fatty liver explants were reduced in size ex vivo to ~35% and stored in the University of Wisconsin solution with and without 8-pCPT-cGMP (300 µM) for 2 h. After transplantation, alanine aminotransferase release (indicator of hepatocellular injury), hyperbilirubinemia (indicator of poor liver function), and cell death were all higher in FPG than in lean partial grafts (LPG). Liver regeneration increased in LPG but was suppressed in FPG. 8-pCPT-cGMP blunted graft injury, improved liver regeneration and function, and increased survival of FPG. Hepatic mitochondrial depolarization detected by intravital multiphoton microscopy of rhodamine 123 in living rats was ~3.5-fold higher in FPG than in LPG. 8-pCPT-cGMP decreased mitochondrial depolarization in FPG almost to the level of LPG. Activation of mammalian target of rapamycin (mTOR), an energy sensitive kinase that stimulates cell proliferation and growth, and p70S6 kinase, a downstream signaling molecule of mTOR, was increased in LPG but suppressed in FPG. 8-pCPT-cGMP restored the activity of mTOR and p70S6 kinase in FPG. 8-pCPT-cGMP also increased activation of cAMP response element-binding protein (CREB) and expression of cyclins D1 and E in FPG. Non-alcoholic steatosis increases injury and suppresses regeneration after partial liver transplantation, at least in part, due to more severe mitochondrial dysfunction. Protection of mitochondria with a cGMP analog effectively improves outcomes of FPG transplantation.

Additive toxic effect of deltamethrin and cadmium on hepatic, hematological, and immunological parameters in mice.

Exposure to natural and man-made environmental toxins concurrently can pose a greater threat to multiple organs. In the present work, we investigated interactions between deltamethrin (DM) and cadmium (Cd), whose mechanisms of action in humans are poorly understood. Albino mice were randomly divided into four groups, each containing six mice: saline as control, DM-treated, cadmium chloride (CdCl2)-treated, and CdCl2 plus DM treated. After 2 weeks of treatment biochemical and hematological effects, total leukocyte count (TLC), differential leukocyte count, humoral-mediated immune responses, and histopathological studies were conducted. Mice exposed to DM and Cd showed a significant increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Also, DM and Cd administration resulted in suppression of humoral immunity, erythrocyte count, hemoglobin, hematocrit, and TLC. Histopathological evidence revealed hepatic damage, supporting the AST and ALT findings. Cd and DM exhibited an additive type of toxicity. It could be concluded that these toxins either target different cellular pathways, or the individual amounts used in this study were not enough to saturate the toxicological target, thus producing additive effects.

Fern-synthesized silver nanocrystals: Towards a new class of mosquito oviposition deterrents?

Mosquitoes act as vectors of devastating pathogens and parasites, representing a key threat for millions of humans and animals worldwide. Eco-friendly control tools are urgently required. We proposed a novel method of fern-mediated biosynthesis of silver nanoparticles (AgNP) using Dicranopteris linearis, acting as a reducing and capping agent. AgNP were characterized by UV-vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), zeta potential and particle size analysis. In mosquitocidal assays, the LC50 of D. linearis extract against Aedes aegypti ranged from 165.213 (larva I) to 255.055ppm (pupa). LC50 of D. linearis-synthesized AgNP ranged from 18.905 (larva I) to 29.328ppm (pupa). In the field, the application of D. linearis extract and AgNP (10×LC50) led to 100% larval reduction after 72h. Smoke toxicity experiments conducted against A. aegypti adults showed that D. linearis leaf-, stem- and root-based coils evoked mortality rates comparable to the permethrin-based positive control (58%, 47%, 34%, and 48% respectively). In ovicidal experiments, egg hatchability was reduced by 100% after treatment with 25ppm of AgNP and 300ppm of D. linearis extract. Interestingly, oviposition deterrent assays highlighted that 100ppm of fern extract reduced oviposition rates of more than 65%, while 10ppm of fern-fabricated AgNP reduced oviposition rates of more than 70% in A. aegypti (OAI were -0.52 and -0.55, respectively). Overall, our results highlighted that D. linearis-synthesized AgNP could be useful candidates to develop nano-formulated oviposition deterrents effective against dengue vectors.

The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice.

Oxidative stress plays an essential role in liver fibrosis. This study investigated whether MitoQ, an orally active mitochondrial antioxidant, decreases liver fibrosis. Mice were injected with corn oil or carbon tetrachloride (CCl4, 1:3 dilution in corn oil; 1 µl/g, ip) once every 3 days for up to 6 weeks. 4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress. MitoQ attenuated oxidative stress after CCl4. Collagen 1α1 mRNA and hydroxyproline increased markedly after CCl4 treatment, indicating increased collagen formation and deposition. CCl4 caused overt pericentral fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy. MitoQ blunted fibrosis after CCl4. Profibrotic transforming growth factor-ß1 (TGF-ß1) mRNA and expression of smooth muscle α-actin, an indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-ß fibrogenic effects, was also activated after CCl4 treatment. MitoQ blunted HSC activation, TGF-ß expression, and Smad2/3 activation after CCl4 treatment. MitoQ also decreased necrosis, apoptosis and inflammation after CCl4 treatment. In cultured HSCs, MitoQ decreased oxidative stress, inhibited HSC activation, TGF-ß1 expression, Smad2/3 activation, and extracellular signal-regulated protein kinase activation. Taken together, these data indicate that mitochondrial reactive oxygen species play an important role in liver fibrosis and that mitochondria-targeted antioxidants are promising potential therapies for prevention and treatment of liver fibrosis.

Insecticide susceptibility in larval populations of the West Nile vector Culex pipiens L. (Diptera:Culicidae) in Saudi Arabia

Objective: To investigate the susceptibility to some conventional and non-conventional insecticides in laboratory and field larval populations of the West Nile vector Culex pipiens L. (Cx. pipiens), the dominant species in Jeddah Province, Saudi Arabia. Methods: The tested conventional insecticides were Actikil and Pesgard, while the non-conventional ones were Bacilod, Dudim and Baycidal. Probit analysis and photo-microscopical observations were carried out to shed light on acute toxicity in laboratory and field Cx. pipiens strains. Results: Cx. pipiens were more susceptible to Pesgard (LC50: 0.045 and 0.032 mg/L) than Actikil (0.052 and 0.038 mg/L) and Bacilod (0.129 and 0.104 mg/L), for the field and laboratory strains, respectively. Results showed that treatments with the chitin syn-thesis inhibitor Dudim and Baycidal evoked morphological effects similar to those induced by other insect growth regulators. According to IC50 values obtained (concen-tration which to inhibit the emergence of 50%of mosquito adults), the compound Dudim (0.000 3 and 0.000 1 mg/L) was more effective against Cx. pipiens L. mosquitoes than Baycidal (0.000 4 and 0.000 3 mg/L) for both the field and laboratory strains, respectively. Conclusions: Our results provide baseline data to enhance control programs and orient public health decisions on the selection of pesticides against mosquito vectors in Saudi Arabia.

Disrupted Renal Mitochondrial Homeostasis after Liver Transplantation in Rats.

BACKGROUND: Suppressed mitochondrial biogenesis (MB) contributes to acute kidney injury (AKI) after many insults. AKI occurs frequently after liver transplantation (LT) and increases mortality. This study investigated whether disrupted mitochondrial homeostasis plays a role in AKI after LT. METHODS: Livers were explanted from Lewis rats and implanted after 18 h cold storage. Kidney and blood were collected 18 h after LT. RESULTS: In the kidney, oxidative phosphorylation (OXPHOS) proteins ATP synthase-ß and NADH dehydrogenase-3 decreased 44% and 81%, respectively, with marked reduction in associated mRNAs. Renal PGC-1α, the major regulator of MB, decreased 57% with lower mRNA and increased acetylation, indicating inhibited synthesis and suppressed activation. Mitochondrial transcription factor-A, which controls mtDNA replication and transcription, protein and mRNA decreased 66% and 68%, respectively, which was associated with 64% decreases in mtDNA. Mitochondrial fission proteins Drp-1 and Fis-1 and mitochondrial fusion protein mitofusin-1 all decreased markedly. In contrast, PTEN-induced putative kinase 1 and microtubule-associated protein 1A/1B-light chain 3 increased markedly after LT, indicating enhanced mitophagy. Concurrently, 18- and 13-fold increases in neutrophil gelatinase-associated lipocalin and cleaved caspase-3 occurred in renal tissue. Both serum creatinine and blood urea nitrogen increased >2 fold. Mild to moderate histological changes were observed in the kidney, including loss of brush border, vacuolization of tubular cells in the cortex, cast formation and necrosis in some proximal tubular cells. Finally, myeloperoxidase and ED-1 also increased, indicating inflammation. CONCLUSION: Suppression of MB, inhibition of mitochondrial fission/fusion and enhancement of mitophagy occur in the kidneys of recipients of liver grafts after long cold storage, which may contribute to the occurrence of AKI and increased mortality after LT.

Recent incidence and descriptive epidemiological survey of breast cancer in Saudi Arabia.

OBJECTIVE: To review and analyze the pattern of breast cancer (BC) in the Kingdom of Saudi Arabia (KSA). METHODS: A retrospective review of BC among female patients was conducted at the Faculty of Sciences, Department of Biology, University of Tabuk, Tabuk, Saudi Arabia from January 1990 to December 2014. This report contains information obtained from the Saudi Cancer Registry and from King Faisal Specialist Hospital and Research Center. RESULTS: The number of women with BC increased steadily from 1990-2010. On the basis of the number of cases, the percentage distribution of BC appears to be increasing. There were 1152 female BC cases in 2008 in comparison with 1308 in 2009, and 1473 in 2010. Breast cancer ranked first among females accounting for 27.4% of all newly diagnosed female cancers (5378) in the year 2010. The average age at the diagnosis of BC was 48; weighted average was 49.8, and range 43-52. CONCLUSION: Among Saudi patients, there was a significant increase in the number of cases of BC, which occurs at an earlier age than in western countries. Continued vigilance, mammographic screening, and patient education are needed to establish early diagnosis and perform optimal treatment.

Phytochemical, antioxidant and mineral composition of hydroalcoholic extract of chicory (Cichorium intybus L.) leaves.

The phytochemical, antioxidant and mineral composition of hydroalcoholic extract of leaves of Cichorium intybus L., was determined. The leaves were found to possess comparatively higher values of total flavonoids, total phenolic acids. The phytochemical screening confirmed the presence of tannins, saponins, flavonoids, in the leaves of the plant. The leaf extract was found to show comparatively low value of IC50 for 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition. The IC50 value of chicory leaves extract was found to be 67.2 ± 2.6 µg/ml. The extracts were found to contain high amount of mineral elements especially Mg and Zn. Due to good phytochemical and antioxidant composition, C. intybus L., leaves would be an important candidate in pharmaceutical formulations and play an important role in improving the human health by participating in the antioxidant defense system against free radical generation.

Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice.

BACKGROUND & AIMS: Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. METHODS: Livers explanted from wild-type, inducible nitric oxide synthase knockout (iNOS(-/-)), JNK1(-/-) or JNK2(-/-) mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. RESULTS: After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS deficiency. JNK inhibition and JNK2 deficiency, but not JNK1 deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS deficiency, JNK inhibition and JNK2 deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. CONCLUSION: The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization, and is an attractive target to improve liver function and survival in CDD liver transplantation recipients.

Ameliorating effect of chicory (Chichorium intybus L.) fruit extract against 4-tert-octylphenol induced liver injury and oxidative stress in male rats.

The current study was carried out to elucidate the modulating effect of chicory (Cichorium intybus L.) fruit extract (CFR) against 4-tert-OP induced oxidative stress and hepatotoxicity in male rats. Rats were divided into four groups and treated for 8 weeks as follow: group 1: normal control-treated (saline); group 2: chicory fruit extract-treated (100 mg/kg); group 3: 4-tert-OP treated; group 4: 4-tert-OP plus chicory fruit extract. The obtained results revealed that rats which received 4-tert-OP showed a significant increase in liver TBARS and bilirubin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGTP) activities. While a significant decrease in the levels of GSH, SOD, catalase recorded. On the other hand, CFR extract succeeded to modulate these observed abnormalities resulting from 4-tert-OP as indicated by the reduction of TBARS and the pronounced improvement of the investigated biochemical and antioxidant parameters. Histopathological evidence, together with observed PCNA and DNA fragmentation, supported the detrimental effect of 4-tert-OP and the ameliorating effect of CFR extract on liver toxicity. So, it could be concluded that chicory has a promising role and it worth to be considered as a natural substance for ameliorating the oxidative stress and hepatic injury induced by 4-tert-OP compound.

Acute ethanol causes hepatic mitochondrial depolarization in mice: role of ethanol metabolism.

BACKGROUND/AIMS: An increase of ethanol metabolism and hepatic mitochondrial respiration occurs in vivo after a single binge of alcohol. Here, our aim was to determine how ethanol intake affects hepatic mitochondrial polarization status in vivo in relation to ethanol metabolism and steatosis. METHODS: Hepatic mitochondrial polarization, permeability transition (MPT), and reduce pyridine nucleotides, and steatosis in mice were monitored by intravital confocal/multiphoton microscopy of the fluorescence of rhodamine 123 (Rh123), calcein, NAD(P)H, and BODIPY493/503, respectively, after gavage with ethanol (1-6 g/kg). RESULTS: Mitochondria depolarized in an all-or-nothing fashion in individual hepatocytes as early as 1 h after alcohol. Depolarization was dose- and time-dependent, peaked after 6 to 12 h and maximally affected 94% of hepatocytes. This mitochondrial depolarization was not due to onset of the MPT. After 24 h, mitochondria of most hepatocytes recovered normal polarization and were indistinguishable from untreated after 7 days. Cell death monitored by propidium iodide staining, histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was low throughout. After alcohol, mitochondrial NAD(P)H autofluorescence increased and decreased, respectively, in hepatocytes with polarized and depolarized mitochondria. Ethanol also caused steatosis mainly in hepatocytes with depolarized mitochondria. Depolarization was linked to ethanol metabolism, since deficiency of alcohol dehydrogenase and cytochrome-P450 2E1 (CYP2E1), the major ethanol-metabolizing enzymes, decreased mitochondrial depolarization by ∼ 70% and ∼ 20%, respectively. Activation of aldehyde dehydrogenase decreased depolarization, whereas inhibition of aldehyde dehydrogenase enhanced depolarization. Activation of aldehyde dehydrogenase also markedly decreased steatosis. CONCLUSIONS: Acute ethanol causes reversible hepatic mitochondrial depolarization in vivo that may contribute to steatosis and increased mitochondrial respiration. Onset of this mitochondrial depolarization is linked, at least in part, to metabolism of ethanol to acetaldehyde.

Abrogation by Trifolium alexandrinum root extract on hepatotoxicity induced by acetaminophen in rats.

OBJECTIVE: Acetaminophen (APAP) is a substance that harms human health by stimulating free radical production. This study investigated the ability of Trifolium alexandrinum root (TAR) extract to reduce the hepatotoxicity induced by APAP in rats. METHODS: Animals were classified into four groups and treated for 6 weeks. Group 1: normal control-treated (saline); Group 2: TAR extract-treated (100 mg/kg); Group 3: APAP-treated; Group 4: APAP plus TAR extract. RESULTS: APAP significantly elevated AST (aspartate amino transferase), ALT (amino alanine transferase), ALP (alkaline phosphatase), GGTP (gamma glutamyl transpeptidase), bilirubin, and malondialdehyde with a significant decrease in glutathione, superoxide dismutase, glutathione peroxidase, catalase, and glutathione S-transferase compared with the control group. Administration of TAR extract combined with APAP improved the liver damage induced by APAP. Histopathological evidence, together with observed DNA fragmentation, supported the detrimental effect of APAP and the ameliorating effect of TAR extract on liver toxicity. CONCLUSION: TAR extract has beneficial properties and can reduce the liver damage and toxicity induced by APAP. DISCUSSION: Free radical mediated processes have been implicated in the pathogenesis of many diseases. The protective effect of TAR root extract on APAP-induced hepatotoxicity in rats appears to be related to inhibition of lipid peroxidation and enhancement of antioxidant enzyme levels, in addition to a free radical scavenging action.

Green tea polyphenols stimulate mitochondrial biogenesis and improve renal function after chronic cyclosporin a treatment in rats.

Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-ß (AS-ß) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-ß, ND3, COX-IV, mtDNA copy number, PGC-1α mRNA and protein, decreased acetylated PGC-1α, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate CsA-induced kidney injury, at least in part, through the stimulation of MB.