Pharmacodynamic Activity and Efficacy of Linezolid in a Rat Model of Pneumococcal Pneumonia

ABSTRACT Linezolid is a new oxazolidinone antibiotic with potent activity against gram-positive bacteria, including Streptococcus pneumoniae. The pharmacodynamic activity and in vivo efficacy of linezolid were compared to those of ceftriaxone in an immunocompetent rat model of pneumococcal pneumonia. Rats infected intratracheally with 8 × 107 CFU of a penicillin-sensitive (MIC, 0.032 μg/ml) strain of S. pneumoniae were treated for 5 days beginning 18 h postinfection. Groups of rats were sham treated with oral phosphate-buffered saline or received oral liquid linezolid at 25 or 50 mg/kg of body weight twice a day (b.i.d.) or subcutaneous ceftriaxone at 100 mg/kg once daily. Mortality was monitored for 10 days postinfection; blood culturing was performed on day 1 (pretreatment) and on days 3, 5, and 10 postinfection for the determination of bacteremia. Serum also was collected for the determination of pharmacokinetic and pharmacodynamic parameters at 30 min and at 3, 5, and 12 h (linezolid) or 3, 5, and 24 h (ceftriaxone) postdose. The cumulative mortality rates were 100% for the sham-treated group, 58.3% for the low-dose linezolid group, 8.3% for the high-dose linezolid group, and 0% for the ceftriaxone group. Rats in each of the antibiotic treatment groups had significantly fewer bacteria (P < 0.00001) in their bronchoalveolar lavage fluid (BALF) on day 3 postinfection than sham-treated rats. There also were significantly fewer organisms in the BALF of rats treated with ceftriaxone than in the BALF of rats treated with either dose of linezolid. Oral linezolid at 50 mg/kg b.i.d. therefore was as effective as ceftriaxone in experimental pneumococcal pneumonia, whereas the 25-mg/kg b.i.d. dose was significantly less effective. All pharmacodynamic parameters reflected efficacy and were significantly different for the two dosage regimens of linezolid (P < 0.01). However, the free-fraction pharmacodynamic parameters predictive of outcome were a value of >39% for the percentage of time in the experimental dosing interval during which the linezolid concentration exceeded the MIC and a value of >147 for the ratio of the area under the serum concentration-time curve to the MIC.

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Effect of Ethanol on Fluoroquinolone Efficacy in a Rat Model of Pneumococcal Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.1.210-219.2006 ◽

2006 ◽

Vol 50 (1) ◽

pp. 210-219 ◽

Cited By ~ 10

Author(s):

Keith M. Olsen ◽

Martha Gentry-Nielsen ◽

Mei Yue ◽

Mary U. Snitily ◽

Laurel C. Preheim

Keyword(s):

Rat Model ◽

Pneumococcal Pneumonia ◽

Lethal Dose ◽

Free Fraction ◽

Liquid Diet ◽

High Dose ◽

Sprague Dawley ◽

Time Curve ◽

Cell Counts ◽

Concentration Time

ABSTRACT This investigation compared the effect of ethanol on fluoroquinolone antibiotic efficacy and pharmacodynamics in an ethanol-fed rat model of pneumococcal pneumonia. Male Sprague-Dawley rats received a liquid diet containing 36% of total calories as ethanol. Paired controls (pair-fed controls) were fed a liquid diet without ethanol or received rat chow. Diets began 7 days before and continued for 10 days after transtracheal infections with 10 times the 50% lethal dose of type 3 Streptococcus pneumoniae. Beginning 18 h after infection, the rats received once daily subcutaneous phosphate-buffered saline, levofloxacin, moxifloxacin, or trovafloxacin at 50 or 100 mg/kg of body weight. White blood cell counts were determined, blood samples were collected for culture, and mortality was recorded. Additional rats were killed on day 5 for pharmacodynamic studies and quantitative cultures of bronchoalveolar lavage fluid. Bacteremia occurred by day 3 in 20 of 22 untreated rats. All 22 untreated rats died by day 9. Moxifloxacin treatment was effective in all diet groups at both the 50- and 100-mg/kg doses. In contrast, 50-mg/kg doses of levofloxacin and trovafloxacin improved survival in ethanol-fed rats but were ineffective in chow-fed rats. High-dose trovafloxacin at 100 mg/kg was associated with increased mortality in pair-fed rats. The free-fraction area under the concentration-time curve/MIC ratio exceeded 50 with all antibiotics in the ethanol group but dropped below 30 with levofloxacin and trovafloxacin in the pair- and chow-fed rats, with higher mortality. Achievement of adequate antibiotic-free fraction area under the concentration-time curve/MIC ratios helps overcome ethanol-induced immune defects induced in experimental pneumococcal pneumonia.

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Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽

10.3390/pharmaceutics13030386 ◽

2021 ◽

Vol 13 (3) ◽

pp. 386

Author(s):

Tung-Hu Tsai ◽

Yu-Jen Chen ◽

Li-Ying Wang ◽

Chen-Hsi Hsieh

Keyword(s):

Stereotactic Body Radiation Therapy ◽

In Vivo Studies ◽

Control Group ◽

High Dose ◽

Dependent Manner ◽

Hep G2 ◽

Time Curve ◽

Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

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Distal tubular electrolyte transport during inhibition of renal 11β-hydroxysteroid dehydrogenase

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.1.f172 ◽

2001 ◽

Vol 280 (1) ◽

pp. F172-F179 ◽

Cited By ~ 13

Author(s):

Katharine J. Biller ◽

Robert J. Unwin ◽

David G. Shirley

Keyword(s):

Distal Tubule ◽

Hydroxysteroid Dehydrogenase ◽

Treated Group ◽

High Dose ◽

Mineralocorticoid Receptors ◽

Distal Nephron ◽

Collecting Ducts ◽

Micropuncture Study ◽

Stimulation Of

To test the proposal that the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) confers aldosterone specificity on mineralocorticoid receptors in the distal nephron by inactivating glucocorticoids, we performed a free-flow micropuncture study of distal tubular function in adrenalectomized rats infused with high-dose corticosterone. One-half of the rats were additionally given intravenous carbenoxolone (CBX; 6 mg/h) to inhibit renal 11β-HSD activity. Although this maneuver lowered fractional Na+ excretion (1.1 ± 0.2 vs. 1.9 ± 0.2%, P < 0.01), Na+ reabsorption within the accessible distal tubule was found to be similar in the two groups of animals. In contrast, distal tubular K+ secretion was enhanced in CBX-treated rats: fractional K+ deliveries to the early and late distal collection sites in the corticosterone-alone group were 13 ± 1 and 20 ± 3%, respectively (not significant), whereas corresponding data in the CBX-treated group were 9 ± 1 and 24 ± 2% ( P < 0.01). This stimulation of distal K+ secretion provides the first direct in vivo evidence that 11β-HSD normally prevents corticosterone from exerting a mineralocorticoid-like effect in the distal tubule. The reduction in fractional Na+ excretion during inhibition of 11β-HSD, in the absence of a change in end-distal Na+delivery, suggests enhanced Na+ reabsorption in the collecting ducts.

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Pharmacokinetics and Time-Kill Study of Inhaled Antipseudomonal Bacteriophage Therapy in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01470-20 ◽

2020 ◽

Vol 65 (1) ◽

pp. e01470-20

Author(s):

Michael Y. T. Chow ◽

Rachel Yoon Kyung Chang ◽

Mengyu Li ◽

Yuncheng Wang ◽

Yu Lin ◽

...

Keyword(s):

Pulmonary Delivery ◽

Lavage Fluid ◽

Treated Group ◽

Multidrug Resistant ◽

Bacteriophage Therapy ◽

Content Type ◽

Optimal Dosing ◽

Potential Alternative ◽

Time Kill

ABSTRACTInhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR) Pseudomonas aeruginosa infections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different from antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study was to investigate the in vivo PK and PD profiles of antipseudomonal phage PEV31 delivered by pulmonary route in immune-suppressed mice. BALB/c mice were administered phage PEV31 at doses of 107 and 109 PFU by the intratracheal route. Mice (n = 4) were sacrificed at 0, 1, 2, 4, 8, and 24 h posttreatment and various tissues (lungs, kidney, spleen, and liver), bronchoalveolar lavage fluid, and blood were collected for phage quantification. In a separate study combining phage with bacteria, mice (n = 4) were treated with PEV31 (109 PFU) or phosphate-buffered saline (PBS) at 2 h postinoculation with MDR P. aeruginosa. Infective PEV31 and bacteria were enumerated from the lungs. In the phage-only study, the PEV31 titer gradually decreased in the lungs over 24 h, with a half-life of approximately 8 h for both doses. In the presence of bacteria, in contrast, the PEV31 titer increased by almost 2-log10 in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Of the 10 colonies tested, four phage-resistant isolates were observed from the lung homogenates sampled at 24 h after phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.

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Protection against ventricular arrhythmias and cardiac death using adenosine and lidocaine during regional ischemia in the in vivo rat

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00273.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. H1286-H1295 ◽

Cited By ~ 39

Author(s):

Sarah J. Canyon ◽

Geoffrey P. Dobson

Keyword(s):

Infarct Size ◽

Rat Model ◽

Cardiac Death ◽

Constant Infusion ◽

Therapeutic Window ◽

High Dose ◽

Sprague Dawley ◽

Myocardial Ischemia And Reperfusion ◽

Regional Ischemia

Despite decades of research, there are few effective ways to treat ventricular fibrillation (VF), ventricular tachycardia (VT), or cardiac ischemia that show a significant survival benefit. Our aim was to investigate the combined therapeutic effect of two common antiarrhythmic compounds, adenosine and lidocaine (AL), on mortality, arrhythmia frequency and duration, and infarct size in the rat model of regional ischemia. Sprague-Dawley rats ( n = 49) were anesthetized with pentobarbital sodium (60 mg·ml−1·kg−1 ip) and instrumented for regional coronary occlusion (30 min) and reperfusion (120 min). Heart rate, blood pressure, and a lead II electrocardiogram were recorded. Intravenous pretreatment began 5 min before ischemia and extended throughout ischemia, terminating at the start of reperfusion. After 120 min, hearts were removed for infarct size measurement. Mortality occurred in 58% of saline controls ( n = 12), 50% of adenosine only (305 μg·kg−1·min−1, n = 8), 0% in lidocaine only (608 μg·kg−1·min−1, n = 8), and 0% in AL at any dose (152, 305, or 407 μg·kg−1·min−1 adenosine plus 608 μg·kg−1·min−1 lidocaine, n = 7, 8, and 6). VT occurred in 100% of saline controls (18 ± 9 episodes), 50% of adenosine-only (11 ± 7 episodes), 83% of lidocaine-only (23 ± 11 episodes), 60% of low-dose AL (2 ± 1 episodes, P < 0.05), 57% of mid-dose AL (2 ± 1 episodes, P < 0.05), and 67% of high-dose AL rats (6 ± 3 episodes). VF occurred in 75% of saline controls (4 ± 3 episodes), 100% of adenosine-only-treated rats (3 ± 2 episodes), and 33% lidocaine-only-treated rats (2 ± 1 episodes) of the rats tested. There was no deaths and no VF in the low- and mid-dose AL-treated rats during ischemia, and only one high-dose AL-treated rat experienced VF (25.5 sec). Infarct size was lower in all AL-treated rats but only reached significance with the mid-dose treatment (saline controls 61 ± 5% vs. 38 ± 6%, P < 0.05). We conclude that a constant infusion of a solution containing AL virtually abolished severe arrhythmias and prevented cardiac death in an in vivo rat model of acute myocardial ischemia and reperfusion. AL combinational therapy may provide a primary prevention therapeutic window in ischemic and nonischemic regions of the heart.

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Efficacy of Ceftaroline against Methicillin-Susceptible Staphylococcus aureus Exhibiting the Cefazolin High-Inoculum Effect in a Rat Model of Endocarditis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00324-17 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 7

Author(s):

Kavindra V. Singh ◽

Truc T. Tran ◽

Esteban C. Nannini ◽

Vincent H. Tam ◽

Cesar A. Arias ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Body Weight ◽

Infective Endocarditis ◽

Rat Model ◽

Type A ◽

Treated Group ◽

Content Type ◽

High Inoculum ◽

Inoculum Effect

ABSTRACT Certain Staphylococcus aureus strains exhibit an inoculum effect (InE) with cefazolin (CFZ) that has been associated with therapeutic failures in high-inoculum infections. We assessed the in vitro activities of ceftaroline (CPT), CFZ, and nafcillin (NAF) against 17 type A β-lactamase (βla)-producing, methicillin-susceptible S. aureus (MSSA) strains, including the previously reported TX0117, which exhibits the CFZ InE, and its βla-cured derivative, TX0117c. Additionally, we determined the pharmacokinetics of CPT in rats after single intramuscular doses of 20 and 40 mg/kg of body weight and evaluated the activities of CPT (40 mg/kg every 8 h [q8h]), CFZ, and NAF against TX0117 and TX0117c in a rat model of infective endocarditis. No InE was observed for CPT or NAF, whereas a marked InE was detected for CFZ (MIC, 8 to ≥128 μg/ml). CPT and NAF treatment against TX0117 resulted in mean bacterial counts of 2.3 and 2.1 log10 CFU/g in vegetations, respectively, compared to a mean of 5.9 log10 CFU/g in the CFZ-treated group (CPT and NAF versus CFZ, P = 0.001; CPT versus NAF, P = 0.9830). Both CFZ and CPT were efficacious against the βla-cured derivative, TX0117c, compared to time zero (t 0) (P = <0.0001 and 0.0015, respectively). Our data reiterate the in vivo consequences of the CFZ InE and show that CPT is not affected by this phenomenon. CPT might be considered for high-inoculum infections caused by MSSA exhibiting the CFZ InE.

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Impaired functional recovery of endothelial colony-forming cells from moyamoya disease in a chronic cerebral hypoperfusion rat model

Journal of Neurosurgery Pediatrics ◽

10.3171/2018.8.peds1883 ◽

2019 ◽

Vol 23 (2) ◽

pp. 204-213 ◽

Cited By ~ 7

Author(s):

Seung Ah Choi ◽

Sangjoon Chong ◽

Pil Ae Kwak ◽

Youn Joo Moon ◽

Anshika Jangra ◽

...

Keyword(s):

Moyamoya Disease ◽

Functional Recovery ◽

Rat Model ◽

Treated Group ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Blue Staining ◽

Vessel Occlusion ◽

Endothelial Colony Forming Cells

OBJECTIVEEndothelial colony-forming cells (ECFCs) isolated from pediatric patients with moyamoya disease (MMD) have demonstrated decreased numbers and defective functioning in in vitro experiments. However, the function of ECFCs has not been evaluated using in vivo animal models. In this study, the authors compared normal and MMD ECFCs using a chronic cerebral hypoperfusion (CCH) rat model.METHODSA CCH rat model was made via ligation of the bilateral common carotid arteries (2-vessel occlusion [2-VO]). The rats were divided into three experimental groups: vehicle-treated (n = 8), normal ECFC-treated (n = 8), and MMD ECFC-treated (n = 8). ECFCs were injected into the cisterna magna. A laser Doppler flowmeter was used to evaluate cerebral blood flow, and a radial arm maze test was used to examine cognitive function. Neuropathological examinations of the hippocampus and agranular cortex were performed using hematoxylin and eosin and Luxol fast blue staining in addition to immunofluorescence with CD31, von Willebrand factor, NeuN, myelin basic protein, glial fibrillary acidic protein, and cleaved caspase-3 antibodies.RESULTSThe normal ECFC-treated group exhibited improvement in the restoration of cerebral perfusion and in behavior compared with the vehicle-treated and MMD ECFC-treated groups at the 12-week follow-up after the 2-VO surgery. The normal ECFC-treated group showed a greater amount of neovasculogenesis and neurogenesis, with less apoptosis, than the other groups.CONCLUSIONSThese results support the impaired functional recovery of MMD ECFCs compared with normal ECFCs in a CCH rat model. This in vivo study suggests the functional role of ECFCs in the pathogenesis of MMD.

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In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii

Pharmaceuticals ◽

10.3390/ph14080823 ◽

2021 ◽

Vol 14 (8) ◽

pp. 823

Author(s):

Tsung-Ying Yang ◽

Sung-Pin Tseng ◽

Heather Nokulunga Dlamini ◽

Po-Liang Lu ◽

Lin Lin ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Antibacterial Activities ◽

Treated Group ◽

Infection Model ◽

High Dose ◽

Mouse Infection Model ◽

Carbapenem Resistant ◽

Time Kill

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies.

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A Validated Liquid Chromatographic Method for Berberine Analysis in Tissue and Application

International Journal of Analytical Chemistry ◽

10.1155/2020/8892696 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Neng Zhou ◽

Dangmei Liu ◽

Xiaowang Bao

Keyword(s):

High Performance ◽

Saturated Model ◽

High Dose ◽

Rat Tissues ◽

Long Term Stability ◽

Liquid Chromatographic Method ◽

Significant Difference ◽

Liquid Chromatographic

Simple and rapid high-performance liquid chromatography methods were developed for the determination of berberine (BB) in various rat tissues so as to evaluate a P-gp inhibitor, glycyrrhetinic acid (GA), on BB’s oral bioavailability. Acetonitrile was used to extract BB from tissues and showed different extraction recoveries in diverse tissues. The intra- and interday precision and accuracy were less than 10%. Long-term stability, pre (post) -preparative stability, and freeze-thaw stability were evaluated, and the results showed it could meet the need of this study. The proposed methods were subsequently applied to investigate the possible drug-drug interaction of GA and BB in vivo from the aspect of tissue distribution. The results showed that no significant difference was found between the group of low dose and high dose at the same time point. The tissue distributions show a saturated model, i.e., the content of BB in tissue tends to be constant while its dose is more than 200 mg/kg. Besides, the contents of BB ranged from high to low according to the order of the liver, kidney, and spleen. The BB content in the liver is especially high as compared to other tissues.

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Salidroside Mitigates Airway Inflammation in Asthmatic Mice via the AMPK/Akt/GSK3β Signaling Pathway

International Archives of Allergy and Immunology ◽

10.1159/000519295 ◽

2021 ◽

pp. 1-11

Author(s):

Xue Luan ◽

Chunai Cui ◽

Jingzhi Jiang ◽

Chongyang Wang ◽

Li Li ◽

...

Keyword(s):

Airway Inflammation ◽

Dose Group ◽

Bronchial Hyperresponsiveness ◽

Lavage Fluid ◽

Inflammatory Factors ◽

Control Group ◽

High Dose ◽

Inflammatory Infiltration ◽

Ifn Γ

Introduction: This study aimed to explore the effects and mechanisms of salidroside (SAL) in airway inflammation in asthmatic mice. Methods: Mice were sensitized with ovalbumin (OVA) to establish an asthma model. They were divided into the control group, OVA group, SAL low-dose group (SAL-L), SAL high-dose group (SAL-H), and dexamethasone (DXM) group. The airway reactivity of the mice was measured, and the total cells, neutrophils, eosinophils, and lymphocytes were counted, respectively. The levels of IL-4, IL-5, IL-13, and IFN-γ in bronchoalveolar lavage fluid (BALF) were detected by ELISA. Immunohistochemistry was used to detect the expression levels of p-AMPK, p-Akt, and p-GSK3β. Western blot was used to detect cytokine levels in lung tissue and p-AMPK, p-Akt, and p-GSK3β levels in LPS-induced 16HBE cells. Results: The airway hyperresponsiveness of asthmatic mice in the SAL-H group decreased (p < 0.05), and the total number of cells, neutrophils, eosinophils, and lymphocytes decreased significantly (p < 0.05). In addition, the airways of mice showed airway inflammatory infiltration and goblet cell proliferation, and the corresponding cellular inflammatory factors IL-4, IL-5, and IL-13 were significantly decreased. However, the expression of IFN-γ in BALF and lung tissues was increased (p < 0.05). Moreover, after the mice were treated with SAL, the phosphorylation level of AMPK was significantly increased, which further reduced the phosphorylation levels of Akt and GSK3β (p < 0.05). Both SAL and AMPK inhibitors exerted effects on LPS-induced 16HBE cells, consistent with in vivo results. Conclusion: SAL can inhibit bronchial hyperresponsiveness and reduce tracheal inflammation by increasing AMPK phosphorylation and inhibiting Akt and GSK3β signaling pathways.

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