The treatment of psoriasis remains elusive, underscoring the need for identifying novel disease targets and mechanism-based therapeutic approaches. We recently reported that the PI3K/Akt/mTOR pathway that is frequently deregulated in many malignancies is also clinically relevant for psoriasis. We also provided rationale for developing delphinidin (Del), a dietary antioxidant for the management of psoriasis. This study utilized high-throughput biophysical and biochemical approaches and in vitro and in vivo models to identify molecular targets regulated by Del in psoriasis.A kinome-level screen and Kds analyses against a panel of 102 human kinase targets showed that Del binds to three lipid (PIK3CG, PIK3C2B, and PIK3CA) and six serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK2, and AURKB) kinases, five of which belong to the PI3K/Akt/mTOR pathway. Surface plasmon resonance and in silico molecular modeling corroborated Del's direct interactions with three PI3Ks (α/c2β/γ), mTOR, and p70S6K. Del treatment of interleukin-22 or TPA-stimulated normal human epidermal keratinocytes (NHEKs) significantly inhibited proliferation, activation of PI3K/Akt/mTOR components, and secretion of proinflammatory cytokines and chemokines. To establish the in vivo relevance of these findings, an imiquimod (IMQ)-induced Balb/c mouse psoriasis-like skin model was employed. Topical treatment of Del significantly decreased (i) hyperproliferation and epidermal thickness, (ii) skin infiltration by immune cells, (iii) psoriasis-related cytokines/chemokines, (iv) PI3K/Akt/mTOR pathway activation, and (v) increased differentiation when compared with controls. Innovation and Conclusion: Our observation that Del inhibits key kinases involved in psoriasis pathogenesis and alleviates IMQ-induced murine psoriasis-like disease suggests a novel PI3K/AKT/mTOR pathway modulator that could be developed to treat psoriasis. Antioxid. Redox Signal. 26, 49-69.
Abstract The most common signature of aggressive cancers such as prostate cancer (PCa) involves metastasis. Tumor cell migration is a key step for formation of cancer metastasis and recent data suggest that mammalian target of rapamycin (mTOR) controls the metastatic landscape of PCa by regulating the expression of genes known to be involved in PCa metastasis. Also, current estimates suggest that PI3K/Akt/mTOR signaling is upregulated in 30-50% of PCa patients. We observed that the expression of a set of four signature genes YB-1, MTA1, CD-44 and vimentin, regulated by mTOR and known to be involved in metastasis, is significantly higher in PCa PC-3 and DU145 cells compared to normal prostate epithelial cells. siRNA mediated knockdown of YB-1 in both PC-3 and DU-145 cells resulted in inhibition of EMT as seen by a significant decrease in mesenchymal morphology associated with induction of E-cadherin and inhibition of YB-1. We recently showed that fisetin, a dietary flavonoid, is also a specific inhibitor of the mTOR pathway. We hypothesized that fisetin will inhibit epithelial to mesenchymal transition (EMT) in PCa cells by binding to and inhibiting the YB-1. Using in silico docking studies, we observed that fisetin interacts with the cold shock domain (CSD) of the YB-1 molecule. Fisetin binds to YB-1 protein located on residues from β1 and β4 strands of the CSD and shows consistent binding modes and tight affinity within the amino acid pocket. Calculated free binding energy for these conformations ranged from -11.9845 to -9.6273 kcal/mol suggesting strong binding affinity. Treatment of PCa PC-3 and DU145 cells with fisetin (0-80 μM) resulted in inhibition of cell motility that was associated with inhibition of phosphorylation of mTOR at Ser2481 and Ser2448 and YB-1. Using immuno-fluorescence we found that fisetin treatment induced E-cadherin re-expression and inhibited vimentin expression in both DU-145 and PC-3 cells suggesting a reversal of the EMT. This reversal of EMT phenotype was also associated with induction of occludin and claudin-1 and inhibition of fibronectin, N-cadherin, MTA1 and CD-44 expression. We also observed that fisetin treatment inhibited nuclear expression of repressors of EMT such as Snail, Slug and Twist. Because tumor cell migration is a key step for formation of cancer metastasis, we determined the effect of fisetin on cell migration using PC-3 cells. Fisetin treatment inhibited cell migration at both 40 and 80 μM that was associated with decrease in the expression of MMP2 and MMP9. In summary, we observed that YB-1 expression induces EMT in PCa cells and identified fisetin as a novel agent that binds to it and potentially interferes with its activity. Based on our observations we suggest that fisetin could be developed as a clinically relevant inhibitor of mTOR/YB-1 with therapeutic benefit for PCa metastasis and invasion. Citation Format: Vaqar Mustafa Adhami, Mohammad Imran Khan, Rahul K. Lall, Imtiaz A. Siddiqui, Deeba N. Syed, Mario Sechi, Shah-Jahan M. Dodwad, Hasan Mukhtar. Role of YB-1, a regulator of epithelial to mesenchymal transition, in prostate cancer: inhibition by a dietary flavonoid fisetin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5551. doi:10.1158/1538-7445.AM2013-5551
The incidence of acute and chronic pancreatitis is increasing in the United States. Rates of acute pancreatitis (AP) are similar in both sexes, but chronic pancreatitis (CP) is more common in males. When stratified by etiology, women have higher rates of gallstone AP, while men have higher rates of alcohol- and tobacco-related AP and CP, hypercalcemic AP, hypertriglyceridemic AP, malignancy-related AP, and type 1 autoimmune pancreatitis (AIP). No significant sex-related differences have been reported in medication-induced AP or type 2 AIP. Whether post-endoscopic retrograde cholangiopancreatography pancreatitis is sex-associated remains controversial. Animal models have demonstrated sex-related differences in the rates of induction and severity of AP, CP, and AIP. Animal and human studies have suggested that a combination of risk factor profiles, as well as genes, may be responsible for the observed differences. More investigation into the sex-related differences of AP and CP is desired in order to improve clinical management by developing effective prevention strategies, diagnostics, and therapeutics.
Dysphagia is associated with increased morbidity, mortality, and resource utilization in hospitalized patients, but studies on outcomes in geriatric trauma patients with dysphagia are limited. We hypothesized that geriatric trauma patients with dysphagia would have worse clinical outcomes compared with those without dysphagia.Patients with and without dysphagia were compared in a single-center retrospective cohort study of trauma patients aged ≥65 years admitted in 2019. The primary outcome was mortality. Secondary outcomes included intensive care unit (ICU) length of stay (LOS), hospital LOS, discharge destination, and unplanned ICU admission. Multivariable regression analyses and Bayesian analyses adjusted for age, Injury Severity Score, mechanism of injury, and gender were performed to determine the association between dysphagia and clinical outcomes.Of 1706 geriatric patients, 69 patients (4%) were diagnosed with dysphagia. Patients with dysphagia were older with a higher Injury Severity Score. Increased odds of mortality did not reach statistical significance (OR 1.6, 95% CI 0.6 to 3.4, p=0.30). Dysphagia was associated with increased odds of unplanned ICU admission (OR 4.6, 95% CI 2.0 to 9.6, p≤0.001) and non-home discharge (OR 5.2, 95% CI 2.4 to 13.9, p≤0.001), as well as increased ICU LOS (OR 4.9, 95% CI 3.1 to 8.1, p≤0.001), and hospital LOS (OR 2.1, 95% CI 1.7 to 2.6, p≤0.001). On Bayesian analysis, dysphagia was associated with an increased probability of longer hospital and ICU LOS, unplanned ICU admission, and non-home discharge.Clinically apparent dysphagia is associated with poor outcomes, but it remains unclear if dysphagia represents a modifiable risk factor or a marker of underlying frailty, leading to poor outcomes. This study highlights the importance of screening protocols for dysphagia in geriatric trauma patients to possibly mitigate adverse outcomes.Level III.
Retrospective review of patient cohort.Our goal was to assess the validity of the Thoracolumbar Injury Classification and Severity (TLICS) score system by comparing the TLICS system to prior management of thoracolumbar injuries at our institution between January 1, 2006 to March 31, 2011.TLICS was introduced in 2005 to classify and assign treatment recommendations for injuries based on 3 axes: mechanism of injury, integrity of the posterior ligamentous complex, and neurological status.We retrospectively obtained and analyzed patient data regarding thoracolumbar junction injuries at a major academic medical center servicing level I trauma. In addition, we compared the American Spinal Injury Association (ASIA) class at time of injury to last follow-up to determine if there was any change in neurological status after intervention. We also compared sex, injury severity score (ISS), length of hospitalization, and age between nonoperatively and operatively treated patients.Included in our study were 201 patients (70% male and 30% female). We found the TLICS system agreed with prior thoracolumbar junction injury management at our institution 98% of the time in nonoperatively treated patients and 78% of the time in operatively treated patients. Age, sex, and ISS were not statistically significant factors in patients who were treated operatively versus nonoperatively, however, there was a trend towards higher ISS in operatively treated patients. Average TLICS score between nonoperative and operative groups was 1.56 and 4.8, respectively, and was a statistically significant difference. There was no statistically significant difference in ASIA class improvement between operative and nonoperative treatment, however, this is likely because of having only 20 patients in this subcohort. Of note, about 50% of the 17 operatively treated patients had improvement in ASIA class.Our data suggest that TLICS is a valuable tool in a spine surgeon's armamentarium in treating thoracolumbar junction injuries. Some surgeons might be more likely to operate on thoracolumbar junction injuries that should be treated nonoperatively according to the TLICS score. As with all classification schemes, the TLICS system should be used in conjunction with sound clinical judgment.
