Pipeline versus non-pipeline flow diverter treatment for M1 aneurysms: A systematic review and meta-analysis.

BACKGROUND: The flow diversion treatment of aneurysms located distal to the Circle of Willis has recently increased in frequency. We conducted a systematic review and meta-analysis of the clinical and radiological outcomes of flow diverter (FD) embolization in treating M1 aneurysms. METHODS: PubMed, Web of Science, Ovid Medline, Ovid Embase, and Scopus were searched up to May 2024 using the Nested Knowledge platform. We included studies assessing the long-term clinical and radiological outcomes for M1 aneurysms. Results of FDs classified as Pipeline Embolization Devices (PED) versus other types of FDs. Angiographic occlusion rates, ischemic and hemorrhagic complications, and favorable clinic outcomes were included. All data were analyzed using R software version 4.2.2. RESULTS: Thirteen studies with 112 total patients (58 patients for PED and 54 patients for other FD devices) were included in our meta-analysis. The overall adequate (complete + near-complete) occlusion rates were 85.1%. The complete occlusion rate was higher with PED than with other FD devices (72.9% PED and 41.6% for non-PED FDs, respectively, p-value <.01). The ischemic complications were 9.9% and 9.0% for the PED and non-PED groups, respectively (p-value = .89). The overall modified Rankin Scale 0-2 was 100% for the non-PED and 97.1% for the PED group (p-value = .51). In-stent stenosis rate was 7.5% for PED devices compared to 2.6% in the non-PED group (p-value = .35). CONCLUSIONS: This relatively small meta-analysis showed high rates of adequate and complete occlusion in FD treatment of M1 segment aneurysms, with favorable safety profiles. PEDs were associated with higher rates of complete aneurysm occlusion compared to other types of FDs.

Safety and efficacy profile of off-label use of the Pipeline Embolization Device: A systematic review and meta-analysis.

OBJECTIVE: The off-label utilization of the Pipeline Embolization Device (PED) is a common practice in numerous medical centers globally. Therefore, we conducted a systematic review and meta-analysis to evaluate the overall outcomes of this off-label usage of PEDs. METHODS: PubMed, Web of Science, Ovid Medline, Ovid Embase, and Scopus were searched up to February 2023 using the Nested Knowledge platform to identify studies assessing the off-label use of PEDs. Any use of PED outside of the FDA-approved indication granted in 2018 is considered off-label use. Overall angiographic occlusion rates, ischemic and hemorrhagic complications, mortality, retreatment rates, and favorable clinic outcomes were included. Statistical analyses were performed to compare the overall outcome rates of anterior cerebral artery(ACA) vs. middle cerebral artery(MCA) and anterior vs posterior circulation subgroups. RESULTS: We included 26 studies involving a total of 1,408 patients. The overall rate of complete occlusion was 80.3 % (95 % CI= 76.0-84.1). Subgroup analysis demonstrated a statistically significant difference in the rate of complete occlusion between anterior circulation (78.9 %) and posterior circulation (69.2 %) (p value=0.02). The rate of good clinical outcomes was 92.8 % (95 % CI= 88.8-95.4). The mortality rate was 1.4 % (95 % CI= 0.5-2.7). The overall rate of ischemic complications was 9.5 % (95 % CI= 7.7-11.6), with a comparable difference between anterior circulation (7.7 %) and posterior circulation (12.8 %) (p value=0.07). There was no statistically significant difference in MCA vs ACA subgroups in all parameters. CONCLUSIONS: Off-label use of PEDs can be a safe and effective treatment option for intracranial aneurysms. However, there is a need for more prospective, high-quality, non-industry-funded registry studies and randomized trials to test the efficacy and safety of off-label usage of PEDs and to expand its indications.

National Institutes of Health grant funding for cerebrovascular diseases.

BACKGROUND: Federal research funding is highly sought after but may be challenging to attain. A clear understanding of funding for specific diseases, such as cerebrovascular disorders, might help researchers regarding which National Institutes of Health (NIH) institutes fund research into specific disorders and grant types. OBJECTIVE: To examine the current scope of NIH grant funding for cerebrovascular conditions. METHODS: The NIH-developed RePORTER was used to extract active NIH-funded studies related to cerebrovascular diseases through January 2023. Duplicate studies were removed, and projects were manually screened and labeled in subcategories as clinical and basic science and as research subcategories. Extracted data included total funding, grant types, institutions that received funding, and diseases studied. Python (version 3.9) and SciPy library were used for statistical analyses. RESULTS: We identified 1232 cerebrovascular projects across seven diseases with US$699 952 926 in total funding. The cerebrovascular diseases with the greatest number of grants were ischemic stroke (705, or 57.2% of all funded projects), carotid disease (193, or 15.7%), and hemorrhagic stroke (163, or 13.2%). R01 grants were the most common mechanism of funding (632 grants, or 51.3%). The National Institute of Neurological Disorders and Stroke (NINDS) funded the most projects (504 projects; US$325 536 405), followed by the National Heart, Lung, and Blood Institute (NHLBI) (376 projects; US$216 784 546). CONCLUSION: Cerebrovascular disease receives roughly US$700 million in NIH funding. Ischemic stroke accounts for the majority of NIH-funded cerebrovascular projects, and R01 grants are the most common funding mechanism. Notably, NHLBI provides a large proportion of funding, in addition to NINDS.

Effects of intravenous thrombolysis on stent retriever and aspiration thrombectomy outcomes: a systematic review and meta-analysis of the randomized controlled trials.

BACKGROUND: Risks and benefits of intravenous thrombolysis (IVT) in patients undergoing mechanical thrombectomy (MT) have been a topic of interest. However, IVT's specific effects on stent retriever (SR) and aspiration thrombectomy (ASP) outcomes remain largely unexplored. In this meta-analysis, we aimed to investigate the effects of IVT on SR and ASP thrombectomy outcomes. METHODS: In accordance with PRISMA guidelines, a systematic literature review was conducted using Medline, Embase, Scopus, Web of Science, and Cochrane Center of Clinical Trials databases. Outcomes of interest included successful recanalization (modified Thrombolysis In Cerebral Infarction (mTICI) ≥2b), modified first pass efficacy (mFPE), functional independence (modified Rankin Scale (mRS) ≤2), symptomatic intracranial hemorrhage (sICH), and embolization to new territories (ENT). RESULTS: Four randomized controlled trials with 1176 patients were included. SR and ASP resulted in similar mTICI ≥2b, mFPE, and mRS 0-2 rates in patients with and without IVT administration. SR without IVT was associated with a significantly lower rate of mFPE compared with the SR+IVT (RR 0.85, 95% CI 0.74 to 0.97). Furthermore, ASP without IVT resulted in a lower rate of mRS 0-2 than the ASP+IVT with a strong trend towards significance (RR 0.78, 95% CI 0.60 to 1.01). Finally, bridging therapy did not increase sICH and ENT rates after ASP or SR thrombectomy. CONCLUSIONS: Our findings suggest that SR and ASP thrombectomy have comparable safety and efficacy profiles, regardless of prior IVT administration. Additionally, our results indicate that the addition of IVT may improve certain efficacy outcomes based on the employed first-line MT technique.

Outcomes of mechanical thrombectomy in M1 occlusion patients with or without hyperdense middle cerebral artery sign: A systematic review and meta-analysis.

BACKGROUND: The comparison of mechanical thrombectomy (MT) outcomes between patients with the hyperdense middle cerebral artery sign (HMCAS) and non-HMCAS is important to evaluate the impact of this radiological finding on treatment efficacy. This meta-analysis aimed to assess the association between HMCAS and clinical outcomes in patients undergoing thrombectomy, comparing the outcomes over non-HMCAS. METHODS: A systematic literature search was conducted in PubMed, Ovid Embase, Google Scholar, and Cochrane Library to identify studies on MT outcomes for M1 occlusions of HMCAS over non-HMCAS. Inclusion criteria encompassed modified Rankin Scale (mRS) score, mortality, symptomatic intracranial hemorrhage (sICH), and successful recanalization. Using R software version 4.1.2, we calculated pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CI). RESULTS: The meta-analysis was performed for 5 studies with 724 patients. There was no association found between presence of HMCAS and achieving mRS 0-2 (OR = 0.65, 95% CI: 0.29-1.47; p = .544). Mortality analysis also showed no significant association with presence of HMCAS (OR = 0.78, 95% CI: 0.37-1.65; p = .520). No significant difference in sICH risk (OR = 1.54, 95% CI: 0.24-9.66; p = .646) was found between groups. Recanalization analysis showed a non-significant positive association (OR = 1.23, 95% CI: 0.67-2.28; p = .501). Heterogeneity was observed in all analyses. CONCLUSION: Our findings showed that there is no statistically significant difference in mRS scores, mortality, sICH, and recanalization success rates between the HMCAS and non-HMCAS groups.

Distal versus conventional transradial access for diagnostic cerebral angiography and neurointerventional procedures: A systematic review and meta-analysis.

BACKGROUND: Distal transradial artery access (dTRA) has received increasing consideration for performing diagnostic cerebral angiography and neurointerventional procedures. In this meta-analysis, we aim to evaluate the safety and efficacy of dTRA compared to conventional transradial access (cTRA) for cerebral angiography and neurointerventions. METHOD: A systematic review and meta-analysis were conducted on studies investigating outcomes of dTRA and cTRA in neurointerventions. The primary outcome was technical success rates. Secondary outcomes included access site complication rates, crossover rates to alternative vessels, fluoroscopy time, and contrast volume. The random effects model was used to calculate the mean difference (MD) and odds ratios (OR) with 95% confidence intervals (Cl). RESULTS: Eight retrospective observational studies with a total of 1477 patients who underwent 1175 diagnostic cerebral angiography and 516 neurointerventional procedures using 546 dTRA and 1164 cTRA approaches were included in our meta-analysis. The technical success rate was similar between dTRA and cTRA groups (95.8% vs 91.4%; OR:1.65; 95% Cl: 0.52 to 5.22; P = 0.40). Similarly, no difference was seen in dTRA and cTRA regarding access site complications (2% vs 1.4%; OR: 1.31; 95% CI: 0.47 to 3.61; P = 0.61) and access site crossover (2.1% vs 5.3%; OR: 0.55; 95% Cl: 0.28 to 1.05; P = 0.07). After resolving heterogeneity among included studies, dTRA was associated with a shorter fluoroscopy time (MD: -0.91 min; 95% CI: -1.74 to -0.09; P = 0.03) and lower contrast volume (MD: -8.32 mL; 95% CI = -14.7 to -1.94; P = 0.011). CONCLUSION: Our findings suggest that the dTRA approach is a safe and effective alternative to the cTRA approach in patients undergoing cerebral angiography and neurointerventions.

Shell Versus Core Architecture and Biology of Thrombi in Acute Ischemic Stroke: A Systematic Review.

BACKGROUND: The presence of an outer shell has been recently described as a common feature of acute ischemic stroke (AIS) thrombi. We performed a systematic review of the current literature on shell genesis, structure, and clinical significance. METHODS: Following PRISMA guidelines, we searched Ovid Cochrane Central Register of Controlled Trials, Embase, Medline, Scopus, and Web of Science for studies reporting the composition and structure of AIS thrombi and clot analogs. Identified studies were added to Covidence software for primary screening. Two reviewers independently screened titles and abstracts followed by full-text screening. RESULTS: From 1290 identified studies, 10 were included in this review. Studies using histology/immunohistochemistry/immunofluorescence described fibrin, platelets, von Willebrand factor, and neutrophil extracellular traps as the main components of the shell. Scanning electron microscopy demonstrated a dense, compact fibrin/platelet-rich shell, and a core rich in polyhedrocytes. Microfluidics studies identified highly activated P-selectin-positive platelets and fibrin forming the core while secondary agonists adenosine diphosphate and thromboxane, along with loosely packed P-selectin-negative platelets constituted the shell. CONCLUSIONS: The composition, compaction, and integrity of the shell may impact thrombolysis and revascularization outcomes. The preponderance of studies supported this conclusion.

Middle meningeal artery embolization without surgical evacuation for chronic subdural hematoma: a single-center experience of 209 cases.

Background: Middle meningeal artery (MMA) embolization is a minimally invasive treatment option for new and recurrent chronic subdural hematomas (cSDH). Objective: To examine the safety and efficacy profile of MMA embolization without surgical evacuation for cSDH patients. Methods: A single-center retrospective study of patients with cSDHs treated by MMA embolization was undertaken. Patient demographics, hematoma characteristics, procedural details, and clinical and radiological outcomes were collected. The primary outcome was the need for retreatment, and the secondary outcomes were at least a 50% reduction in the maximum width of cSDH on the last CT imaging, complications, and an improvement in the modified Rankin scale (mRS) score. All results were presented as descriptive statistics. Results: A total of 209 MMA embolizations were successfully performed on 144 patients. Polyvinyl alcohol particles were the primary embolization agent in all procedures. Of the total of 206 cSDH, the median maximum width at pre-intervention and last follow-up were 12 and 3 mm, respectively, and the median reduction percentage was 77.5%, with a >50% improvement observed in 72.8% at the last follow-up imaging. A total of 13.8% of patients needed retreatment for recurrent, refractory, or symptomatic hematomas after embolization. The mRS score improved in 71 (49.3%) patients. Of 144 patients, 4 (2.8%) experienced complications related to the procedure, and 12 (8.4%) died during follow-up due to causes unrelated to the MMA embolization procedures. Conclusion: This study supports the fact that MMA embolization without surgical evacuation is a safe and effective minimally invasive option for the treatment of cSDHs.

Middle meningeal artery embolization combined with surgical evacuation for chronic subdural hematoma: A single-center experience of 75 cases.

BACKGROUND: Chronic subdural hematoma (cSDH) is a challenging and common neurosurgical condition. Our goal is to demonstrate that middle meningeal artery (MMA) embolization combined with surgical evacuation can be a promising adjuvant option for treatment of cSDHs and prevent recurrence in symptomatic patients who require surgical treatment. METHOD: We retrospectively collected data from patients who underwent MMA embolization using polyvinyl alcohol particles and surgical evacuation with burr hole or craniotomy in a single center for the treatment of new and recurrent cSDHs. The primary outcome was recurrence of cSDH requiring surgical rescue during follow up, and secondary outcomes were defined as >50% decrease in the maximum width of cSDHs on the longest follow-up computed tomography (CT) scan, complications following procedure, and improvement in modified Rankin scale (mRS) score. RESULTS: A total of 51 patients successfully underwent 72 MMA embolization procedures (96% of the total 75 cases in the cohort) combined with surgical evacuation. Seventy cases (93.3%) achieved at least 50% reduction in the size of the cSDHs on the last CT imaging. A surgical evacuation was required in five cases (6.7%) due to cSDH recurrence during the follow-up period. There were three complications (6.0%) related to embolization procedure. Forty patients (78.4%) showed improvement in mRS score. There was one mortality (2%) regardless of the embolization and evacuation. CONCLUSIONS: Our study demonstrates the safety and efficacy of adjunct MMA embolization in significantly reducing size and recurrence of cSDHs.

Metabolite signature in acute ischemic stroke thrombi: a systematic review.

Metabolites are reliable biomarkers for many diseases. However, their role in acute ischemic stroke (AIS) pathogenesis is not well understood. In this systematic review we aim to evaluate the current literature on the presence of metabolites in thrombi retrieved by mechanical thrombectomy from AIS patients. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines, we searched OVID Medline, PubMed, OVID Embase, Scopus, and Web of Science until July 13, 2022. Metabolites lists were extracted, and pathway analysis was performed in MetaboAnalyst database. Four articles listing metabolites were included in this systematic review. D-Glucose, diacylglycerol, phytosphingosine, galabiosylceramide, glucosylceramide and 4-hydroxynonenal were reported to be associated with clots. Metabolomics data analysis showed that glycolysis, lactose, and sphingolipid metabolism pathways were enriched. In conclusion, results of the present study show that the thrombi niche has a glycolytic phenotype. Future studies should work to better understand the metabolic properties of AIS thrombi.

Endovascular treatment outcomes of vertebrobasilar junction aneurysms: Systematic review and meta-analysis.

BACKGROUND: Vertebrobasilar junction (VBJ) aneurysms represent a relatively rare and often anatomically complex subgroup of saccular aneurysms. This systematic review and meta-analysis aimed to assess the safety and efficacy of endovascular treatment (EVT) of VBJ aneurysms. METHODS: PubMed, Web of Science, Ovid Medline, Ovid Embase, and Scopus were searched from inception to 20 December 2022. We included primary studies assessing the long-term clinical and angiographic outcomes for VBJ aneurysms treated with endovascular techniques. We excluded surgically managed studies. All data were analyzed using R software version 4.2.1. We calculated pooled prevalence rates and their corresponding 95% confidence intervals (CI). RESULTS: In this meta-analysis, a total of 76 VBJ aneurysms from seven studies were included for quantitative analysis. The results showed that the rate of adequate occlusion (complete + near complete occlusion) was 94.1% (95% CI = 76.71-98.71), and the rate of complete occlusion was 77.7% (95% CI = 63.07-87.65). A modified Rankin Scale (mRS) score of 0-2 was achieved in 93.9% of patients (95% CI = 67.65-99.14). The mortality rate was found to be 5.9% (95% CI = 0.97-28.55), and the retreatment rate was 4.6% (95% CI = 1.50-13.36). The overall ischemic complication rate was 4.7% (95% CI = 0.73-25.4), while the overall hemorrhagic complication rate was 4.6% (95% CI = 1.5-13.36). CONCLUSIONS: The treatment of VBJ aneurysms with EVT is effective in achieving curative treatment and is associated with good clinical outcomes and low mortality rates. These findings provide important insights into the clinical and angiographic outcomes and the complication rates of EVT for VBJ aneurysms.

2b Or 2c-3? A meta-analysis of first pass thrombolysis in cerebral infarction 2b vs multiple pass thrombolysis in cerebral infarction 2c-3 following mechanical thrombectomy for stroke.

BACKGROUND: Procedural success following mechanical thrombectomy for acute ischemic stroke is assessed using the thrombolysis in cerebral infarction scale. We conducted a systematic review and meta-analysis to determine whether outcomes differed between first pass thrombolysis in cerebral infarction 2b and multiple pass thrombolysis in cerebral infarction 2c-3. METHODS: We conducted a systematic review of the literature using PubMed, Embase, Scopus, and Web of Science. We included original studies in which outcomes were stratified based on first pass thrombolysis in cerebral infarction 2b and multiple pass thrombolysis in cerebral infarction 2c-3. The primary outcome of interest was the rate of modified Rankin Scale 0-2. Secondary outcomes of interest were rates of modified Rankin Scale 0-1, symptomatic intracranial hemorrhage, and mortality. We calculated odds ratios and corresponding 95% confidence intervals. RESULTS: Four studies with 1554 patients were included in the quantitative analysis. Rate of modified Rankin Scale 0-2 (odds ratio = 0.91, 95% confidence interval = 0.70-1.18; P-value = 0.49), modified Rankin Scale 0-1 (odds ratio = 1.21, 95% confidence interval = 0.86-1.71; P-value = 0.27), symptomatic intracranial hemorrhage (odds ratio = 1.36, 95% confidence interval = 0.47-3.98; P-value = 0.57), and mortality (odds ratio = 0.91, 95% confidence interval = 0.67-1.25; P-value = 0.56) did not differ between first pass thrombolysis in cerebral infarction 2b and multiple pass thrombolysis in cerebral infarction 2c-3. There was no heterogeneity among included studies for modified Rankin Scale 0-2, modified Rankin Scale 0-1, or mortality; however, there was moderate heterogeneity among studies for symptomatic intracranial hemorrhage (I2 = 53%, P-value = 0.12). CONCLUSIONS: Clinical and safety outcomes did not differ between first pass thrombolysis in cerebral infarction 2b and multiple pass thrombolysis in cerebral infarction 2c-3. Future prospective studies and clinical trials should determine whether first pass thrombolysis in cerebral infarction 2b is a viable endpoint to thrombolysis in cerebral infarction 2c-3.

The safety profile of single antiplatelet therapy with flow diverters: Systematic review and meta-analysis.

BACKGROUND: Dual antiplatelet therapy (DAPT) is frequently used in treating cerebral aneurysms with flow diverters (FDs), whereas single antiplatelet therapy (SAPT) is used mostly with coated FDs and in ruptured aneurysms. We conducted a systematic review and meta-analysis to explore the safety profile of SAPT in FDs. METHODS: PubMed, Web of Science, OVID Embase, OVID Medline, and Scopus were searched to 1st November 2022. Outcomes of interest included ischemic and hemorrhagic complications, conversion to DAPTs, and in-stent stenosis rates under long-term SAPT. SAPT is divided into aspirin (ASA) vs. non-ASA group (ticagrelor or prasugrel). Subgroup analysis was performed for ruptured vs. non-ruptured aneurysms and coated vs. non-coated FDs. All data were analyzed using R software version 4.2.2. RESULTS: Twelve studies with 240 total patients (43 patients in the ASA group and 197 patients in the non-ASA group) were included in our meta-analysis. The pooled ischemic occlusion rate was 9.8% (95% CI = 4.87-18.95: p-value = 0.09) for SAPTs. The ASA group had significantly higher ischemic complication rates compared to the non-ASA group (20.8% vs. 6.3%, respectively, p-value = 0.02). The pooled hemorrhagic complication rate was 3.5% (95% CI = 1.38-8.81: p-value > 0.99). The hemorrhagic rates of ASA group were 9.3%% (95% CI = 3.54-22.30) over the non-ASA group 2.1% (95% CI = 0.58-7.54) (p-value > 0.99). The overall in-stent stenosis rate was 2.3% (95% CI = 1.06-5.14: p-value > 0.99). The ischemic complication rates were comparable between coated vs non-coated FDs (10.7% vs. 5.5% p-value = 0.39). In stent stenosis rate were 1.9% (95% CI = 0.72-4.96) in coated FDs over 4.4% (95% CI = 1.11-16.11) (p-value = 0.32). The ruptured and non-ruptured groups also showed comparable results in terms of ischemic (17.6% vs. 7.1% respectively, p-value = 0.24) and hemorrhagic complications (9.8% vs. 1.1%, respectively, p-value = 0.08). CONCLUSIONS: Flow diverter treatment under ASA monotherapy resulted in relatively high ischemic complication rates. However, SAPT with prasugrel or ticagrelor monotherapy is promising for coated FDs and ruptured aneurysm treatments. Given the overall small sample size and also the likely presence of known and unknown biases regarding choice of antiplatelet therapy between groups, larger cohort studies are needed to evaluate SAPT treatment outcomes.

Correlation of von Willebrand factor and platelets with acute ischemic stroke etiology and revascularization outcome: an immunohistochemical study.

BACKGROUND: Platelets and von Willebrand factor (vWF) are key components of acute ischemic stroke (AIS) emboli. We aimed to investigate the CD42b (platelets)/vWF expression, its association with stroke etiology and the impact these components may have on the clinical/procedural parameters. METHODS: CD42b/vWF immunostaining was performed on 288 emboli collected as part of the multicenter STRIP Registry. CD42b/VWF expression and distribution were evaluated. Student's t-test and χ2 test were performed as appropriate. RESULTS: The mean CD42b and VWF content in clots was 44.3% and 21.9%, respectively. There was a positive correlation between platelets and vWF (r=0.64, p<0.001**). We found a significantly higher vWF level in the other determined etiology (p=0.016*) and cryptogenic (p=0.049*) groups compared with cardioembolic etiology. No significant difference in CD42b content was found across the etiology subtypes. CD42b/vWF patterns were significantly associated with stroke etiology (p=0.006*). The peripheral pattern was predominant in atherosclerotic clots (36.4%) while the clustering (patchy) pattern was significantly associated with cardioembolic and cryptogenic origin (66.7% and 49.8%, respectively). The clots corresponding to other determined etiology showed mainly a diffuse pattern (28.1%). Two types of platelets were distinguished within the CD42b-positive clusters in all emboli: vWF-positive platelets were observed at the center, surrounded by vWF-negative platelets. Thrombolysis correlated with a high platelet content (p=0.03*). vWF-poor and peripheral CD42b/vWF pattern correlated with first pass effect (p=0.03* and p=0.04*, respectively). CONCLUSIONS: The vWF level and CD42b/vWF distribution pattern in emboli were correlated with AIS etiology and revascularization outcome. Platelet content was associated with response to thrombolysis.

Zerumbone Sensitizes the Anti-Cancer Efficacy of Cisplatin in Hepatocellular Carcinoma Cells.

BACKGROUND: Zerumbone (ZER) exerts potent antiproliferative, apoptotic, and antiangiogenic functions against variety of cancer cells. Cisplatin (CIS), a standard chemotherapeutic drug, is effective against different types of cancers. However, the combined effect of ZER and CIS on hepatocellular carcinoma remains unknown. OBJECTIVE: The present study is attempted to examine the effectiveness of the combination of ZER and CIS in liver cancer in vitro using the hepatocellular carcinoma Huh-7 cell line. METHODS: Effect of ZER, CIS, and their combination therapy on cell viability and cytotoxicity was assessed by MTT and LDH leakage assays. Cell cycle and apoptosis analysis were performed by flow cytometry. Quantitative real-time PCR was used to examine the m-RNA expression of genes involved in apoptosis, angiogenesis, and invasion. Caspase activity was studied using commercial kit method in the Huh-7 cell line. RESULTS: Cells exposed to ZER, CIS individually, and both together significantly inhibited cell proliferation with IC50 values of 10 µM for ZER and 3 µM for CIS. The combination treatment of ZER and CIS revealed a synergistic effect with a CI value < 1. CIS treatment, either alone or in combination with ZER, caused cell cycle arrest in the S phase. More importantly, ZER combined with CIS exhibited synergistic effects in up-regulating Bax/Bcl-2 ratio, leading to caspase cascade activation. CONCLUSION: In conclusion, the current study indicates that the treatment of 4.62 µM of ZER combined with 1.93 µM of CIS in human liver cancer cells exerts synergistic effects on cell growth inhibition, apoptosis induction, angiogenesis, and invasion by modulating gene expression.

Evaluation of anti-cancer effect of zerumbone and cisplatin on N-nitrosodiethylamine induced hepatic cancer in freshwater fish (Danio rerio).

Cancer is the uncontrolled proliferation of abnormal cells in the body. There is a foreseeable need for an effective anti-carcinogenic drug. In this regard, zerumbone (ZER) is identified as one such therapeutic herbal compound that has been shown to enhance the anticancer activity of cisplatin (CIS), with negligible side effects. Yet, the fundamental mechanisms of co-treatment of ZER and CIS on Hepatocellular carcinoma remain indefinable. The current study is endeavored to evaluate the anti-cancer effect of the individual and co-treatment of ZER, CIS and its combination on Diethyl nitrosamine induced hepatic cancer in wild-type zebra fish (Danio Rerio) models. Our careful analysis on treated and untreated fishes shows that CIS + ZER combination group restricted further progression of hepatocellular carcinoma cells significantly, which concludes that co-treatment of ZER with CIS was therapeutically effective for treating human HCC cancer cells which were induced into zebra fish.

Beta-Caryophyllene Suppresses Ovarian Cancer Proliferation by Inducing Cell Cycle Arrest and Apoptosis.

BACKGROUND: Ovarian cancer is the fifth most common cause of cancer deaths among women with lesser prognostics. Current treatment options are chemotherapy with platinum and taxane based chemotherapy. ß-Caryophyllene (BCP) an essential oil found in many plant species is known to possess an anti-proliferative effect. OBJECTIVE: We aimed to investigate the antiproliferative, cytotoxic, and apoptotic role of BCP against ovarian cancer cells PA-1 and OAW 42. METHODS: The antiproliferative effect of BCP was determined by MTT assay and cell viability by trypan blue exclusion assay. Cell cycle and live/dead cell analyses were performed by flow cytometry to determine cell cycle distribution and apoptosis, respectively. RESULTS: Results of MTT assay proved the anti-proliferative effect of BCP in a dose and time-dependent manner in ovarian cancer cells. Cell cycle analysis showed that BCP induced S Phase arrest in OAW 42 cells. Results of apoptosis assay confirmed the apoptosis inducing potential of BCP in ovarian cancer cells. The apoptosis is mediated by caspase-3 activation and PARP cleavage. CONCLUSION: The results of our present study prove that BCP exerts its action partly by inducing cell cycle arrest and apoptosis in ovarian cancer. We conclude that BCP is a potential anti-cancer agent.

Induction of differentiation in psoriatic keratinocytes by propylthiouracil and fructose.

Psoriasis is characterized by uncontrolled proliferation and poor differentiation. Sirtuin1 (SIRT1) a class III deacetylase, crucial for differentiation in normal keratinocytes, is reduced in psoriasis. Down regulated SIRT1 levels may contribute to poor differentiation in psoriasis. In addition, the levels of early differentiation factors Keratin1 (K1) and Keratin10 (K10) are depleted in psoriasis. We attempted to study a possible effect of fructose, a SIRT1 upregulator and Propylthiouracil (PTU) to augment differentiation in psoriatic keratinocytes. Keratinocytes were cultured from lesional biopsies obtained from psoriatic patients and control cells were obtained from patients undergoing abdominoplasty. Cells were treated with fructose and PTU individually. K1 and K10 transcript levels were measured to evaluate early differentiation; SIRT1 protein expression was also studied to decipher its role in the mechanism of differentiation. The K1, K10 transcript levels, SIRT1 protein and transcript levels in fructose treated psoriatic keratinocytes were improved. This suggests keratinocyte differentiation was induced by fructose through SIRT1 upregulation. Whereas PTU induced differentiation, as confirmed by improved K1, K10 transcript levels followed a non-SIRT1 mechanism. We conclude that the use of fructose and PTU may be an adjunct to the existing therapies for psoriasis.

Zerumbone, a Sesquiterpene, Controls Proliferation and Induces Cell Cycle Arrest in Human Laryngeal Carcinoma Cell Line Hep-2.

Zerumbone (ZER), a sesquiterpene found in Zingiber zerumbet Smith, has been shown to possess antiproliferative, anticancer, antioxidant, and anti-inflammatory activity against various types of human carcinoma. The molecular mechanism by which ZER mediates its activity against many cancer types is revealed by many studies. Upregulation of proapoptotic molecules and suppression of antiapoptotic gene expression are few of the mechanisms by which ZER mediates its effect. The present study is focused on investigating the effect of ZER on proliferation of laryngeal carcinoma cells (Hep-2). MTT assay results showed that ZER (0.01-100 µM) induced death of Hep-2 cells in a concentration-dependent manner; significant suppression of proliferation of Hep-2 cells was seen with a IC50 value of 15 µM. ZER at a concentration of 15 and 30 µM for 48 h showed early signs of apoptosis as evidenced by confocal microscopy imaging. Flow cytometry studies showed that ZER induced cell cycle arrest. ZER arrested Hep-2 proliferation at S and G2/M phases of cell cycle. In conclusion, these results indicate that ZER has antiproliferative effect and arrests cell cycle in Hep-2 cells in vitro. This could be a potential anticancer drug against laryngeal carcinoma.