Fourteen immunomodulatory alkaloids and two prenylated phenylpropanoids with dual therapeutic approach for COVID-19: molecular docking and dynamics studies.

The pandemic outbreak of COVID-19 caused by the new severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a global health burden. To date, there is no highly effective antiviral therapy to eradicate the virus; as a result, researchers are racing to introduce new potential therapeutic agents. Alternatively, traditional immunity boosters and symptomatic treatment based on natural bioactive compounds are also an option. The 3-chymotrypsin-like protease (3CLpro) crystal structure, the main proteolytic enzyme of SARS-CoV-2, has been unraveled, allowing the development of effective protease inhibitors via in silico and biological studies. In COVID-19 infected patients, the loss of lung function, and mortality are reported to be linked to several inflammatory mediators and cytokines. In this context, the approach of introducing immunomodulatory agents may be considered a dual lifesaving strategy in combination with antiviral drugs. This study aims to provide immunomodulatory natural products exhibiting potential protease inhibitory activities. Selected groups of alkaloids of different classes and two prenylated phenylpropanoids from the Brazilian green propolis were in silico screened for their ability to inhibit COVID-19 3CLpro protease. Results showed that compounds exhibited binding energy scores with values ranging from -6.96 to -3.70 compared to the reference synthetic protease inhibitor O6K with a binding energy score of -7.57. O6K binding energy was found comparable with lead phytochemicals in our study, while their toxicity and drug-likeness criteria are better than that of O6K. The activities of these molecules are mainly ascribed to their ability to form hydrogen bonding with 3CLpro crucial amino acid residues of the catalytic site. In addition, the molecular dynamics simulations further showed that some of these compounds formed stable complexes as evidenced by the occupancy fraction measurements. The study suggested that the major immunomodulators 3ß, 20α-diacetamido-5α-pregnane, (20S)-(benzamido)-3ß-(N,N-dimethyamino)-pregnane, and baccharin are 3CLpro inhibitors. Biological screenings of these phytochemicals will be valuable to experimentally validate and consolidate the results of this study before a rigid conclusion is reached, which may pave the way for the development of efficient modulatory bioactive compounds with dual bioactions in COVID-19 intervention. Communicated by Ramaswamy H. Sarma.

Presentation and outcomes of thoracic and thoracoabdominal aortic aneurysms in females, existing gaps, and future directions: A descriptive review.

Thoracic and thoracoabdominal aortic aneurysms are more common in men. Yet, females often have worse outcomes, fewer interventions, and lower treatment rates. Females have also benefited less from the research and treatment of those diseases than men. Understanding sex- and sex-specific differences in thoracic and thoracoabdominal aortic aneurysms can improve care delivery, reduce disparities, and optimize outcomes for females with thoracic aortic aneurysms and thoracoabdominal aortic aneurysms. The authors reviewed the literature on the presentation and outcomes of thoracic and thoracoabdominal aortic aneurysms in females, discussing the existing gaps and future directions to address them.

Hybrid management of type B aortic dissection in a patient with right-sided aortic arch and aberrant left subclavian artery.

This report describes a patient with a right-sided aortic arch, aberrant left subclavian artery and Kommerell diverticulum, who presented with aneurysmal degeneration of the aortic root to the descending aorta, in addition to an acute type B2-10 aortic dissection. He underwent hybrid treatment with a valve-sparing aortic root replacement, transverse arch replacement with reattachment of the right subclavian artery, bilateral common carotid arteries, and thoracic endovascular aneurysm repair with left subclavian artery embolization and a left common carotid to subclavian artery bypass.

Deep Hypothermic Circulatory Arrest With Retrograde Cerebral Perfusion: How Long Is Safe?

BACKGROUND: Cerebral protection strategies during proximal aortic repair remains controversial due to lack of evidence and large patient cohort studies. We herein evaluated our 3-decade experience using hypothermic circulatory arrest with retrograde cerebral perfusion (DHCA/RCP) to evaluate for its safety and safe duration during proximal aortic repair. METHODS: All proximal aortic repairs using DHCA/RCP from January 1991 to December 2020 performed at our institution were included in the analyses. Perioperative variables were evaluated for mortality and cerebrovascular accident (CVA; combined stroke and transient ischemic attack). RESULTS: In all, 1429 repairs were performed using DHCA/RCP. Of these, 464 (32%) were acute aortic dissection and 297 (21%) were resternotomy. The median age was 61 years (interquartile range 50-70 years). Operative mortality was 8.9% and CVA occurred in 8.4% (stroke 7.8%, transient ischemic attack 0.6%). There was a linear relationship between the RCP time and the incidence of immediate postoperative CVA. Incidence of CVA was less than 5% when RCP time was less than 20 minutes, 6.3% at 30 minutes, and 11.5% at 60 minutes. Multivariable analysis demonstrated acute type A aortic dissection (odds ratio 2.58, 95% CI1.49-4.48, P = .001) was the only predictor for postoperative CVA but RCP time was not (odds ratio 0.991, 95% CI 0.962-1.02, P = .527). CONCLUSIONS: DHCA/RCA provided satisfactory outcomes after proximal aortic operations. The safe duration of RCP with DHCA was up to 30 minutes in our experience. When the circulatory arrest time is expected to exceed 60 minutes, other adjuncts for cerebral protection should be recommended.

Effect of sacubitril/valsartan on cognitive impairment in colchicine-induced Alzheimer's model in rats.

Alzheimer's disease (AD) is a complex neurodegenerative disease. There is epidemiological evidence that heart failure (HF) patients are at higher risk of developing AD, and the impact of sacubitril/valsartan, the first angiotensin receptor-neprilysin inhibitor (ARNI) approved for HF, on cognitive functions is still controversial. To investigate the effect of sacubitril/valsartan on cognitive functions in colchicine-induced AD rat model. Forty adult male Wistar rats were equally allocated into four groups (each of 10 rats): Group I: normal control, Group II: intracerebroventricular injection of colchicine (15 µg/5 µl/bilaterally), Group III: colchicine (15 µg/5 µl/bilaterally, icv) + oral sacubitril/valsartan (100 mg/kg/day) for 25 days, and Group IV: colchicine (15 µg/5 µl/bilaterally, icv) + oral valsartan (50 mg/kg/day) for 25 days. Behavioral assessment was done using Morris water maze and passive avoidance tasks. Biochemically, ß-amyloid (1-40 and 1-42) peptides, oxidative stress (malondialdehyde and superoxide dismutase) and inflammatory (tumor necrosis factor-alpha) parameters were measured in hippocampus and prefrontal cortex. Sacubitril/valsartan exaggerated colchicine-induced cognitive impairment in both Morris water maze and passive avoidance tasks and was associated with significant increase in ß-amyloid accumulation, oxidative stress, and inflammation versus valsartan. Sacubitril/valsartan caused deleterious effect on cognitive impairment and biochemical alterations in colchicine-induced AD rat model. Hence, special caution should be taken following long-term intake of ARNI on cognitive functions.

Study of cardioprotective activity of the methanolic extract of the aerial parts of Bauhinia madagascariensis compared to Bauhinia purpurea against adrenaline-induced myocardial toxicity in rats.

Cardiovascular ailments result in a great rate of mortality all over the world. Myocardial infarction is a common presentation of cardiovascular disease. The current work aimed to investigate and compare the cardioprotective potentials of methanolic extracts from the aerial parts from Bauhinia purpurea and Bauhinia madagascariensis in adrenaline-induced cardiotoxicity in rats. The rats were categorized into five groups as follows: control group, adrenaline-treated group, Bauhinia purpurea extract + adrenaline treated group, Bauhinia madagascariensis+ adrenaline treated group, reference drug (captopril) + adrenaline treated group. The extracts as well as the reference drug were orally administered for 21 consecutive days. On day 22, adrenaline was injected as a single dose for 2 consecutive days. The adrenaline injection caused a significant increase (p < 0.05) in serum cardiac markers (ALT, AST, CK-MB, LDH), angiotensin-converting enzyme (ACE) and matrix metalloproteinase (MMP-9), inducible nitric oxide synthase (iNOS) activities, tumor necrosis factor-α (TNF-α) cardiac lipid peroxides (MDA) levels and a significant decline (p < 0.05) in cardiac reduced glutathione (GSH) levels compared to their corresponding controls. The pretreatment extracts significantly ameliorated (p < 0.05) these alterations. Histopathological investigations supported the biochemical data. Bauhinia madagascariensis extract exerted a significant anti-inflammatory activity than that of Bauhinia purpurea. In addition, Bauhinia madagascariensis extract revealed a significant inhibitory activity on ACE compared to that of Bauhinia purpurea, (p < 0.05). These data reveal that both extracts had a strong protective activity against adrenaline-induced cardiotoxicity via improving cardiac function, reducing ECG and histopathological changes that could be mediated in part through its anti-oxidant, anti-inflammatory effects, inhibition of ACE, MMP-9, and iNOS.

Outcomes of open repairs of chronic distal aortic dissection anatomically amenable to endovascular repairs.

OBJECTIVE: To review short-term outcomes and long-term survival and durability after open surgical repairs for chronic distal aortic dissections in patients whose anatomy was amenable to thoracic endovascular aortic repair (TEVAR). METHODS: Between February 1991 and August 2017, we repaired chronic distal dissections in 697 patients. Of those patients, we enrolled 427 with anatomy amenable to TEVAR, which included 314 descending thoracic aortic aneurysms (DTAAs) and 105 extent I thoracoabdominal aortic aneurysms (TAAAs). One hundred eighty-five patients (44%) had a history of type A dissection, and 33 (7.9%) had a previous DTAA/TAAA repair. Variables were assessed with logistic regression for 30-day mortality and Cox regression for long-term mortality. Time-to-event analysis was performed using Kaplan-Meier methods. RESULTS: Thirty-day mortality was 8.4% (n = 36). In all, 22 patients (5.2%) developed motor deficit (paraplegia/paraparesis), and 17 (4.0%) experienced stroke. Multivariable analysis identified low estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m2), previous DTAA/TAAA repair, and chronic obstructive pulmonary disease (COPD) as associated with 30-day mortality. Patients without all 3 risk factors had a 30-day mortality rate of 2.6%. During a median follow-up of 6.5 years, 160 patients died. The survival rate was 81% at 1 year and 61% at 10 years. Cox regression analysis identified preoperative aortic rupture, eGFR <60 mL/min/1.73 m2, previous DTAA/TAAA repair, COPD, and age >60 years as predictive of long-term mortality. Forty-five patients required subsequent aortic procedures, including 8 reinterventions to the treated segment. Freedom from any aortic procedures was 85% at 10 years, and aortic procedure-free survival was 45% at 10 years. Hereditary aortic disease was the sole predictor for any aortic interventions (hazard ratio, 3.2; P = .004). CONCLUSIONS: Open surgical repair provided satisfactory low neurologic complication rates and durable repairs in chronic distal aortic dissection. Patients without low eGFR, redo, and COPD are the low-risk surgical candidates and may benefit from open surgical repair at centers with similar experience to ours. Patients with hereditary aortic disease warrant close surveillance.

Feasibility and Durability of the Modified Cabrol Coronary Artery Reattachment Technique.

BACKGROUND: This study evaluated the feasibility and durability of the modified Cabrol coronary reattachment technique after aortic root replacement. METHODS: The study retrospectively reviewed 370 patients who underwent aortic root replacement, during 1991 and 2018, and who were separated into 2 groups: a modified Carol (mCabrol) group (n = 84), consisting of patients with 1 or both coronary ostia reimplanted using a modified Cabrol technique; and a Carrel group (n = 286), consisting of patients with both coronary ostia reimplanted using the Carrel button technique. RESULTS: Baseline characteristics were similar in the 2 groups, except the mCabrol group had higher rates of redo sternotomy (74% vs 16%), chronic aortic dissection (58% vs 19%), and infection (14% vs 3%). In the mCabrol group, 60% had both coronary arteries reattached with the technique, and 40% of the procedures were unilateral. Operative mortality was significantly higher in mCabrol group compared with the Carrel group. However, in the stratified analysis for resternotomy, operative mortality between 2 groups were similar (16% vs 13%; P = .786). The survival rate at 5 years and 10 years was 68 ± 6% and 44 ± 6%, respectively, in the mCabrol group and 87 ± 2% and 80 ± 3%, respectively, in the Carrel group (log-rank P < .001). After propensity adjustment, chronic kidney disease and prior coronary artery bypass grafting, but not the modified Cabrol technique, were independent predictors of both operative mortality and follow-up mortality (operative, P = .518; follow-up, P = .080). A total of 47 (66%) of 71 discharged patients in the mCabrol group had follow-up imaging, and no Cabrol graft was occluded. Two patients in the mCabrol group required interventions related to the reattachment technique: 1 coronary ostial anastomosis stenosis and 1 graft-to-graft anastomosis pseudoaneurysm. CONCLUSIONS: The modified Cabrol reattachment technique was not predictive of increased mortality and has excellent patency.

Open Descending and Thoracoabdominal Aortic Repairs in Patients Younger Than 50 Years Old.

BACKGROUND: The purpose of this study was to redefine indications of open descending and thoracoabdominal aortic aneurysm repair in the younger population. METHODS: Between 1991 and 2017, 2012 patients undergoing descending and thoracoabdominal aortic aneurysm repair at our institution were divided into 2 groups for comparison: younger (<50 years; 276 [14%]) and older (≥50 years; 1736 [86%]). Patient demographics and perioperative outcomes were retrospectively reviewed. RESULTS: Younger patients had significantly more heritable thoracic aortic disease (HTAD; 53% vs 9%, P < .001) and chronic dissections (64% vs 26%, P < .001) and fewer comorbidities. The younger cohort underwent more extent II repairs (28% vs 15%, P < .001). Operative mortality was significantly lower in younger patients (6% vs 17%, P < .001). Significant disabling complications (composite of operative mortality, paraplegia/paraparesis, stroke, and dialysis) were seen in 17% of the younger patients and in 40% of older patients 40% (P < .001). In multivariate analysis, extent of repair and chronic obstructive pulmonary disease were independent predictors for significant disabling complications in the younger cohort. Additional aortic interventions were required in 12% in the younger group and in 4% in the older group (P < .001), and nearly one-third were in the treated segment (ie, treatment failure) in both groups. Younger patients requiring additional reintervention had significantly higher incidence of HTAD (66% vs 9%, P < .001). Survival rate was significantly higher in the younger patient group, with a 10-year survival rate of 74.6% ± 2.9% vs 40.7% ± 1.3% (log-rank P < .001). CONCLUSIONS: Patients younger than 50 years with descending and thoracoabdominal aortic aneurysm have low surgical risks, and open repairs can be performed with excellent short-term and durable long-term results. Open surgical repairs should be considered initially in younger patients requiring descending and thoracoabdominal aortic aneurysm repairs. HTAD warrants closer postoperative surveillance.

Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T.

BACKGROUND: Cardiac hypertrophy is a major risk factor for morbidity and mortality in a number of cardiovascular diseases. Consequently, the signaling pathways that inhibit cardiac hypertrophy are currently receiving much interest. Among them, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase I, has been recognized as a negative regulator of cardiac hypertrophy. The present study investigated the in-vivo effect of sildenafil as a phosphodiestrase-5A (PDE-5A) inhibitor on the hypertrophic response of rat heart to isoproterenol and the relation of this effect to the level of myocardial cGMP and integrity of the constitutive nitric oxide synthase (cNOS) activity. RESULTS: The results showed that daily intraperitoneal administration of sildenafil per se for 10 days was without noticeable adverse effects on survival or myocardium. Conversely, daily subcutaneous administration of isoproterenol for 10 days caused significant myocardial hypertrophy, cell injury and decline in survival. When sildenafil was injected daily, one hour before isoproterenol, survival was significantly improved and the myocardium didn't show significant hypertrophy or cell injury. Interestingly, sildenafil was accompanied by significant rise in myocardial cGMP level, a parameter which was found in the present study to possess a significant negative correlation with cardiac hypertrophy and leak of cardiac troponin T into serum. At the same time, cGMP was found to possess a positive correlation with myocardial creatine kinase activity that reflects the efficiency of the energy utilization processes in the myocardium. However, in rats given Nomega-nitro-L-arginine (L-NNA) as a competitive inhibitor of cNOS, sildenafil failed to show any favorable effect on survival or the myocardial injury parameters used to assess isoproterenol-induced injury. CONCLUSION: The present study suggests that increased cardiac cGMP level by sildenafil have a cardioprotective effect probably through acting as a post-receptor negative regulator of cardiac sympathetic responsiveness. Integrity of NOS function was an essential prerequisite for sildenafil's mediated cardioprotection encountered in the present study.