Quercetin Phytosome® as a potential candidate for managing COVID-19.

When looking for new antiviral compounds aimed to counteract the COVID-19, a disease caused by the recently identified novel Coronavirus (SARS-CoV-2), the knowledge of the main viral proteins is fundamental. The major druggable targets of SARS-CoV-2 include 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase, and spike (S) protein. Molecular docking studies have highlighted that quercetin, a natural polyphenol belonging to the flavonol class, inhibits 3CLpro, PLpro and S proteins. Biophysical technics have then very recently confirmed that quercetin is reasonably a potent inhibitor of 3CLpro. The likely antiviral properties of quercetin are anyway challenged by its very poor oral bioavailability profile and any attempt to overcome this limit should be welcome. A phospholipid delivery form of quercetin (Quercetin Phytosome®) has been recently tested in humans to evaluate a possible improvement in oral bioavailability. After hydrolysis of the conjugated form (mainly glucuronide) of quercetin found in human plasma, the pharmacokinetics results have demonstrated an increased bioavailability rate by about 20-fold for total quercetin. It has been also observed that the presence of specific glucuronidase could yield free systemic quercetin in human body. Taking also into considerations its anti-inflammatory and thrombin-inhibitory actions, a bioavailable form of quercetin, like Quercetin Phytosome®, should be considered a possible candidate to clinically face COVID-19.

Densely substituted piperidines as a new class of elastase inhibitors: Synthesis and molecular modeling studies.

Elastase is the only enzyme that has the capability to degrade elastin and collagen, the two proteins essential for skin and bones. The synthesis of some densely substituted piperidines functionalized with the trifluoromethyl group (4a-j) was carried out. The newly prepared compounds were subjected to elastase enzyme inhibitory potential and antioxidant activity assays. Among the series, 4i (IC50 = 0.341 ± 0.001 µM) exhibited the maximum inhibition against elastase. Binding analysis delineated that the fluorine atom of ligand 4i showed hydrogen and hydrophobic bonds with Thr41 and Thr96, with bond distances of 3.84 and 5.631 Å, respectively. The obtained results indicate that these trifluoromethyl functionalized piperidine derivatives could be considered as potential candidates to treat skin disorders.

Cytotoxicity, Pro-apoptotic Activity and in silico Studies of Dithiocarbamates and their Structure Based Design and SAR Studies.

BACKGROUND: Cancer is a far-reaching and lethal but curable disease. Researchers have investigated numerous anticancer agents with only a few commercially available effective drugs which are very costly. OBJECTIVE: Herein, we report the synthesis , characterization and anti cancer assays of a series of novel dithiocarbamates derivatives. METHODS: All compounds were synthesized from different secondary amines and substituted benzyl chlorides in a single step. The structures of newly synthesized dithiocarbamate derivatives were confirmed by spectroscopic techniques (IR, NMR and HR-MS). RESULTS: The synthesized compounds showed a significant anti-proliferative effect in cancer cells (HeLa) with the maximum inhibitory activity of compound SHD-2 with an IC50 = 0.31 ± 0.09 µM. However, the same compound exhibited 19.2% inhibition towards Baby Hamster Kidney fibroblasts (BHK-21), normal cell lines. Moreover, quantification of cellular DNA by flow cytometry for the evaluation of pro-apoptotic activity in HeLa cells demonstrates that arrest in cell cycle along with apoptosis advance towards drug cytotoxicity. However, molecular docking studies of the potent compound suggested that it binds to the major groove of the DNA. CONCLUSION: The cytotoxic and pro-apoptotic potential of the potent inhibitor may be further investigated in the animal models to advance their anti-cancer prospective.

Profound bilateral post-partum retinal circulation ischemia in two diabetic mothers with pre-eclampsia.

PURPOSE: We report 2 cases of young diabetic mothers with pre-eclampsia and no previously documented visual deficits prior to pregnancy who were found to have profound retinal circulation loss during the postpartum period. OBSERVATIONS: Fluorescein angiogram in both cases documented profound ischemia of retinal and macular circulation with resulting severe vision loss, leading to legal blindness. CONCLUSIONS AND IMPORTANCE: While Pre-eclampsia and Eclampsia are well known clinical entities with potentially grave effects on both the mother and child, there is little information about the possible combined effects of diabetes and Pre-eclampsia/Eclampsia on the retinal circulation. We aim to raise awareness about this devastating association with a need for aggressive monitoring and prompt treatment of similar patients to potentially avoid poor visual outcomes.

Hypoglycemia: Role of Hypothalamic Glucose-Inhibited (GI) Neurons in Detection and Correction.

Hypoglycemia is a profound threat to the brain since glucose is its primary fuel. As a result, glucose sensors are widely located in the central nervous system and periphery. In this perspective we will focus on the role of hypothalamic glucose-inhibited (GI) neurons in sensing and correcting hypoglycemia. In particular, we will discuss GI neurons in the ventromedial hypothalamus (VMH) which express neuronal nitric oxide synthase (nNOS) and in the perifornical hypothalamus (PFH) which express orexin. The ability of VMH nNOS-GI neurons to depolarize in low glucose closely parallels the hormonal response to hypoglycemia which stimulates gluconeogenesis. We have found that nitric oxide (NO) production in low glucose is dependent on oxidative status. In this perspective we will discuss the potential relevance of our work showing that enhancing the glutathione antioxidant system prevents hypoglycemia associated autonomic failure (HAAF) in non-diabetic rats whereas VMH overexpression of the thioredoxin antioxidant system restores hypoglycemia counterregulation in rats with type 1 diabetes.We will also address the potential role of the orexin-GI neurons in the arousal response needed for hypoglycemia awareness which leads to behavioral correction (e.g., food intake, glucose administration). The potential relationship between the hypothalamic sensors and the neurocircuitry in the hindbrain and portal mesenteric vein which is critical for hypoglycemia correction will then be discussed.

Doubly Regioselective C-H Hydroarylation of Unsymmetrical Alkynes Using Carboxylates as Deciduous Directing Groups.

A catalyst system composed of [(C6Me6)RuCl2]2, potassium carbonate/guanidine carbonate, and mesitoic acid efficiently promotes the doubly regioselective C-H hydroarylation of unsymmetrical alkynes. The process involves carboxylate-directed ortho-C-H bond activation followed by regioselective addition to the alkyne C-C triple bond with concerted decarboxylation. This action of the carboxylate as a deciduous directing group ensures exclusive monovinylation with high selectivity for the (E)-1,2-diarylalkene.

Evaluation of iron deficiency anaemia for gastrointestinal causes in patients without GI symptoms in high prevalent GI malignancy zones.

BACKGROUND AND STUDY AIMS: Gastric cancer is highly prevalent in Kashmir, as are lower gastrointestinal (LGI) malignancies. Colonic cancer, gastric cancer, and coeliac disease are the most important gastrointestinal (GI) causes of iron deficiency anaemia (IDA) worldwide. Approximately 9% of patients with IDA present with a suspicious lesion in the GI tract upon examination. However, the absence of GI symptoms and a possible lesion accounting for blood loss in IDA have not been studied in this zone with a high prevalence of GI malignancy. We aimed to examine IDA patients without GI symptoms to determine the most plausible cause of their blood loss. PATIENTS AND METHODS: A total of 100 patients with IDA and 250 control subjects without IDA and referred for gastrointestinal endoscopy were enrolled in a cross-sectional, comparative study. Patients presenting with a significant lesion proportionate to their anaemia in the upper GI tract were not examined further, if no further strong indications were present. RESULTS: Twenty-nine patients (29%) were found to have malignancy: 13 with gastric cancer and 16 with colonic malignancies. Other apparent causes of GI blood loss included peptic ulcer disease in 10 (10%) patients, haemorrhoids in 22 (25%), polyps in eight (three in the upper GI tract and five in the LGI tract), gastric erosions in eight (8%), and angiodysplasia, diverticulitis, and trichuriasis in two (2%) each. CONCLUSION: In light of the high incidence of GI malignancies in this patient group, a low threshold for GI screening as well as mass screening for IDA is needed.

[Pd(µ-Br)(P(t)Bu3)]2 as a highly active isomerization catalyst: synthesis of enol esters from allylic esters.

The dimeric Pd(I)-complex [Pd(µ-Br)(P(t)Bu3)]2 was found to be highly active for catalyzing double-bond migration in various substrates such as unsaturated ethers, alcohols, amides, and arenes, under mild conditions. It efficiently mediates the conversion of allylic esters into enol esters, rather than inserting into the allylic C-O bond. The broad applicability of this reaction was demonstrated with the synthesis of 22 functionalized enol esters.

Thrombotic thrombocytopenic purpura: a hematological emergency.

BACKGROUND: Thrombotic thrombocytopenic purpura is a hematological emergency and diagnostic challenge. The critical determinant of outcome is timely diagnosis and treatment. OBJECTIVES: Describe the pathophysiology, presentation, diagnosis, and treatment of thrombotic thrombocytopenic purpura. DISCUSSION: Thrombotic thrombocytopenic purpura has a varied presentation and a tendency to mimic several disorders. However, it may be at least provisionally diagnosed in the patient with thrombocytopenia and microangiopathic hemolytic anemia without alternate cause. The mainstay of treatment is immediate plasma exchange to be repeated until platelet count is stabilized. Adjuvant therapies include corticosteroids, rituximab, and cyclosporine. CONCLUSION: It is essential for the emergency physician to be aware of thrombotic thrombocytopenic purpura's range of presentations, diagnostic criteria, and treatment.

Microwave-assisted Cu-catalyzed protodecarboxylation of aromatic carboxylic acids.

An effective protocol has been developed that allows the smooth protodecarboxylation of diversely functionalized aromatic carboxylic acids within 5-15 min. In the presence of at most 5 mol % of an inexpensive catalyst generated in situ from copper(I) oxide and 1,10-phenanthroline, even nonactivated benzoates were converted in high yields and with great preparative ease.

Retinal arteriolar macroaneurysms overlying the optic nerve.

BACKGROUND: Retinal arteriolar macroaneurysms typically involve the second and third order arterioles. Macroaneurysms involving the first order arterioles, specifically overlying the optic nerve, have been infrequently reported. METHODS: This is a retrospective case series. RESULTS: Two patients were found to have an arteriolar macroaneurysm overlying the optic nerve. The first, a 77-year-old man, had focal laser photocoagulation to the macroaneurysm. The second, a 75-year-old woman, had spontaneous resolution of the lesion without treatment. Final visual acuity was 20/25 in the treated patient compared to 20/80 in the untreated patient. CONCLUSION: Retinal arteriolar macroaneurysms overlying the optic nerve will involute spontaneously or as a result of focal laser photocoagulation. The associated macular edema may result in permanent visual loss. Focal laser treatment over the optic nerve did not cause optic nerve damage.

Gall bladder emptying in patients with corrosive-induced esophageal strictures.

Ingestion of corrosive substances can lead to strictures of the esophagus and stomach. Cicatrization of the lower part of the esophagus can entrap vagal fibers in the process of fibrosis. The aim of the present study was to evaluate gallbladder dysfunction as a sequel to vagal damage in patients with corrosive-induced esophageal strictures. The cephalic phase of gallbladder emptying was stimulated by modified sham feeding according to the chew-and-spit method. Gallbladder volume was measured by ultrasonography using the ellipsoid method after an overnight fast and every 15 min for a period of 90 min after sham feeding in 22 patients and 10 controls. Mean fasting gallbladder volume was significantly greater in patients than in controls (22.09 +/- 9.78 vs. 14.61 +/- 4.42 ml; P = 0.025). After sham feeding the gallbladder ejection fraction was significantly lower in patients than in controls (32.86 +/- 17.21 vs. 49.40 +/- 7.86%; P = 0.007). Patients with cicatrization in the distal one-third of the esophagus had a greater basal gallbladder volume (24.57 +/- 9.2 ml) and significantly lower ejection fraction (20.47 +/- 8.9%) than patients with strictures at other sites (gallbladder volume, 18.50 +/- 10.69 ml; ejection fraction, 47.48 +/- 13.3%; P = 0.001). In conclusion, patients with corrosive-induced esophageal strictures, especially those in the distal one-third, had an increased fasting gallbladder volume and decreased cephalic phase of gallbladder emptying, pointing to impaired vagal cholinergic transmission, possibly due to vagal entrapment in the cicatrization process.