Tenellones A and B from a Diaporthe sp.: two highly substituted benzophenone inhibitors of parasite cGMP-dependent protein kinase activity

Parasite cGMP-dependent protein kinase (PKG) has been recently validated as a biochemical target for the treatment of coccidiosis. To discover new anticoccidial leads, we have screened our library of natural product extracts for inhibitors of parasite PKG. Bioassay-guided fractionation of the microbial extracts has led to the discovery of tenellones A (2) and B (3), two new highly substituted benzophenones. The isolation, structure, and activity of these compounds are described.     

Guttiferone I, a new prenylated benzophenone from Garcinia humilis as a liver X receptor ligand

Liver X receptors (LXR) have been implicated in cholesterol homeostasis. Agonists of LXR are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of plant extracts using a LXR-SPA binding assay and bioassay-guided fractionation of the bark and stem extract of Garcinia humilis led to the discovery of a new polyisoprenylated benzophenone named guttiferone I (1). The IC(50) value for this compound in the LXRalpha-SPA binding assay was 3.4 muM. Details of the isolation, structure elucidation, and ligand binding activity of 1 are described.     

Diterpenoid, steroid, and triterpenoid agonists of liver X receptors from diversified terrestrial plants and marine sources

It has been demonstrated that liver X receptors (LXR) play a significant role in cholesterol homeostasis. Agonists of LXR are expected to increase cellular cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of plant extracts using a LXR-SPA binding assay and bioassay-guided fractionation of a number of plant and marine gorgonian extracts led to the isolation of a number of active compounds. These included acanthoic acid (1) and alcohol (2), viperidone (3), polycarpol (4), rosacea acid (5), a cycloartane derivative (6), a new cycloartane analogue (7), betulinic acid (8), and gorgostane derivatives (9, 10, and 11). Of these compounds, 1, 4, and 11 exhibited potent binding affinity for alpha-receptor with IC(50) values of 0.25, 0.12, and 0.07 microM, respectively. Functionally they also showed strong coactivator association stimulation for LXRalpha receptor with EC50 values of 0.18, 0.03, and 0.05 microM, respectively. They also exhibited 15-, 8-, and 13-fold induction of the alpha-receptor in a transactivation assay in HEK-293 cells, respectively. In general these compounds were selective for the LXR alpha-receptor over the beta-receptor in all assays and were much better stimulators of the alpha-receptor than the endogenous steroid ligands.     

Tobacco use and oral hygiene as risk indicators for periodontitis

OBJECTIVE: To detect the periodontal status of male smokers and betel chewers in a rural community in Sri Lanka and compare it with that of male non-tobacco users of the same community. METHODS: A cross-sectional community based study was carried out in a sample of 2277 rural adult males aged 20-60 years, adopting multistage cluster sampling technique. The present analysis was confined to 2178 subjects who were mutually exclusive smokers, betel chewers or non-tobacco users. The periodontal status was assessed by clinical measurement of levels of bacterial plaque (PLI), gingival inflammation (GI) and loss of epithelial attachment (LA). All measurements were carried out on four sites of all teeth present except third molars and the mean values for periodontal parameters were calculated. RESULTS: Bivariate analysis revealed that the overall periodontitis levels were significantly higher in betel chewers and smokers than in non-tobacco users. Multiple linear regression analysis showed that there were no significant effects of smoking and betel chewing per se on LA, independent of age, socioeconomic status (SES) and whether or not controlled for PLI. The effect of the quantified tobacco use on LA was statistically significant regardless of age, PLI or SES. However, the effect of the quantified tobacco use was considered limited when compared to that of oral hygiene. CONCLUSIONS: The findings highlighted the importance of oral hygiene in the aetiology of periodontitis while confirming the statistical significance of the quantified tobacco use on LA. Oral hygiene and the quantified tobacco use may be considered as risk indicators for periodontitis.     

Botulinum toxin treatment of synkinesia and hyperlacrimation after facial palsy

OBJECTIVES—Toinvestigate the effects of injection of botulinum toxin type A (BTX A)into the orbicularis oculi muscle and lacrimal gland in patients withaberrant regeneration after facial palsy (facial synkinesias and hyperlacrimation).
METHODS—The effect ofthe toxin injection (on average 75 mouse units of BTX A) into theorbicularis oculi muscle on facial synkinesias was assessed on a fivepoint (0 to 4) scale in 10 patients with aberrant regeneration offacial nerve fibres after a peripheral facial nerve palsy. Six patientsunderwent a videographic control, which was assessed by a blindedindependent investigator. In two patients with hyperlacrimation anextra dose of botulinum toxin (on average 20 mouse units BTX A) wasinjected into the lacrimal gland and the effect was assessed using theSchirmer test and on a three point scale.
RESULTS—Botulinumtoxin type A had a good to excellent (grades 3 and 4) effect over anaverage of six months after 91% of injections. In 9% the injectionshad a moderate (grade 2) effect. Patients with hyperlacrimation showeda nearly complete recovery. There were no systemic side effects butfocal side effects due to a temporary weakness of the orbicularis oculimuscle were not uncommon.
CONCLUSIONS—Botulinumtoxin type A is the treatment of choice in motor and autonomic effectsof aberrant regeneration of facial nerve after a peripheral palsy. Therequired dose is similar to or slightly lower than the dose usuallyrecommended for hemifacial spasm.

     

Attractive and defensive functions of the ultraviolet pigments of a flower (Hypericum calycinum)

The flower of Hypericum calycinum, which appears uniformly yellow to humans, bears a UV pattern, presumably visible to insects. Two categories of pigments, flavonoids and dearomatized isoprenylated phloroglucinols (DIPs), are responsible for the UV demarcations of this flower. Flavonoids had been shown previously to function as floral UV pigments, but DIPs had not been demonstrated to serve in that capacity. We found the DIPs to be present in high concentration in the anthers and ovarian wall of the flower, suggesting that the compounds also serve in defense. Indeed, feeding tests done with one of the DIPs (hypercalin A) showed the compound to be deterrent and toxic to a caterpillar (Utetheisa ornatrix). The possibility that floral UV pigments fulfill both a visual and a defensive function had not previously been contemplated. DIPs may also serve for protection of female reproductive structures in other plants, for example in hops (Humulus lupulus). The DIPs of hops are put to human use as bitter flavoring agents and preservatives in beer.     

Plasma from the second and third weeks after open colorectal resection for cancer stimulates in vitro endothelial cell growth,migration, and invasion

Introduction  

Angiogenesis is central to wound healing and tumor growth. Postoperative (postop) plasma from weeks 2 and 3 after minimally invasive colorectal resection (MICR) stimulates endothelial cell (EC) migration (MIG), invasion (INV), and proliferation (all vital to angiogenesis) compared with preoperative (preop) plasma results and may promote postop tumor growth. The purpose of this study was to determine whether plasma from open colorectal resection (OCR) patients has similar proangiogenic EC effects in vitro.     

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.     

Does the measurement of the difference of resistive indexes in spleen and kidney allow a selective assessment of chronic kidney injury?

Purpose: To determine whether the difference of resistive indexes (RIs) in spleen and kidney (DI-RISK) is a more specific ultrasonographic (US) marker of intrarenal parenchymal damage than intrarenal RI alone. Materials and Methods: The study was approved by the local ethics committee. All study participants provided informed consent. The authors defined standard values for renal RI, splenic RI, and DI-RISK in 152 healthy subjects; carotid intima media thickness (IMT) was assessed as a marker of systemic vascular disease. Next, the authors measured these US parameters and collected echocardiographic data in 290 patients with chronic kidney disease (stage 2-4) recruited between September 2008 and February 2011 to evaluate the DI-RISK across the spectrum of stages of kidney function. Correlation coefficients were calculated with the Spearman test, and multivariate linear regression was used to analyze independent predictors of renal RI, splenic RI, and DI-RISK. Results: Healthy subjects had a mean age of 34.3 years ± 8.7, and patients with chronic kidney disease had a mean age of 65.0 years ± 12.3 (P < .001). In healthy subjects, both renal and splenic RIs were associated with IMT (renal RI: r = 0.19, P = .022; splenic RI: r = 0.23, P = .005); there was no correlation between DI-RISK and IMT (r = -0.10, P = .215). Similarly, in patients with chronic kidney disease, renal and splenic RIs correlated with IMT (renal RI: r = 0.33, P < .001; splenic RI: r = 0.30, P = .001). DI-RISK was associated with the estimated glomerular filtration rate (eGFR; r = -0.19, P = .001) but not with IMT (r = 0.08, P = .174). At multivariate regression analysis, DI-RISK was independently associated with eGFR but not with extrarenal factors. Conclusion: In patients with chronic kidney disease, renal RIs do not selectively indicate organ damage, but also mirror systemic vascular disease. The authors introduced DI-RISK as a potential US marker that may more specifically reflect kidney damage. ? RSNA, 2012.