Ophiocordyceps formosana improves hyperglycemia and depression-like behavior in an STZ-induced diabetic mouse model.

BACKGROUND: A newly defined Cordyceps species, Ophiocordyceps formosana (O. formosana) has been implicated in multitudinous bioactivities, including lowering glucose and cholesterol levels and modulating the immune system. However, few literatures demonstrate sufficient evidence to support these proposed functions. Although the use of Cordyceps spp. has been previously addressed to improve insulin insensitivity and improve the detrimental symptoms of depression; its mechanistic nature remains unsettled. Herein, we reveal the effects of O. formosana in ameliorating hyperglycemia accompanied with depression. METHODS: Diabetes was induced in mice by employing streptozotocin(STZ), a chemical that is toxic to insulin-producing ß cells of the pancreas. These streptozotocin (STZ)-induced diabetic mice showed combined symptoms of hyperglycemia and depressive behaviors. Twenty-four STZ-induced mice were randomly divided into 3 groups subjected to oral gavage with 100 µL solution of either PBS or 25 mg/mL Ophiocordyceps formosana extract (OFE) or 2 mg/mL rosiglitazone (Rosi, positive control group). Treatments were administered once per day for 28 days. An additional 6 mice without STZ induction were treated with PBS to serve as the control group. Insulin sensitivity was measured by a glucose tolerance test and levels of adiponectin in plasma and adipose tissue were also quantified. Behavioral tests were conducted and levels of monoamines in various brain regions relating to depression were evaluated. RESULTS: HPLC analysis uncovered three major constituents, adenosine, D-mannitol and cordycepin, within O. formosana similar to other prestigious medicinal Cordyceps spp.. STZ-induced diabetic mice demonstrated decreased body weight and subcutaneous adipose tissue, while these symptoms were recovered in mice receiving OFE treatment. Moreover, the OFE group displayed improved insulin sensitivity and elevated adiponectin within the plasma and adipose tissue. The anti-depressive effect of OFE was observed in various depression-related behavior tests. Concurrently, neurotransmitters, like 5-HT and dopamine in the frontal cortex, striatum and hippocampus were found to be up-regulated in OFE-treated mice. CONCLUSIONS: Our findings illustrated, for the first time, the medicinal merits of O. formosana on Type I diabetes and hyperglycemia-induced depression. OFE were found to promote the expression of adiponectin, which is an adipokine involved in insulin sensitivity and hold anti-depressive effects. In addition, OFE administration also displayed altered levels of neurotransmitters in certain brain regions that may have contributed to its anti-depressive effect. Collectively, this current study provided insights to the potential therapeutic effects of O. formosana extracts in regards to hyperglycemia and its depressive complications.

Objective Quantification of Image Quality and Optical Scatter Before and After Nd:YAG Capsulotomy Using a Double-Pass Technique.

PURPOSE: The purpose of this study is to evaluate and compare the correlation between changes in vision and HD Analyzer dual-pass metrics versus changes in vision and conventional subjective slit lamp gradings in pseudophakic patients with posterior capsular opacity undergoing neodymium:yttrium-aluminum-garnet (Nd:YAG) capsulotomy. PATIENTS AND METHODS: High contrast (HC) and low contrast (LC) best spectacle-corrected distance visual acuity (BCVA) and HD Analyzer evaluation were prospectively performed on patients with mild-to-moderate posterior capsular opacification (PCO) and monofocal and accommodating intraocular lens implants. Differences between pre- and post-operative measurements were calculated, along with the correlation of HD Analyzer metrics and slit lamp grading to changes in visual acuity. RESULTS: Following Nd:YAG capsulotomy (n=29), there was statistically significant improvement in HC-BCVA and LC-BCVA, decrease in optical scatter, and corresponding improvement in Strehl ratio and HD Analyzer values at all contrast levels tested (p≤0.05). Pearson test showed a high correlation between the improvement in HC-BCVA (r coefficient = 0.78) and LC-BCVA (r coefficient = 0.71) to the improvement in Objective Scatter Index (OSI). There was a higher correlation of change in HC-BCVA to pre-op OSI  (r2=0.61) than to the subjective PCO grading score (r2 = 0.19). There was also a higher correlation of change in LC-BCVA to pre-op OSI (r2 = 0.49) than to subjective grading (r2 = 0.16). CONCLUSION: The HD Analyzer provides objective measurements of forward light scatter (ie, light directed towards the retina) that can assist with both PCO grading and prediction of improvement of visual quality after YAG laser capsulotomy with higher accuracy than conventional slit lamp assessment based upon backscatter (ie, light traveling to the observer) in patients tested with monofocal and accommodating intraocular lens implants.

Differentiation of rodent behavioral phenotypes and methylphenidate action in sustained and flexible attention tasks.

Methyphenidate (MPH) is the primary drug treatment of choice for ADHD. It is also frequently used off-label as a cognitive enhancer by otherwise healthy individuals from all age groups and walks of life. Military personnel, students, and health professionals use MPH illicitly to increase attention and improve workplace performance over extended periods of work activity. Despite the frequency of its use, the efficacy of MPH to enhance cognitive function across individuals and in a variety of circumstances is not well characterized. We sought to better understand MPH׳s cognitive enhancing properties in two different rodent models of attention. We found that MPH could enhance performance in a sustained attention task, but that its effects in this test were subject dependent. More specifically, MPH increased attention in low baseline performing rats but had little to no effect on high performing rats. MPH exerted a similar subject specific effect in a test of flexible attention, i.e. the attention set shifting task. In this test MPH increased behavioral flexibility in animals with poor flexibility but impaired performance in more flexible animals. Overall, our results indicate that the effects of MPH are subject-specific and depend on the baseline level of performance. Furthermore, good performance in in the sustained attention task was correlated with good performance in the flexible attention task; i.e. animals with better vigilance exhibited greater behavioral flexibility. The findings are discussed in terms of potential neurobiological substrates, in particular noradrenergic mechanisms, that might underlie subject specific performance and subject specific responses to MPH. This article is part of a Special Issue entitled SI: Noradrenergic System.

Involvement of p38 MAPK in the Anticancer Activity of Cultivated Cordyceps militaris.

Cordyceps militaris is a traditional Chinese medicine frequently used for tonic and therapeutic purposes. Reports from our laboratory and others have demonstrated that extracts of the cultivated fruiting bodies of C. militaris (CM) exhibit a potent cytotoxic effect against many cancer cell lines, especially human leukemia cells. Here, we further investigated the underlying mechanism through which CM is cytotoxic to cancer cells. The CM-mediated induction of PARP cleavage and its related DNA damage signal (γH2AX) was diminished by caspase inhibitor I. In contrast, a ROS scavenger failed to prevent CM-mediated leukemia cell death. Moreover, two signaling molecules, AKT and p38 MAPK, were activated during the course of apoptosis induction. Employing MTT analysis, we found that a p38 MAPK inhibitor but not an AKT inhibitor could rescue cells from CM-mediated cell death, as well as inhibit the cleavage of PARP, formation of apoptotic bodies and up-regulation of the γH2AX signal. These results suggest that CM-mediated leukemia cell death occurs through the activation of the p38 MAPK pathway, indicating its potential therapeutic effects against human leukemia.

Evaluation of an Epitypified Ophiocordyceps formosana (Cordyceps s.l.) for Its Pharmacological Potential.

The substantial merit of Cordyceps s.l. spp. in terms of medicinal benefits is largely appreciated. Nevertheless, only few studies have characterized and examined the clinical complications of the use of health tonics containing these species. Here, we epitypified C. formosana isolates that were collected and characterized as Ophiocordyceps formosana based on morphological characteristics, molecular phylogenetic analyses, and metabolite profiling. Thus, we renamed and transferred C. formosana to the new protologue Ophiocordyceps formosana (Kobayasi & Shimizu) Wang, Tsai, Tzean & Shen comb. nov. Additionally, the pharmacological potential of O. formosana was evaluated based on the hot-water extract from its mycelium. The relative amounts of the known bioactive ingredients that are unique to Cordyceps s.l. species in O. formosana were found to be similar to the amounts in O. sinensis and C. militaris, indicating the potential applicability of O. formosana for pharmacological uses. Additionally, we found that O. formosana exhibited antioxidation activities in vitro and in vivo that were similar to those of O. sinensis and C. militaris. Furthermore, O. formosana also displayed conspicuously effective antitumor activity compared with the tested Cordyceps s.l. species. Intrinsically, O. formosana exhibited less toxicity than the other Cordyceps species. Together, our data suggest that the metabolites of O. formosana may play active roles in complementary medicine.

Aberrant responses in social interaction of dopamine transporter knockout mice.

The dopamine (DA) transporter (DAT) controls the temporal and spatial resolution of dopaminergic neurotransmission. Disruption of the Dat1 gene in mice leads to increased extracellular DA concentrations and reduced expression of D1- and D2-like receptors in striatum. The mutants are hyperactive in the open field and they display deficits in learning and memory. In humans, dopaminergic dysfunction has been associated with a number of different psychiatric disorders and some of these conditions are accompanied by abnormal social responses. To determine whether social responses were also impaired in DAT knockout (KO) mice, behaviors of group- and isolation-housed animals were compared. All group-housed animals readily established hierarchies. However, the social organizations of the mutants were changed over time. Under both group- and isolation-housed conditions, mutants exhibited increased rates of reactivity and aggression following mild social contact. In isolation, exposure to a novel environment exacerbated these abnormal responses. Regardless of housing context, stereotyped and perseverative patterns of social responses were a common feature of the KO repertoire. In fact, many abnormal behaviors were due to the emergence and predominance of these inflexible behaviors. These data suggest that KO mice may serve as a useful animal model for understanding not only how DA dysfunction contributes to social abnormalities, but also how behavioral inflexibility distorts their social responses.

A prospective randomized clinical evaluation of 3 presbyopia-correcting intraocular lenses after cataract extraction.

PURPOSE: To compare contrast sensitivity, visual acuity (VA), and halos in subjects bilaterally implanted with 1 of 3 FDA-approved presbyopia-correcting intraocular lenses. DESIGN: Prospective, randomized, partially masked, multicenter clinical trial. METHODS: Seventy-eight subjects were randomized sequentially for bilateral implantation with the Crystalens AO (Bausch & Lomb Surgical), AcrySof IQ ReSTOR +3.0 (Alcon Laboratories), or Tecnis Multifocal (Abbott Medical Optics) lenses. Subjects were evaluated through visit 4 (4 to 6 months after surgery) with the following monocular and binocular assessments: high- and low-contrast VA, contrast sensitivity without glare, halos or starbursts, defocus curves, optical scatter, retinal point spread function, and safety. RESULTS: The Crystalens AO and ReSTOR +3.0 demonstrated better monocular and binocular contrast sensitivity without glare at low to mid spatial frequencies compared with the Tecnis Multifocal lens. Binocular uncorrected distance VA was not significantly different between the 3 lenses. The Crystalens AO had significantly better binocular low-contrast distance-corrected VA than the ReSTOR +3.0 and better mean monocular low-contrast DCVA than the Tecnis Multifocal lens. The Crystalens AO demonstrated significantly better monocular and binocular uncorrected and distance-corrected intermediate VA than the ReSTOR +3.0 or Tecnis Multifocal lenses. The ReSTOR+3.0 lens had significantly better monocular and binocular uncorrected and distance-corrected near VA tested at 40 cm compared with the Crystalens AO and Tecnis Multifocal lens. The Crystalens AO elicited significantly less halos than the Tecnis Multifocal lens and less optical scatter than the ReSTOR +3.0 or Tecnis Multifocal lens. CONCLUSIONS: The Crystalens AO had statistically better uncorrected intermediate VA and distance-corrected intermediate VA than the ReSTOR +3.0 or Tecnis Multifocal lenses and fewer photic phenomenon than the Tecnis Multifocal lens. Both multifocals had better distance-corrected near VA and uncorrected near VA than the Crystalens AO. These findings may guide intraocular lens selection for individual patients seeking to optimize vision at specific vergences or lighting conditions.

Synergistic property of cordycepin in cultivated Cordyceps militaris-mediated apoptosis in human leukemia cells.

Cordyceps militaris is a well-known Chinese traditional medicinal mushroom frequently used for tonics and recently of a potential interest for cancer intervention. Here, we explored the cancer cell killing activity of the hot water extracts of C. militaris cultured mycelia (CM(MY)) and cultivated fruiting bodies (CM(FB)). We found that CM(FB) exhibited a greater cytotoxic effect against various cancer cells over CM(MY). Apoptotic phenotypes including apoptotic body formation, DNA laddering, caspase 3 activation and cleavage of PARP proteins were induced by CM(FB) treatment but only slightly induced by same concentration of CM(MY) treatment in human HL-60 leukemia cells. Cordycepin in CM(FB) (10.47 mg/g) is significantly higher (∼ 15.2 times) than that of CM(MY) (0.69 mg/g). Using isobolographic analysis, the synergy of cytotoxicity was observed across different combined concentrations of CM(MY) and cordycepin. By complementing cordycepin into CM(MY) to the level comparable with CM(FB), we observed that CM(MY) (500 µg/ml) with cordycepin (4.8 µg/ml) induced apoptosis to a level similar to that induced by CM(FB) (500 µg/ml). Together, our results suggest that cordycepin possesses a synergistic cytotoxic effect with Cordyceps militaris-mediated apoptosis in human leukemia cells and therefore explaining a better anti-proliferating activity of CM(FB) over CM(MY).

Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells.

Serotonin [5-hydroxytryptamine (5-HT)]-mediated cardiac valvular disease has been commonly observed in patients with carcinoid tumors. Previous research by others using reverse transcriptase-polymerase chain reaction demonstrated that aortic valve cells expressed predominantly 5-HT(2A/2B) receptors (5-HT(2A)R). Related investigations by our group using sheep aortic valve interstitial cell (SAVIC) cultures demonstrated that 5-HT both up-regulates transforming growth factor (TGF)-beta1 expression and activity, and also results in increased phospholipase C (PLC) activity. Thus, the present study investigated the hypothesis that the 5-HT signaling pathway in SAVICs involves 5-HT(2)Rs with associated G-protein signal transduction. The objectives were to functionally characterize in SAVIC cultures the native serotonin receptor subtypes using specific agonists and antagonists, and to delineate the serotonin-signaling pathway. 5-HT administration caused a marked stimulation of PLC activity. SAVIC studies of specific agents that target the 5-HT(2)R subtypes indicate that this response seemed to be mediated predominantly by 5-HT(2A)Rs. Furthermore, the sheep 5-HT(2A)R was identified by reverse transcriptase-polymerase chain reaction with sequence confirmation including comparisons to pig and human 5-HT(2A)R. Extracellular signal-regulated kinase (Erk 1/2) is a signaling molecule downstream from the 5-HT(2A)R. Both a protein kinase C inhibitor, GF109203X, and a Src inhibitor, PP1, attenuated 5-HT-stimulated Erk 1/2 activation. However, a 5-HT(2A)R antagonist, MDL 100907, inhibited 5-HT up-regulation of PLC and TGF-beta1, while having far less pronounced effects on Erk 1/2. In conclusion, these studies of the signal transduction activity of SAVICs in response to 5-HT have demonstrated that the 5-HT(2A)Rs are the most functionally active of the 5-HT(2)Rs in this cell type. Furthermore, 5-HT(2A)Rs are also involved in 5-HT up-regulation of active TGF-beta. 5-HT also mediated strong Erk 1/2 signaling via the MAP-kinase pathway, which was only in part because of 5-HT(2A)R activity. Thus, major 5-HT Erk 1/2 signaling beyond that controlled by 5-HT(2)Rs must involve other serotonin receptor types and/or secondary signaling events.