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Fresno sex offender who recorded abuse could face longest punishment in California history

FRESNO, Calif. - A jury has found Cornelio Jimenez guilty on all 36 counts of sex crimes and child porn. He could face more than 1,882 years to life in prison at sentencing, which would be the longest in California history, according to court experts.

Jimenez lied to police about where he lived for more than a year. The registered sex offender only showed up on their radar when they traced child porn to the home where he lived. During that time, prosecutors say he discussed molesting kids in emails.

"There's this very cute little 4-year-old girl that I babysit about once a week," prosecutors Deborah Miller said, quoting one of Jimenez's emails. "I have hella pictures of her. I have to molest her every chance I get."

Investigators found videos showing Jimenez engaging in sexual activity with two girls -- ages four and seven -- who lived in the home he wouldn't tell police about. Prosecutors showed jurors pieces of the videos as evidence of 36 counts of sex crimes and child porn.

"And how do we know?" Miller asked the jury about Jimenez's guilt. "Because on 30 of them we saw pictures and video of it."

At least a couple people related to the victims walked out of court as still photos from the videos came up again in closing arguments Tuesday. After his arrest, police say Jimenez admitted to the crimes, but his public defender argued two of the 36 counts really involve the same criminal act.

"The easy thing to do in this case is to clump all the counts together," said Angelica Rivera. "That's the easy thing to do. The right thing is to take them separately."

Jimenez turned down an offer of 75 years to life before trial.

He faces more than 1,882 years to life in prison. According to several experts, there has not been a longer sentence in California court history.

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The header photo was taken in a Californian sex doll factory.

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Kaempferia parviflora, a plant used in traditional medicine to enhance sexual performance contains large amounts of low affinity PDE5 inhibitors

Aim of the study

A number of medicinal plants are used in traditional medicine to treat erectile dysfunction. Since cyclic nucleotide PDEs inhibitors underlie several current treatments for this condition, we sought to show whether these plants might contain substantial amounts of PDE5 inhibitors.

Materials and methods

Forty one plant extracts and eight 7-methoxyflavones from Kaempferia parviflora Wall. ex Baker were screened for PDE5 and PDE6 inhibitory activities using the two-step radioactive assay. The PDE5 and PDE6 were prepared from mice lung and chicken retinas, respectively. All plant extracts were tested at 50 µg/ml whereas the pure compounds were tested at 10 µM.

Results

From forty one plant extracts tested, four showed the PDE5 inhibitory effect. The chemical constituents isolated from rhizomes of Kaempferia parviflora were further investigated on inhibitory activity against PDE5 and PDE6. The results showed that 7-methoxyflavones from this plant showed inhibition toward both enzymes. The most potent PDE5 inhibitor was 5,7-dimethoxyflavone (IC50 = 10.64 ± 2.09 µM, selectivity on PDE5 over PDE6 = 3.71). Structure activity relationship showed that the methoxyl group at C-5 position of 7-methoxyflavones was necessary for PDE5 inhibition.

Conclusions

Kaempferia parviflora rhizome extract and its 7-methoxyflavone constituents had moderate inhibitory activity against PDE5. This finding provides an explanation for enhancing sexual performance in the traditional use of Kaempferia parviflora. Moreover, 5,7-dimethoxyflavones should make a useful lead compound to further develop clinically efficacious PDE5 inhibitors.

1. Introduction

Phosphodiesterase5 (PDE5) is one of eleven isozymes in PDE family. Its role is to regulate tissue cGMP levels by cGMP hydrolysis (Essayan, 1999). It is abundant in vascular smooth muscle cells and plays a significant role in generating tone in smooth muscle of the penile corpus cavernosum. The PDE5 inhibitor, sildenafil, is currently used for erectile dysfunction as it increases the level of cGMP which induces vascular smooth muscle relaxation, vasodilation and increases blood flow to penile tissue (Corbin et al., 2002). However, sildenafil also inhibits PDE6 which is present in the retina and this inhibition may give rise to visual disturbances as an unavoidable side effect of this treatment (Uckert et al., 2006).

Many medicinal plants including some from Thailand have been used traditionally to enhance sexual performance by treating erectile dysfunction and therefore might contain compounds that act via PDE5 inhibition. In a previous study, we found that some of these plant extracts could indeed inhibit a mixture of PDEs a major component of which was PDE1 (Temkitthawon et al., 2008). Therefore, in this study we aimed to determine the PDE5 inhibitory effect of these medicinal plant extracts and to identify the compounds responsible for this action.

2. Materials and methods

2.1. Plant materials

The plant materials were collected from Northern Thailand. Nineteen voucher specimens of the collected medicinal plants used as sexual performance enhancers (Table 1) are kept at Queen Sirikit Botanic Garden, Chiangmai. The dried stem of Mucuna colettii was a gift from Professor Wichai Cherdshevasart, Department of Biology, Faculty of Sciences, Chulalongkorn University, Bangkok, Thailand. Butea superba and 20 voucher specimens of leguminoseous plants (Table 2) are kept at Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok and at the PBM Herbarium, Faculty of Pharmacy, Mahidol University, Bangkok.

2.2. Chemicals

cGMP, crude snake venom (Crotalus atrox), histone, bovine serum albumin (BSA), ethylene glycol tetraacetic acid (EGTA), imidazole, tris(hydroxymethyl)aminomethane (Tris), magnesium chloride (MgCl2), diethylaminoethyl sephadex (DEAE-Sephadex) and dipyridamole were purchased from Sigma Chemical (St. Louis, MO, U.S.A.). [3H]cGMP was obtained from Perkin Elmer (Boston, MA, U.S.A.).

2.3. Plant extraction and isolation

Plant materials were cut into small pieces and dried in a hot air oven at 55 °C. The dried materials were macerated in ethanol twice, for 3 days each, and filtered. Both filtrates were combined and evaporated under reduced pressure until dried.

Flavonoids from Kaempferia parviflora were isolated as reported previously (Sawasdee et al., 2009).

2.4. Enzyme preparation

PDE5 was obtained from mouse lung tissue. Briefly, fresh tissue was minced and homogenized in 1 ml of Tris buffer (50 mM Tris, pH 7.5, 2 mM EDTA, 1 mM DTT and 1:100 of 100 mM phenylmethylsulfonyl fluoride). The homogenate was centrifuged at 14,000 rpm for 20 min at 4 °C and the supernatant was used as a source of PDE5. The PDE5 inhibitor, sildenafil, was used to confirm that the supernatant contained abundant PDE5. PDE6 was prepared from chicken retinas as previously described (Huang et al., 2004). All of the tissues were obtained from animals for which we have approval by Institutional Animal Care and Use Committee (IACUC) Committee of University of Washington.

2.5. PDE assay

PDE activity was measured according to the method based on two-step radioactive procedure as described by Sonnenburg et al. (1998). The reaction mixture was composed of 25 µl of buffer A (100 mM Tris–HCl (pH 7.5), 100 mM imidazole, 15 mM MgCl2 and 1.0 mg/ml BSA), 25 µl of 10 mM EGTA, 25 µl of PDE solution and 25 µl of test sample or only solvent (5% DMSO) as a control. The reaction mixture was mixed with a substrate, 25 µl of 1 µM [3H]cGMP and incubated at 30 °C for 10 min. After that, the reaction was stopped by placing the tube in boiling water for 1 min and cooled for 5 min. For the second enzymatic reaction, 25 µl of 2.5 mg/ml snake venom containing 5'-nucleotidase enzyme was added to the reaction mixture, incubated at 30 °C for 5 min. Then, 250 µl of 20 mM Tris–HCl, pH 6.8 (buffer 1) was added. The reaction mixture was transferred to a DEAE ion exchange resin column and eluted 4 times with 500 µl of buffer 1 to obtain the hydrolysis product, uncharged [3H]guanosine. The eluant was mixed with a scintillant cocktail and the radioactivity was measured using a ß-counter. The PDE in the study was standardized to have a hydrolysis activity of 15–20% of the total substrate counts. The calculation of hydrolysis is shown in Eq. (1). The PDE inhibitory activity is calculated from Eq. (2). where CPMsample is the radioactive count rate of the assay with enzyme and CPMbackground is the same but without enzyme. CPMtotal count is the count rate of 25 µl of substrate plus 2 ml of buffer 1. where % hydrolysissample and % hydrolysiscontrol were the enzyme activities of the sample and solvent (1% DMSO) used in the assay, respectively.

In preliminary screening, the plant extracts were tested at the final concentration of 50 µg/ml whereas pure compounds were tested at the final concentration of 10 µM. All samples were dissolved in DMSO and diluted with water. The final concentration of DMSO was 1% in the assay medium. For extracts that gave >60% PDE5 inhibition, the IC50s were determined. For each enzyme preparation, the assay was performed in triplicate.


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