Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor (P-elF2α) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.

Overcoming dormancy in stored and recently harvested Passiflora cincinnata Mast. seeds / Superação de dormência em sementes de Passiflora cincinnata Mast. armazenadas e recém-colhidas

The treatment of seeds using growth regulators can overcome seed dormancy and increase the emergence and development of seedlings. The objective of this research was to evaluate the effect of different concentrations of GA4+7 + N-(phenyl methyl)-aminopurine on the dormancy breaking of Passiflora cincinnata Mast. seeds recently harvested and stored for six years. The study was conducted in a greenhouse at Embrapa Cassava and Tropical Fruits, in completely randomized design, in a 2 x 4 factorial scheme, with the following factors: year of seed harvest (2010 and 2016) and the emergence promoter GA4+7 + N-(phenyl methyl)-aminopurine at four concentrations (0%; 0.03%; 0.45% and 0.90%), with 4 replicates of 25 seeds. Emergence percentage, first count, emergence speed index, number of leaves, root length, stem diameter, dry matter of shoots, roots and total, and root/shoot ratio were evaluated. The results showed that GA4+7 + N-(phenyl methyl)-aminopurine is recommended to overcome dormancy of Passiflora cincinnata in recently harvested seeds (2016) and increase the emergence of seedlings from seeds stored for six years in cold chamber (2010). The emergence promoter concentration of 0.03% can be used to overcome dormancy in recently harvested seeds and maintains the vigor of seeds stored for six years. Passiflora cincinnata seeds remain physiologically viable for six years and their emergence is potentiated by the use of GA4+7 + N-(phenyl methyl)-aminopurine.

O tratamento de sementes com reguladores de crescimento pode superar a dormência das sementes, aumentar o vigor e o desenvolvimento das mudas. O objetivo desta pesquisa foi avaliar o efeito de diferentes concentrações de GA4 + 7 + N- (fenilmetil) -aminopurina na quebra de dormência de sementes de Passiflora cincinnata recentemente colhidas e armazenadas por seis anos. O estudo foi conduzido em uma estufa na Embrapa Mandioca e Fruticultura, em delineamento inteiramente casualizado, em esquema fatorial 2 x 4, com os seguintes fatores: ano de colheita de sementes (2010 e 2016) e promotor de emergência GA4 + 7 + N - (fenilmetil) - aminopurina em quatro concentrações (0%; 0,03%; 0,45% e 0,90%), com 4 repetições de 25 sementes. Foram avaliados a porcentagem de emergência, a primeira contagem, o índice de velocidade de emergência, o número de folhas, o comprimento da raiz, o diâmetro do caule, a matéria seca da parte aérea, das raízes, total e a relação raiz/parte aérea. O GA4 + 7 + N - (fenilmetil) - aminopurina é recomendado para superar a dormência de Passiflora cincinnata em sementes recentemente colhidas (2016) e aumenta a emergência de sementes armazenadas por seis anos em câmara fria. A concentração do promotor de emergência de 0,03% pode ser usada para superar a dormência em sementes recentemente colhidas e potencializa o vigor das sementes armazenadas durante seis anos. As sementes de Passiflora cincinnata permanecem fisiologicamente viáveis por seis anos e seu vigor é potencializado pelo uso de GA4 + 7 + N - (fenilmetil) - aminopurina.

Activation of AMP-Activated Protein Kinase Attenuates Tumor Necrosis Factor-alpha-Induced Lipolysis via Protection of Perilipin in 3T3-L1 Adipocytes

BACKGROUND: Tumor necrosis factor (TNF)-alpha and AMP-activated protein kinase (AMPK) are known to stimulate and repress lipolysis in adipocytes, respectively; however, the mechanisms regulating these processes have not been completely elucidated. METHODS: The key factors and mechanism of action of TNF-alpha and AMPK in lipolysis were investigated by evaluating perilipin expression and activity of protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2alpha) by Western blot and an immunofluorescence assay in 24-hour TNF-alpha-treated 3T3-L1 adipocytes with artificial manipulation of AMPK activation. RESULTS: Enhancement of AMPK activity by the addition of activator minoimidazole carboxamide ribonucleotide (AICAR) suppressed TNF-alpha-induced lipolysis, whereas the addition of compound C, an inhibitor of AMPK phosphorylation, enhanced lipolysis. Perilipin, a lipid droplet-associated protein, was decreased by TNF-alpha and recovered following treatment with AICAR, showing a correlation with the antilipolytic effect of AICAR. Significant activation of PERK/eIF2alpha, a component of the unfolded protein response signaling pathway, was observed in TNF-alpha or vesicle-treated 3T3-L1 adipocytes. The antilipolytic effect and recovery of perilipin expression by AICAR in TNF-alpha-treated 3T3-L1 adipocytes were significantly diminished by treatment with 2-aminopurine, a specific inhibitor of eIF2alpha. CONCLUSION: These data indicated that AICAR-induced AMPK activation attenuates TNF-alpha-induced lipolysis via preservation of perilipin in 3T3-L1 adipocytes. In addition, PERK/eIF2alpha activity is a novel mechanism of the anti-lipolytic effect of AICAR.

The Treatment Experience Used Famciclovir in Herpes Zoster with Voiding Dysfunction in Female Patients

OBJECTIVE: Voiding dysfunction may be occurred due to the herpes zoster with lumbosacral lesion. We studied the clinical symptoms in patients with voiding dysfunction caused by herpes zoster. METHODS: We have investigated the medical records in 10 patients. These patients had urinary symptoms associated with herpes zoster. RESULTS: Dermatome levels were sacral(s) in 10 patients (s2, 4 patients; s3, 6 patients). Urologic symptoms were acute urinary retention in 10 patients who showed detrusor areflexia (7 patients) or detrusor hyporeflexia (3 patients) in urodynamics. All patients were managed by inserting catheter with alpha blocker. After 1 week we removed indwelling catheter. All patients were no problem in urination. CONCLUSION: The cause of voiding dysfunction is not known clearly in herpes zoster infection. But we investigated that Famciclovir 750 mg using oral medication and the urethral catheter insertion performed by one week was recovered from herpes zoster. Authors think it is useful for patients with impaired urination.

A Case of Herpes Zoster Peripheral Polyneuropathy Manifested by Foot Drop in Chronic Myeloid Leukemia

In herpes zoster infection, neurological complications may be overlooked because pain is a more prominent symptom and because peripheral polyneuropathy associated with weakness is rare. A 57-year-old male visited our hospital, complaining of pain and skin eruptions on the right flank. He was diagnosed as having herpes zoster and the symptoms were alleviated by administration of acyclovir for a week. After three weeks, the herpes zoster relapsed. He was re-admitted and diagnosed with chronic myeloid leukemia (CML), and imatinib mesylate was prescribed for five weeks. Ten weeks after the onset of herpes zoster, bilateral foot drops and numbness of the right foot dorsum developed. Through an electrodiagnostic study, he was diagnosed as having peripheral polyneuropathy that was suspected to be caused by neural invasion by varicella zoster virus. After administration of famciclovir, not only the pain but also the neurologic symptoms improved. We herein report a case of peripheral polyneuropathy that was supposed to be related to herpes zoster.

Drug Treatment of Herpes Simplex Infection

Herpes simplex virus (HSV) is one of Herpesviridae family viruses which belong to DNA viruses. HSV-associated diseases are among the most widespread infections, affecting nearly 60% to 95% of human adults. Labial herpes typically results from infection with HSV type 1 (HSV-1), whereas most genital herpes is caused by HSV type 2 (HSV-2). They are incurable and persist during the lifetime of the host, often in latent form. Antiviral agents do not cure HSV infections, but rather modify the clinical course of the disease. Topical, oral, or intravenous antiviral agents may be used in the management of HSV infections. Acyclovir, valacyclovir hydrochloride, and famciclovir are the 3 antiviral drugs commonly used to treat symptomatic HSV infections. However, it is very difficult to choose an appropriate drug and dosing regimen.

Comparative hepatotoxic study between acyclovir and famciclovir in adult male albino rats

Eighty adult male albino rats, which were divided into four groups, ninety rats each. Group 1 [negative control group], Group 2 [positive control group] gavaged orally with distilled water, Group 3 [Acyclovir group] gavaged orally with Acyclovir 432 mg/kg B. wt. once daily for 4 weeks and lastly Group 5 [Famcyclovir] gavaged orally with Famcyclovir 135 mg/kg B. wt. After 4 weeks, blood samples, for estimation of serum albumin and alkaline phosphatase, were withdrawn from each rat and then rats were sacrificed. Liver specimens were obtained for histopathological examination by light microscope after staining with haematoxylin and eosin and special stain for immunohistochemical detection of Appoptotic changes. As compared to control groups and Famcyclovir group, Acyclovir group showed significant decrease of serum albumin, elevation of alkaline phosphatase activity associated with a severe apoptotic changes as evidenced by Bc12 overexpression in liver cells. The present study doesn't recommend the use of Acyclovir in patient with liver impairment and if strongly indicated, it's wiser to use Farmcyclovir

New antiviral agents.

During the last three decades, a better understanding of viral replication and disease states caused by viral infections have led to the development of newer antiviral agents with enhanced activity and better tolerability. This review focuses on newer systemic and topical antiviral agents that are used in treatment of herpes viruses including herpes simplex type-1 (HSV-1) and type-2 (HSV-2), varicella-zoster virus (VZV) and cytomegalovirus CMV) as well as the human papilloma virus (HPV). Included in this article are the agents famciclovir, penciclovir, valganciclovir, imiquimod, docosanole and brivudin.

Clinical investigation of famciclovir in chronic hepatitis B patients irresponsive to alpha interferon treatment / 中华肝脏病杂志

<p><b>OBJECTIVES</b>To evaluate the efficacy and safety of famciclovir on the decreasing levels of serum HBV-DNA and ALT and HBeAg/antiHBe seroconversion in chronic hepatitis B patients irresponsive to 3 months treatment with alpha interferon.</p><p><b>METHODS</b>Two hundred and nineteen patients with chronic HBV infection, defined as positive HBsAg, HBeAg and HBV DNA, were enrolled and randomly half-and- half put into famciclovir and placebo groups. The two groups received either famciclovir 500 mg tid or a placebo treatment for 24 weeks, and then were followed-up for another 24 weeks with no treatment.</p><p><b>RESULTS</b>At the end of 24 weeks, the log value of HBV DNA dropped from 6.54+/-1.26 to 5.70+/-2.03 in the famciclovirt group and were elevated from 6.30+/-1.32 to 6.51+/-1.65 in the placebo group (P < 0.01). The rate of cases with persistence HBV DNA dropped 2 log of quantity in the famciclovir group and was 28.28% (28/99); it was 9.47% (9/95) in the placebo group (P < 0.01). Those with persistence negative HBV DNA was 28.28% (28/99) in the flamciclovir treated group and 14.74% (14/95) in the placebo group (P < 0.05). Those persistently being HBeAg negative were 7.69% (7/91) in the famciclovir treated group and 3.33% (3/90) in the placebo group (P > 0.05). The HBeAg/antiHBe seroconversion was 4.40% (4/91) in the famciclovir group and 2.22% (2/90) in the placebo group (P > 0.05). The percentage of cases with normal of ALT level was 15.15% in the famciclovir group and 6.35% in the placebo group (P < 0.05).</p><p><b>CONCLUSION</b>Famciclovir is effective in inhibiting HBV DNA replication and in decreasing serum ALT levels. The rate of HBeAg/antiHBe seroconversion in the famciclovir treated group was similar to that of the placebo group. Famciclovir was well tolerated without severe adverse effects during our treatment.</p>

Effect of activation and inhibition of cellular PKR on coxsackievirus B3 replication

The ds-RNA activated protein kinase [PKR] is a serine-threonine kinase with MW of 68 KDa. It belongs to a family of kinases that control one of the translational initiation factors, eIF2. PKR is produced at high level in response to viral infection. This protein by phosphorylating eIF2 inhibits cellular protein synthesis. In this study, the effect of gamma interferon [IFN- gamma], an activator, and 2-aminopurine [2AP], an inhibitor of PKR production on coxsackievirus B3 [CVB3] replication were studied. After addition of IFN- gamma and 2AP to Vero and HeLa cultures, cells were infected with CVB3. After 48 h and appearance of cytopathic effect [CPE], cells were collected and viral replication was assessed by standard method. For molecular detection of PKR, RT-PCR technique was used. The data show that interferon inhibited [or lowered] and 2AP promoted viral replication, though in all samples presence of PKR-mRNA could be detected. It seems that PKR plays a key role in CVB3 replication. Therefore, PKR can be considered as a promising and considerable target for designing small molecules and drugs against CVB3

Treatment of patients with chronic hepatitis B virus infect ion with lamivudine combined with famciclovir / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To evaluate the clinical efficacy of combined treatment with lamivudine and famciclovir on chronic hepatitis B virus (HBV) infection.</p><p><b>METHODS</b>Ninety patients with chronic HBV infection were divided into 3 groups. Group one had 28 patients and was treated with combination of lamivudine (0.1 g/d, PO) and famciclovir (1.5 g/d,PO) for 24 weeks. Group two and three had 30 and 32 cases, respectively, and were treated with lamivudine 100 mg/day PO and famciclovir (1.5 g/d,PO) alone. All the patients had positive markers of HBsAg, HBeAg and anti-HBcAg in serum assayed by ELISA and of HBV DNA tested by PCR.</p><p><b>RESULTS</b>Three strategies of treatment had no different effects on the change of patients' ALT levels. The serum HBV DNA became negative after treatment in 89.3% (25/28) of patients treated with combination of lamivudine and famciclovir, 66.7% (20/30) of patients treated with lamivudine, and 40.6% (13/32) of patients treated with famciclovir. The rate of serum HBeAg loss in 3 groups were 28.6% (8/28), 23.3% (7/30) and 21.9% (7/32), respectively.</p><p><b>CONCLUSIONS</b>The combination treatment of lamivudine and famciclovir for chronic HBV infection is safer than and superior to that of either drug alone.</p>

Prevention and treatment of HBV reinfection following liver transplantation / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the prevention and treatment of HBV reinfection after liver transplantation.</p><p><b>METHODS</b>Total 19 cases of chronic fulminant hepatitis B, the end-stage of liver cirrhosis and liver carcinoma complicated with HBV cirrhosis. Were performed liver transplantation and given anti-viral drugs pre and post transplantation. Famciclovir was administered in 4 cases, lamivudine in 13 cases and lamivudine+HBIG in 2 cases. The serum HBVM and liver biopsy immunohistochemistry were performed.</p><p><b>RESULTS</b>Four cases given famciclovir developed reinfection. Serum HBsAg, HBeAg and HBV DNA were positive in 3 cases. Liver biopsy immunohistochemistry showed HBsAg and HBeAg phenotype. Classical viral hepatitis in 1 case occurred, three cases died. In the lamivudin group 7 cases showed positive for HBsAg, 2 cases positive for HBV DNA, 4 cases HBsAg or HBcAg phenotype. One case showed positive for serum anti-HBc the other negative for HBVM, and liver biopsy immunohistochemistry was negative too.</p><p><b>CONCLUSIONS</b>These date suggest that anti-virus prevention and treatment in pre and post liver transplantation with HBV infected correlative disease is necessary, feasible and effective.</p>

Famciclovir treatment of patients with chronic hepatitis B virus infection / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To evaluate the effects of famciclovir treatment of patients with chronic hepatitis B virus (HBV) infection.</p><p><b>METHODS</b>Eighty-nine patients with chronic HBV infection were randomly divided into three groups. Thirty-two patients were treated with famciclovir, 29 patients and 28 patients with chronic HBV infection were treated with interferon (IFN) alpha and lamivudine, respectively, as the control.</p><p><b>RESULTS</b>The serum HBV DNA became negative after treatment in 40.62% (13/32) of patients treated with famciclovir, 37.93% (11/29) of patients treated with IFN alpha, and 67.90% (19/28) of patients treated with lamivudine. The rate of serum HBeAg loss for the three groups were 21.88% (7/32), 41.38% (12/29) and 21.43% (6/28), respectively. The average time for patients to become serum HBV DNA negative was 1.3 months.</p><p><b>CONCLUSIONS</b>Famciclovir is an effective and safe nucleoside drug for the treatment of patients with chronic HBV infection.</p>