Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The properties such as clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the translation of siRNA is restricted by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.

CRISPR-Cas9: A method for establishing rat models of drug metabolism and pharmacokinetics

The 2020 Nobel Prize in Chemistry recognized CRISPR-Cas9, a super-selective and precise gene editing tool. CRISPR-Cas9 has an obvious advantage in editing multiple genes in the same cell, and presents great potential in disease treatment and animal model construction. In recent years, CRISPR-Cas9 has been used to establish a series of rat models of drug metabolism and pharmacokinetics (DMPK), such as

SIRT6 as a key event linking P53 and NRF2 counteracts APAP-induced hepatotoxicity through inhibiting oxidative stress and promoting hepatocyte proliferation

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively.

Natural products, PGC-1 , and Duchenne muscular dystrophy

Peroxisome proliferator-activated receptor (PPAR) is a transcriptional coactivator that binds to a diverse range of transcription factors. PPAR coactivator 1 (PGC-1) coactivators possess an extensive range of biological effects in different tissues, and play a key part in the regulation of the oxidative metabolism, consequently modulating the production of reactive oxygen species, autophagy, and mitochondrial biogenesis. Owing to these findings, a large body of studies, aiming to establish the role of PGC-1 in the neuromuscular system, has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases. Among these, some evidence has shown that various signaling pathways linked to PGC-1 are deregulated in muscular dystrophy, leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species (ROS) production. In the light of these results, any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies. PGC-1 is influenced by different patho-physiological/pharmacological stimuli. Natural products have been reported to display modulatory effects on PPAR activation with fewer side effects in comparison to synthetic drugs. Taken together, this review summarizes the current knowledge on Duchenne muscular dystrophy, focusing on the potential effects of natural compounds, acting as regulators of PGC-1.

Development of Trans Attack Anticancer Gene Vaccine Interact in HPV Oncoprotein Expression Inhibition / 대한산부인과학회잡지

OBJECTIVE: Adeno-associated virus Rep 78 protein is known to inhibit the promoter site of several onco-genes and viral gene, including the human papillomavirus type 16 E6 transforming genes. In this study, we investigated AAV Rep 78 mediated inhibition of HPV 16 E6 promotor activity. METHODS: pcDNA3.1/V5/His-Topo vector, cloned by AAV mediated Rep 78, is transfected into cervical cancer cell line (Caski). After that, we confirmed HPV16 derived E6 expression and cell growth inhibition. RESULTS: Transfection rate of Rep78 GFP-vector, approximately from 30 to 60 per-cent, is highly expressed at first day. But E6 expression is lower at this day. The growth of CaSki and HeLa cervical cancer cell lines was inhibited by Rep78 (p<0.05). But, the other cervical cancer cells were unaffected by Rep78 transfection. CONCLUSION: In spite of the high Rep78 transfection efficiency and expression rate, we could not show the cervical cancer cell growth inhibition. In our data, long term expression of Rep78 strategy is needed for cervical carcinoma gene therapy using adeno-associated virus vector.

Relationship Between Adeno-Associated Virus and High Risk Human Papilloma Viruses in Cervical Biopsies Using Microdissection Technique / 대한산부인과학회잡지

OBJECTIVE: Adeno associated virus (AAV) is a human DNA virus and is included in the Parvovirus family. AAV has been detected in cervical tissues as well as cervical cancer cell lines. Previous studies showed that AAV infection has some negative effects on HPV infection and that the cervical cancer cell growth is inhibited by AAV infection. The aim of this study is to determine the prevalence of AAV 2 infection and its possible roles for influencing HPV 16 and 18 infection in Korean women by analyzing adjacent normal, CIN, and invasive cervical cancer tissue samples. METHODS: CIN I (20), CIN II (24), CIN III (25), invasive cervical cancer (23) tissues were investigated by microdissection and PCR analyses using primers of HPV 16, 18 and AAV 2 as well as beta- globin as an internal control. RESULTS: AAV 2 was detected in 57 out of 92 cervical lesion biopsies. Among these, mild dysplasia, moderate dysplasia, severe dysplasia and invasive cancer showed 55% (11/20), 95.8% (23/24), 52% (13/25) and 52.2% (12/23), respectively. However, HPV 16 was detected in 14 out of 92 cervical lesion biopsies. Among these, mild dysplasia, moderate dysplasia, severe dysplasia and invasive cancer showed 0% (0/20), 8.3% (2/24), 24% (6/25) and 26.1% (6/23), respectively. HPV 18 was detected in 3 out of 92 cervical lesion biopsies. Among these, mild dysplasia, moderate dysplasia, severe dysplasia and invasive cancer showed 0% (0/20), 4.2% (1/24), 8% (2/25) and 0% (0/23), respectively. In contrast, In 92 perilesional normal biopsies, AAV 2, HPV 16 and HPV 18 were detected to be 57.6% (53/92), 3.3% (3/92) and 0% (0/92), respectively. CONCLUSION: AAV 2 was detected in CIN and invasive cervical cancer biopsies by microdissection and PCR analyses in Korean women. It is difficult to confirm any significant roles of AAV 2 infection for developing cervical cancer. However, we observe that there is some correlation between AAV 2 and HPV infection in the carcinogenesis of cervical cancer. Further research remains to be done to further elucidate AAV 2 infection and its role for HPV infection and cervical cancer.