Samir A. Kouzi

Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals

Doxorubicin (Dox) is an effective chemotherapeutic agent, but known to cause cardiac and hepatic toxicity. Mechanisms of toxicity have not been clearly identified, but shown to involve oxidative stress and mitochondrial dysfunction. However, antioxidant supplementation has only shown modest protection from Dox‐induced toxicity in clinical trials. Therefore, further research is required to discern alternative mechanisms that may also play an important role in Dox‐induced toxicity. Thus, we aimed to investigate the role of mitochondrial fusion and fission in Dox‐induced hepatic toxicity, which has not yet been investigated. Six‐week‐old male F344 rats were injected IP with 20 mg/kg of Dox or saline. Once administered, both groups of animals were fasted with no food or water until sacrifice 24 h later. Dox decreased content of primary regulators of mitochondrial fusion (OPA1, MFN1, and MFN2) with no effect on regulators of fission (DRP1 and FIS1), thus shifting the balance favoring mitochondrial fission. Moreover, it was determined that mitochondrial fission was likely not coupled to cell proliferation or cytochrome c release leading to the activation of mitochondrial‐mediated apoptotic signaling. Rather, mitochondrial fission may be coupled to mitophagy and may be an adaptive response to protect against Dox‐induced hepatic toxicity. This is the first study to report the role of altered mitochondrial dynamics and mitophagy machinery in Dox‐induced hepatic injury.

Can short-term fasting protect against doxorubicin-induced cardiotoxicity?

Doxorubicin (Dox) is one of the most effective chemotherapeutic agents used in the treatment of several types of cancer. However the use is limited by cardiotoxicity. Despite extensive investigation into the mechanisms of toxicity and preventative strategies, Dox-induced cardiotoxicity still remains a major cause of morbidity and mortality in cancer survivors. Thus, continued research into preventative strategies is vital. Short-term fasting has proven to be cardioprotective against a variety of insults. Despite the potential, only a few studies have been conducted investigating its ability to prevent Dox-induced cardiotoxicity. However, all show proof-of-principle that short-term fasting is cardioprotective against Dox. Fasting affects a plethora of cellular processes making it difficult to discern the mechanism(s) translating fasting to cardioprotection, but may involve suppression of insulin and insulin-like growth factor-1 signaling with stimulated autophagy. It is likely that additional mechanisms also contribute. Importantly, the literature suggests that fasting may enhance the antitumor activity of Dox. Thus, fasting is a regimen that warrants further investigation as a potential strategy to prevent Dox-induced cardiotoxicity. Future research should aim to determine the optimal regimen of fasting, confirmation that this regimen does not interfere with the antitumor properties of Dox, as well as the underlying mechanisms exerting the cardioprotective effects.

Strategies for Developing Oral Vaccines for Human Papillomavirus (HPV) Induced Cancer using Nanoparticle mediated Delivery System

Human Papillomaviruses (HPV) are a diverse group of small non-enveloped DNA viruses. Some HPVs are classified as low-risk as they are very rarely associated with neoplasia or cancer in the general population, and cause lenient warts. Other HPVs are considered as high-risk types because they are responsible for several important human cancers, including cervical cancer, a large proportion of other anogenital cancers, and a growing number of head and neck cancers. Transmission of HPV occurs primarily by skin-to-skin contact. The risk of contracting genital HPV infection and cervical cancer is influenced by sexual activity. Currently two prophylactic HPV vaccines, Gardasil® (Merck, USA) and Cervarix® (GlaxoSmithKline, UK), are available and recommended for mass immunization of adolescents. However, these vaccines have limitations as they are expensive and require cold chain storage and trained personnel to administer them by injection. The use of nano or micro particulate vaccines could address most of these limitations as they are stable at room temperature, inexpensive to produce and distribute to resource poor regions, and can be administered orally without the need for adjuvants in the formulation. Also it is possible to increase the efficiency of these particulate vaccines by decorating the surface of the nano or micro particulates with suitable ligands for targeted delivery. Oral vaccines, which can be delivered using particulate formulations, have the added potential to stimulate mucosa-associated lymphoid tissue located in the digestive tract and the gut-associated lymphoid tissue, both of which are important for the induction of effective mucosal response against many viruses. In addition, oral vaccines provide the opportunity to reduce production and administration costs and are very patient compliant. This review elaborately discusses different strategies that can be pursued to develop a nano or micro particulate oral vaccine for HPV induced cancers and other diseases.

Pycnogenol for chronic venous insufficiency

Chronic venous insufficiency (CVI) is a vascular disorder affecting 1–5% of the population and is most common in the elderly.[1][1],[2][2] Complications of CVI include edema and venous stasis ulcers, which can contribute to increased morbidity and health care costs.[3][3],[4][4] Unfortunately, few

Oral ivermectin for the treatment of head lice infestation

PURPOSE Published literature describing the use of oral ivermectin for the treatment of head lice infestation is reviewed. SUMMARY In the United States and globally, head lice infestation, or pediculosis capitis, remains a public health issue with both social and medical implications. Treatment with oral or topical medications is typically required for head lice eradication. Resistance to traditional topical therapies for head lice infestation is increasing, creating a need for consideration of additional treatment options. A growing body of data describing the potential role of oral ivermectin for the treatment or prevention of head lice infestation is available. A literature search identified 5 clinical trials that evaluated safety and/or effectiveness outcomes of oral ivermectin use as an alternative to malathion, other topical prescription medications, and traditional, nonprescription remedies; those studies were conducted in various parts of the world (e.g., Australia, Brazil, Mexico, Egypt) and likely involved varying types and degrees of lice resistance. Clinical research findings to date, while not consistently robust, suggest that oral ivermectin is comparable or superior in effectiveness to other topical treatment options for head lice infestation while being well tolerated and favorably perceived by patients and caretakers. CONCLUSION Oral ivermectin is an option for the treatment of head lice infestation, especially in individuals who have experienced a treatment failure. Published evidence from clinical trials indicates that oral ivermectin is as effective as currently available topical treatments.

Effects of acute doxorubicin treatment on hepatic proteome lysine acetylation status and the apoptotic environment.

AIM To determine if doxorubicin (Dox) alters hepatic proteome acetylation status and if acetylation status was associated with an apoptotic environment. METHODS Doxorubicin (20 mg/kg; Sigma, Saint Louis, MO; n = 8) or NaCl (0.9%; n = 7) was administered as an intraperitoneal injection to male F344 rats, 6-wk of age. Once animals were treated with Dox or saline, all animals were fasted until sacrifice 24 h later. RESULTS Dox treatment decreased proteome lysine acetylation likely due to a decrease in histone acetyltransferase activity. Proteome deacetylation may likely not be associated with a proapoptotic environment. Dox did not increase caspase-9, -8, or -3 activation nor poly (adenosine diphosphate-ribose) polymerase-1 cleavage. Dox did stimulate caspase-12 activation, however, it likely did not play a role in apoptosis induction. CONCLUSION Early effects of Dox involve hepatic proteome lysine deacetylation and caspase-12 activation under these experimental conditions.

Constitutive protein content of procaspases in murine tissue

Caspases are proteases most notably involved in apoptosis and inflammation. Although mRNA content is better described, the constitutive protein content of procaspases between tissue types is not well documented. Since mRNA and protein content do not necessarily correlate, we aimed to discern protein content differences between various tissues. Protein content of procaspase-1, -8, -9, and -12 was assessed in gastrocnemius, heart, liver, and kidney. Since highly expressed in skeletal muscle, content of procaspase-12 was also analyzed in muscles with different fiber type compositions to discern any fiber type differences. Furthermore, Western analysis for procaspase-12 revealed prominent bands of ∼40 kDa and ∼30 kDa under basal conditions, in addition to the 50 kDa band corresponding to the full-length procaspase. Therefore, the content of these caspase-12 related species in the tissue and muscle types is also described. Results show protein content of procaspase-1,-8, -9, and -12 and caspase-12 related species differs between tissue types and do not necessarily correlate with mRNA content reported in the published literature. Procaspase-12 content in skeletal muscle may be fiber-type dependent with higher expression in more oxidative fibers. Furthermore, the 40 kDa species of caspase-12 was the dominant form of the protein in most tissues analyzed.