Anti-human immunodeficiency virus-1 activity of MoMo30 protein isolated from the traditional African medicinal plant Momordica balsamina.

BACKGROUND: Plants are used in traditional healing practices of many cultures worldwide. Momordica balsamina is a plant commonly used by traditional African healers as a part of a treatment for HIV/AIDS. It is typically given as a tea to patients with HIV/AIDS. Water-soluble extracts of this plant were found to contain anti-HIV activity. METHODS: We employed cell-based infectivity assays, surface plasmon resonance, and a molecular-cell model of the gp120-CD4 interaction to study the mechanism of action of the MoMo30-plant protein. Using Edman degradation results of the 15 N-terminal amino acids, we determined the gene sequence of the MoMo30-plant protein from an RNAseq library from total RNA extracted from Momordica balsamina. RESULTS: Here, we identify the active ingredient of water extracts of the leaves of Momordica balsamina as a 30 kDa protein we call MoMo30-plant. We have identified the gene for MoMo30 and found it is homologous to a group of plant lectins known as Hevamine A-like proteins. MoMo30-plant is distinct from other proteins previously reported agents from the Momordica species, such as ribosome-inactivating proteins such as MAP30 and Balsamin. MoMo30-plant binds to gp120 through its glycan groups and functions as a lectin or carbohydrate-binding agent (CBA). It inhibits HIV-1 at nanomolar levels and has minimal cellular toxicity at inhibitory levels. CONCLUSIONS: CBAs like MoMo30 can bind to glycans on the surface of the enveloped glycoprotein of HIV (gp120) and block entry. Exposure to CBAs has two effects on the virus. First, it blocks infection of susceptible cells. Secondly, MoMo30 drives the selection of viruses with altered glycosylation patterns, potentially altering their immunogenicity. Such an agent could represent a change in the treatment strategy for HIV/AIDS that allows a rapid reduction in viral loads while selecting for an underglycosylated virus, potentially facilitating the host immune response.

Scientific Hero: Dr. James E. K. Hildreth.

Note from the editor: This column was originally published in 2013. Currently, Dr. Hildreth serves as president and CEO of Meharry Medical College, leading the technological, academic, and clinical transformation of the nation's largest private historically Black academic health sciences center. Because of his standing as a world-class infectious disease expert, Hildreth emerged as an important national figure in the response to the COVID-19 pandemic. In September 2020, he was appointed to the FDA Vaccines and Related Biological Products Advisory Committee that reviewed COVID-19 vaccine candidates for approval, and in February 2021, Dr. Hildreth was named to President Joseph Biden's Health Equity Task Force.

Evaluation of Quantra Hologic Volumetric Computerized Breast Density Software in Comparison With Manual Interpretation in a Diverse Population.

OBJECTIVE: Increased mammographic breast density is a well-established risk factor for breast cancer development, regardless of age or ethnic background. The current gold standard for categorizing breast density consists of a radiologist estimation of percent density according to the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) criteria. This study compares paired qualitative interpretations of breast density on digital mammograms with quantitative measurement of density using Hologic's Food and Drug Administration-approved R2 Quantra volumetric breast density assessment tool. Our goal was to find the best cutoff value of Quantra-calculated breast density for stratifying patients accurately into high-risk and low-risk breast density categories. METHODS: Screening digital mammograms from 385 subjects, aged 18 to 64 years, were evaluated. These mammograms were interpreted by a radiologist using the ACR's BI-RADS density method, and had quantitative density measured using the R2 Quantra breast density assessment tool. The appropriate cutoff for breast density-based risk stratification using Quantra software was calculated using manually determined BI-RADS scores as a gold standard, in which scores of D3/D4 denoted high-risk densities and D1/D2 denoted low-risk densities. RESULTS: The best cutoff value for risk stratification using Quantra-calculated breast density was found to be 14.0%, yielding a sensitivity of 65%, specificity of 77%, and positive and negative predictive values of 75% and 69%, respectively. Under bootstrap analysis, the best cutoff value had a mean ± SD of 13.70% ± 0.89%. CONCLUSIONS: Our study is the first to publish on a North American population that assesses the accuracy of the R2 Quantra system at breast density stratification. Quantitative breast density measures will improve accuracy and reliability of density determination, assisting future researchers to accurately calculate breast cancer risks associated with density increase.

Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation.

INTRODUCTION: This 7-year, prospective, matched-cohort, clinical study evaluated the effects of intramuscular depot medroxyprogesterone acetate (DMPA) (150 mg/mL) on bone mineral density (BMD) in women aged 25-35 years. METHODS: Bone mineral density changes in new DMPA-IM users (n=248) were compared with those in women using nonhormonal contraception (n=360) for up to 240 weeks of treatment and 96 weeks of posttreatment follow-up (in subjects receiving >or=1 dose). RESULTS: At week 240 of treatment, mean percentage changes from baseline in DMPA-IM vs. nonhormonal subjects were: -5.16% (n=21) vs. +0.19% (n=65), total hip (p<.001); -5.38% (n=33) vs. +0.43% (n=105), lumbar spine (p<.001). At week 96 posttreatment, these values were: -0.20% (n=25) vs. +0.84% (n=43), total hip (p=.047); -1.19% (n=41) vs. +0.47% (n=66), lumbar spine (p=.017). CONCLUSIONS: These results show BMD declines during DMPA-IM use; following discontinuation, significant increases in BMD occur through 96 weeks posttreatment.

Conventional medical therapies for endometriosis.

Endometriosis is a common gynecologic disorder that affects approximately 14% of all women and 30% to 50% of infertile women. Since the most common symptoms of endometriosis--progressive dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility--are also symptoms of multiple disorders, a diagnosis of endometriosis can be elusive and confirmed only by visualization, that is, laparoscopy. Endometriosis is often treated surgically upon diagnosis; however, the rate of recurrence is high, suggesting that a combination of therapeutic approaches might provide better outcomes than any one option alone. The most widely utilized hormonal treatments for endometriosis are GnRH agonists and oral contraceptives; agents indicated by the Food and Drug Administration include GnRH agonists and the androgen, danazol. The majority of evidence in support of medical therapy for endometriosis is largely observational, with the exception of studies of GnRH agonists, danazol, and a few progestins. Conventional treatment approaches for the medical management of endometriosis focus on suspected endometriosis, following a diagnosis of endometriosis, following surgical treatment of endometriosis, long-term management, and retreatment. Although major advances have been made in the treatment of endometriosis in recent decades, lack of randomized clinical trials evaluating the use of agents such as oral contraceptives alone or as add-back therapy for GnRH agonists, or those that examine combined medical and surgical treatments, has hampered the ability of physicians to provide the broadest range of medical therapies for this disorder. Future trials addressing these issues are warranted.

Optimizing the dose of hormone replacement therapy.

Over the last 5 years we have seen the evolution of several new products and several new regimens for estrogen replacement in menopause. Before this time, the decision surrounding hormone replacement therapy (HRT) mainly focused on whether to take estrogen or not, and if the addition of a progestogen was required. However, with new paradigms we now have several options for HRT, with various doses of estrogen ranging from very low doses of oral estrogen (0.3 mg conjugated equine estrogen [CEE], 0.25 mg 17beta-estradiol), transdermal patches which deliver a minimum of 20 microg of 17beta-estradiol per day, or intranasal methods which deliver 100-400 microg of 17beta-estradiol, to the more commonly prescribed doses of 0.625 mg of CEE or 0.5 mg 17beta-estradiol. The decision to add a progestogen to the regimen of replacement therapy is well accepted, particularly in a woman who has an intact uterus; however, now the controversy has focused on which progestogen least attenuates the lipid benefits received from the estrogen replacement therapy. Estrogen treatment in the postmenopausal woman has several proven benefits. For the woman who has vasomotor symptoms or complaints related to urogenital atrophy, there is little controversy regarding its use. However, a continuing controversial area is that of long-term prevention of osteoporosis and cardiovascular disease. It is in these areas that the decision on the dose and the addition of a progestin to hormone replacement therapy is under review.

Preferential effect of akt2-dependent signaling on the cellular viability of ovarian cancer cells in response to EGF.

OBJECTIVE: Overexpression of the epidermal growth factor receptor (EGFR) is associated with the malignant phenotype in many cancers including ovarian cancer, which leads to increased cell proliferation and survival. In spite of emerging EGFR inhibitors as a potentially useful agent, they are largely ineffective in patients with advanced or recurrent ovarian cancers. Since Akt as a key downstream factor of EGFR is highly activated in some high grade serous ovarian tumors, the augmented Akt activation may attribute to irregular EGFR-mediated signaling observed in ovarian cancer. Here we investigated the differential effect of Akt on the EGF-induced cell viability in a panel of ovarian cancer cell lines. METHODS: Cellular viability assay and western blot analysis were used to measure cell viability and expression levels of proteins, respectively. Knockdown of Akt was achieved with siRNA and stable transfection of expression vectors was performed. RESULTS: Cellular viability increased in OVCAR-3 ovarian cancer cells exposed to EGF, but little to no difference was observed in the 5 other ovarian cancer cells including SKOV-3 cells despite of the expression of EGFR. In OVCAR-3 cells, EGF activated Erk and Akt, but an Erk inhibitor had no impact on cellular viability. On the other hand, the EGFR and PI3K inhibitors decreased EGF-induced cellular viability, indicating the involvement of Akt signaling. Although EGF activated Erk in SKOV-3 cells, the Akt activation was very weak as compared to OVCAR-3 cells. Furthermore, we observed a different expression of Akt isoforms: Akt1 was constitutively expressed in all tested ovarian cancer cells, while Akt3 was little expressed. Interestingly, Akt2 was highly expressed in OVCAR-3 cells. Knockdown of Akt2 blocked EGF-induced OVCAR-3 cell viability whereas knockdown for Akt1 and Erk1/2 had no significant effect. Stable transfection of Akt2 into SKOV-3 cells phosphorylated more Akt and enhanced cell viability in response to EGF. CONCLUSIONS: Akt2-dependent signaling appears to play an important role in EGFR-mediated cellular viability in ovarian cancer and targeting specific Akt isoform may provide a potential therapeutic approach for EGFR-expressing ovarian cancers.