Targeting AMPKa1 Gene in PC3 Cells by Triphenylmethanol Derivatives

Epidemiological studies indicate that treatment with metformin, an AMP-activated protein kinase (AMPK) activator, reduces the incidence of cancers. Activation of AMPK has also been reported to oppose tumor progression in diverse types of cancers and offers promising cancer therapy. Furthermore, AMPK is a primary regulator of energy metabolism and has also been implicated in cell cycle progression, angiogenesis, cell transformation, migration, and cancer. We have recently synthesized novel flavonoids, namely, triphenylmethanol derivatives (TPMs), but the effectiveness of the TPMs on the activity of AMPK remains unclear. We hypothesized that the novel TPMs would inhibit cancer cell proliferation through the activation of AMPK isoforms in cells. The effects of TPMs on prostate cells (PC-3) were investigated. Cells were exposed to TPMs for either 12 or 24 hr. at the respective doses of 0, 25, 50 100, and 200 µM based on the cell viability studies by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) (MTT) assay. The results indicate that cells exposed to the respective doses of TPMs increased both phospho- and total-AMPKα1 in a dose- and time-dependent manner. The effects of the increases for the phospho- and total-AMPKα in cells were greater for the 24-hr than the 12-hr. incubation. Further studies are currently going on to elucidate the specificities of the said insults in increasing the phospho- and total-AMPKα activities and for the other respective isoforms.

Increase in Organochlorine Contaminant Levels in Major Water Sources of the United States in Response to the Coronavirus Pandemic

Organochlorine contaminants, such as triclosan (TCS), are present in major water sources across the United States. These antimicrobial compounds are widely used as multipurpose ingredients in everyday consumer products. They can be ingested or absorbed through the skin and are found in human blood, breast milk, and urine samples. Studies have shown that the increased use of antimicrobial agents leads to their presence and persistence in the ecosystem, particularly in soil and watersheds. Many studies have highlighted emerging concerns associated with the overuse of TCS, including dermal irritations, a higher incidence of antibacterial-related allergies, microbial resistance, disruptions in the endocrine system, altered thyroid hormone activity, metabolism, and tumor metastasis and growth. Organochlorine contaminant exposures play a role in inflammatory responsiveness, and any unwarranted innate response could lead to adverse outcomes. The capacity of TCS and other organochlorine contaminants to induce inflammation, resulting in persistent and chronic inflammation, is linked to various pathologies, such as cardiovascular disease and several types of cancers. Chronic inflammation presents a severe consequence of exposure to these antimicrobial agents, as any changes could result in the loss of immune competence. Organochlorine contaminant levels were established by the United States Environmental Protection Agency (EPA) in 2019-2020 and have consistently increased in response to the novel coronavirus (nCoV) (COVID-19) pandemic. Our previous research examined the overuse of products containing triclosan (TCS), which led to an increase in total trihalomethane (TTHM) levels affecting the quality of our water supply. We also investigated the impact of the FDA ban that now requires pre-market approval. To comprehend the consequences of excessive antimicrobial use on water quality, we conducted an analysis of the levels of total trichloromethane (chloroform), a byproduct of free chlorine added to TCS, in primary water sources in metropolitan areas across the United States in 2019-2020. We repeated this analysis after the peak of the COVID-19 pandemic in 2021-2022 to examine its correlation with organochlorine exposure. Our study found that the COVID-19 pandemic, along with the increased use of antimicrobial products, has significantly raised the levels of total trihalomethanes compared to those reported in water quality reports from 2019-2020, in contrast to the reports from 2021-2022.

Triphenylmethanol Conjugates of Triptorelin as Cell-Penetrating Anti-Cancer Prodrugs

Some Triptorelin® (TRP) conjugates of triphenylmethanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxy benzenes with 1,3,5-trioxane, followed by the conjugation with TRP and sebacic acid to produce TRP-TPMs derivatives. Comparative antiproliferative assays between TRP-TPMs conjugates and the corresponding non-covalent physical mixtures of the TPMs derivatives and TRP were used to treat human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3) and mouse preadipocytes (3T3-L1) cells. TRP-TPMs conjugates at the 50 μM inhibited cell proliferation in CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 21% - 37%, 24% - 73%, 37% - 56%, respectively following incubation for 72 h. These findings indicate that TRP-TPMs derivatives have the potential to enhance the biological activity of TRP.

Puerto Rico’s Water Supply: An Investigation of the Levels of Trihalomethanes and Other Contaminants

The US Commonwealth of Puerto Rico is comprised of 143 islands, atolls, cays, and islets. Of the 143 localities, only 3 islands are inhabited: The mainland (often referenced as Puerto Rico), Culebra, and Vieques. To properly analyze the water supply quality, the mainland will be the focal point for examining environmental and social injustices. Puerto Rico is a racially diverse but ethnically homogenous territory, with most of the commonwealth living below the poverty level. Access to clean water sources is always tenuous in Puerto Rico. Over 70 percent of the island is served by water, violating US health standards. However, the recent hurricanes made the situation even more detrimental. According to data reported between January 2015 and March 2018 by the Consumer Confidence Report (CCR), 97 percent of the population of Puerto Rico utilizes a common drinking water system with one or more recent violations of the Safe Drinking Water Act for its testing requirements for lead and copper levels. The amounts found were far higher than any US state, meaning that virtually everyone on the island gets water from systems that violated testing or reporting requirements. In this study, we have collected and analyzed the levels of trihalomethanes (THMs), haloacetic acids (HAAs), copper, lead, and total organic compounds (TOCs) in drinking water providing systems in Puerto Rico and compared them with the recommended levels of contaminants provided by the US Environmental Protection Agency (EPA) guidelines. Many of these reported contaminants can have serious and detrimental health effects after prolonged exposure to higher concentrations of the contaminants found in the drinking water sources of Puerto Rico.

Diversifying Clean Water: An Examination of Drinking Water Quality and Social Disparities in Michigan

Water is one of the most essential resources required to sustain life. However, it could be detrimental to the health of those without access to water that is properly treated. Although the Safe Drinking Water Act of 1974 set regulations to protect citizens from naturally occurring and man-made contaminants, some people are still without clean and safe water, which is speculated to be because of their race. This research examines the disproportionality of available clean water provided by government sources in Michigan and its correlation with race and household income. In the study, it has been found that one of the leading causes of water contamination is industrial activity, with the automobile industry being responsible for approximately 300 million tons of lead contamination in water, and that the manufacturing company’s locations mostly centered in minority and low-income areas. Lower income cities, such as Hamtramck and Benton Harbor, have an average of 14.8 drinking water standard violations with the highest being 99 total violations, while higher income cities, like Novi and Bloomfield hills, have an average of 4 violations. Cities, like Flint and Detroit, which have a higher minority population, are 10 times more likely to have a water standard violation, and the minority population is proportionally related to the possibility of industrial manufacturing being located in those areas. These communities also face a higher risk of birth defects, developmental issues in children, and organ failure in adults, due to continuous exposure to water contaminants. Race as a direct causation could not be proven, but there are links to direct correlation through historical redlining and housing trends.

Radioactive Contaminants in U.S. Drinking Water and Water Quality Disparities

Radioactive contaminants, such as radium, radon, and uranium isotopes are naturally present in drinking water, and gas and oil extraction like hydraulic fracturing can exasperate radionuclide leakage into groundwater. The concentration of radionuclide in drinking water is dependent upon the water source and the underlying lithology within the aquifers. In United States, the Environmental Protection Agency regulates the level of radioactivity in drinking water via the gross alpha test, which is conducted to measure the emitted alpha particles as a result of the radioactive elements’ natural decay. Radionuclides, such as radium and uranium, are known to cause bone cancer and other forms of cancer. Communities with crippling water purification infrastructure may be at a higher risk of being exposed to radionuclides, and this is a significant environmental justice concern. The radionuclide concentrations for the metropolitan or most populated city in each state in the United States and its territories (Puerto Rico, US Virgin Islands and Guam) were analyzed and correlated to the annual household income, to determine any disparities that maybe present. Lower income communities had elevated levels of radionuclides when compared to higher income communities which had lower frequency in elevated radionuclide contaminants.

Comparative Analysis of Chemical, Physical and Biological Contaminants in Drinking Water in Various Developed Countries around the World

Sustaining a reliable and contaminant-free drinking water is becoming an increasing challenge worldwide due to human activity, industrial waste, and agricultural overuse. Surface water is the main source of drinking water around the world. However, groundwater is also becoming increasingly popular, due to its clarity and minimal need for processing to reduce turbidity. Over the years, the demand and growth in the agricultural industry has also been the means of groundwater contamination. Due to the health burden that raw water can pose, water must be processed and purified prior to consumption. Raw water quality can be compromised by physical, chemical (heavy metals and disinfection by-products), and biological contaminants. Biological contaminants can significantly impact immunocompromised populations, while chemical contaminants can impact the growth and development of young children. Although obtaining a steady and high-quality water flow to the general population is an increasing challenge, developed countries have utilized state-of-the-art technologies and techniques to provide contaminant-free water to their citizens. This research aims to provide information about the regulatory parameters, characteristics, and sources of safe drinking water in the world as a model for future use in the developing world. In this, secondary data was used to compare and contrast drinking water quality among countries in the European Union, the United States, Canada, the United Kingdom, Singapore, New Zealand, Australia, Qatar, and the United Arab Emirates. The data indicates that Ireland and the United Kingdom have relatively lower amounts of contaminants in their drinking water. Upon completing this research, it is recommended that countries desiring clean drinking water systems should initiate and invest in programs that control and protect treatment plants, water distribution systems, water sources, and catchments.

Drinking Water Disparities in Tennessee: The Origins and Effects of Toxic Heavy Metals

Several toxic metals, commonly present in drinking water, are believed to play important roles in the development of cancerous tumors. Although the US Safe Drinking Water Act requires drinking water to meet health standards set by the Environmental Protection Agency, violations occur regularly. In this study, we have investigated the role of the two predominant toxic heavy metals identified in the drinking water sources in Tennessee: copper and lead. We have analyzed the levels of copper and lead, as well as the total water hardness among different counties of Tennessee, with different socioeconomic backgrounds. We determined that the effects of lead and copper in drinking water were random, although counties with typically lower average household incomes typically had higher levels of the metals. The contaminant levels were found to remain below the threshold established by the Environmental Protection Agency and the State of Tennessee. Water from the Cumberland River was harder than water obtained from other rivers in Tennessee. Furthermore, the total hardness of water did not correlate with the average household income of the various counties.

Total Trihalomethane Levels in Major Watersheds across the United States

Trihalomethanes, such as chloroform, bromoform, dibromo(chloro)methane, and bromo(dichloro)methane, are present in the major watersheds across the United States. These chemicals play an important role in the development of cancer, have adverse reproductive outcomes, and were found to be present above the threshold established by the Environmental Protection Agency. To understand the impact of socioeconomic background on the quality of water and possible disparities, we have analyzed the levels of total trihalomethanes in the metropolitan areas in the major watersheds across the United States, in 2018, as they correlated to average household incomes. Our study found that Arkansas, Nevada, and Rhode Island demonstrated higher than federally mandated levels of total trihalomethanes in their watersheds. The median annual household and per capita incomes of the three states (Arkansas, Nevada, and Rhode Island) were lower than the national average. In addition, Delaware, New Hampshire, and Wisconsin, which had higher median income levels, demonstrated the lowest total trihalomethane levels across the United States.

Triphenylmethanol Conjugates of Triptorelin as Anti-Lipid Peroxidation Prodrugs

Antioxidants are substances that can prevent or slow damage to cells caused by free radicals, unstable molecules that the body produces as a reaction to environmental and other pressures. Free radicals may play a role in heart disease, cancer and other diseases. If the body cannot process and remove free radicals efficiently, oxidative stress can result. This can harm cells and body function. Free radicals are also known as reactive oxygen species (ROS). In this research, Triptorelin®(TRP) conjugates of triphenylmethanol derivatives (TPMs) were synthesized to evaluate their in vitro lipid peroxidation potency. Comparative lipid peroxidation assays between TRP-TPMs conjugates and the corresponding TPMs derivatives were measured using thiobarbituric reactive substance (TBARS) in a dose- and time-dependent manner following the Fenton’s pathway. Overall, TBARS decreased between 20% - 30% for the treated samples of synthesized conjugates compared to their respective control physical mixtures. These data suggest that TRP-TPMs derivatives can be used to improve the biological activity of TRP.

The Effect of Trihalomethanes in Contaminating the Major Watersheds of Middle Tennessee

We have analyzed the contamination of the three major watersheds in Middle Tennessee (Middle Cumberland River Watershed, Stones River Watershed, and Harpeth River Watershed) by trihalomethanes, such as chloroform, bromodichloromethane, dibromochloromethane, and bromoform. These chemicals play an important role in the develop-ment of cancer and adverse reproductive outcomes, and were found to be present above the threshold established by the Environmental Protection Agency. Certain portions of each watershed were found to be contaminated by the trihalomethanes, and deemed un-healthy. The household incomes in the major areas in the three watershed regions were also examined to determine a possible relationship with the level of water contamination. We concluded that income did not necessarily relate to water quality. Specific areas within each watershed that had lower average household incomes were found to have a higher concentration of the trihalomethanes in their drinking water, while other high-income areas were also affected by unhealthy water. However, these effects were random, and the level of contamination remained below the guidelines regulated by the State of Tennessee.

Synthesis and Antiproliferative Activities of Triphenylmethanol Conjugates of Leuprorelin

Leuprorelin®(LEP) is an FDA drug for breast cancer and prostate cancer treatment. There are several reported adverse effects such as transient hypertension, excessive salivation, and increased dysuria during treatment with LEP. In this study, the efficacy and toxicity of LEP were modified by using a drug delivery system to adjust the physicochemical properties. In this regard, Leuprorelin®conjugates of triphenylmethanol derivatives (TPMs) were synthesized as prodrugs. Comparative antiproliferative assays showed that LEP-TPMs conjugates had significantly higher antiproliferative activities than the corresponding non-covalent physical mixtures of the TPMs and LEP against human invasive ductal carcinoma (BT-549), human prostate carcinoma (PC3), human lung cancer (A549) and mouse pre-adipocytes (3T3-L1) cells.

Triphenylmethanol and Tris(2-(hydroxymethyl)phenol) Derivatives: Synthesis and Application as Indicators for Acid-Base Volumetric Titration

Polyphenols are naturally occurring compounds found largely in fruits, vegetables, cereals and beverages. Currently, there is much interest in the potential health benefits of dietary plant polyphenols as antioxidants. The effect of polyphenols on human cancer cells is most often protective and induces a reduction in the number of tumors or rate of growth. During our course of study on anticancer prodrugs, twelve triphenylmethanol and one tris(2-(hydroxymethyl) phenol derivatives were synthesized as a carrier of several drugs with optimized lipophilicity. Besides application of these compounds as a foundation for anticancer drug delivery systems, these compounds were evaluated as indicators for the acid-base volumetric titration of a standard solution of hydrochloric acid with a standard solution of sodium hydroxide. The experiments indicated a moderate-to-sharp color transition of the solutions near the neutralization point for most indicators. These indicators may have potential applications for acid-base titrations in a narrow range.