An Insight into Molecular Targets of Breast Cancer Brain Metastasis.

Brain metastasis is one of the major reasons of death in breast cancer (BC) patients, significantly affecting the quality of life, physical activity, and interdependence on several individuals. There is no clear evidence in scientific literature that depicts an exact mechanism relating to brain metastasis in BC patients. The tendency to develop breast cancer brain metastases (BCBMs) differs by the BC subtype, varying from almost half with triple-negative breast cancer (TNBC) (HER2- ER- PR-), one-third with HER2+ (human epidermal growth factor receptor 2-positive, and around one-tenth with luminal subclass (ER+ (estrogen positive) or PR+ (progesterone positive)) breast cancer. This review focuses on the molecular pathways as possible therapeutic targets of BCBMs and their potent drugs under different stages of clinical trial. In view of increased numbers of clinical trials and systemic studies, the scientific community is hopeful of unraveling the underlying mechanisms of BCBMs that will help in designing an effective treatment regimen with multiple molecular targets.

Green Tea Catechins Attenuate Neurodegenerative Diseases and Cognitive Deficits.

Neurodegenerative diseases exert an overwhelming socioeconomic burden all around the globe. They are mainly characterized by modified protein accumulation that might trigger various biological responses, including oxidative stress, inflammation, regulation of signaling pathways, and excitotoxicity. These disorders have been widely studied during the last decade in the hopes of developing symptom-oriented therapeutics. However, no definitive cure has yet been discovered. Tea is one of the world's most popular beverages. The same plant, Camellia Sinensis (L.).O. Kuntze, is used to make green, black, and oolong teas. Green tea has been most thoroughly studied because of its anti-cancer, anti-obesity, antidiabetic, anti-inflammatory, and neuroprotective properties. The beneficial effect of consumption of tea on neurodegenerative disorders has been reported in several human interventional and observational studies. The polyphenolic compounds found in green tea, known as catechins, have been demonstrated to have many therapeutic effects. They can help in preventing and, somehow, treating neurodegenerative diseases. Catechins show anti-inflammatory as well as antioxidant effects via blocking cytokines' excessive production and inflammatory pathways, as well as chelating metal ions and free radical scavenging. They may inhibit tau protein phosphorylation, amyloid beta aggregation, and release of apoptotic proteins. They can also lower alpha-synuclein levels and boost dopamine levels. All these factors have the potential to affect neurodegenerative disorders. This review will examine catechins' neuroprotective effects by highlighting their biological, pharmacological, antioxidant, and metal chelation abilities, with a focus on their ability to activate diverse cellular pathways in the brain. This review also points out the mechanisms of catechins in various neurodegenerative and cognitive diseases, including Alzheimer's, Parkinson's, multiple sclerosis, and cognitive deficit.

Remodelin, a N-acetyltransferase 10 (NAT10) inhibitor, alters mitochondrial lipid metabolism in cancer cells.

Remodelin is a small molecule inhibitor of N-acetyltransferase 10 (NAT10), reported to reverse the effect of cancer conditions such as epithelial to mesenchymal transition, hypoxia, and drug resistance. We analysed RNA seq data of siNAT10 and found many metabolic pathways were altered, this made us perform unbiased metabolic analysis. Here we performed untargeted metabolomics in Remodelin treated cancer cells using high-performance liquid chromatography-tandem mass spectrometry. Statistical analysis revealed a total number of 138 of which 52 metabolites were significantly modified in Remodelin treated cells. Among the most significantly altered metabolites, we identified metabolites related with mitochondrial fatty acid elongation (MFAE) and mitochondrial beta-oxidation such as lauroyl-CoA, cholesterol, triglycerides, (S)-3-hydroxyhexadecanoyl-CoA, and NAD+ . Furthermore, assessment showed alteration in expression of Enoyl-CoA hydratase, short chain 1, mitochondrial (ECHS1), and Mitochondrial trans-2-enoyl-CoA reductase (MECR) genes, associated with MFAE pathway. We also found statistically significant decrease in total cholesterol and triglycerides in Remodelin treated cancer cells. Overall, our results showed that Remodelin alters mitochondrial fatty acid metabolism and lipid accumulation in cancer cells. Finally, we validated these results in NAT10 knockdown cancer cells and found that NAT10 reduction results in alteration in gene expression associated with mitochondrial fatty acid metabolism, clearly suggesting the possible role of NAT10 in maintaining mitochondrial fatty acid metabolism.

Occupational exposure to HIV among healthcare workers in PMTCT sites in Port Harcourt, Nigeria.

BACKGROUND: Rivers State is among the states with high HIV prevalence in Nigeria. Occupational exposure to HIV through blood or body fluids of HIV/AIDS patients is a recognised risk factor of HIV infections among healthcare workers. We identified the determinants of occupational exposures to HIV among healthcare workers in Prevention of Maternal to Child Transmission (PMTCT) sites within Port Harcourt metropolis in Rivers State. METHODS: A descriptive cross-sectional study was conducted and multi-stage sampling technique was used to select 341 healthcare providers from 22 public and 22 private health facilities in PMTCT sites in Port Harcourt metropolis. The data collected were analysed using descriptive statistics, Chi-square and logistic regression models (p-value = 0.05). RESULTS: Respondents' mean age was 35.9 ± SD8.4 years, 270 (80.1%) and 171(50.7%) were females, and from public health facilities respectively. Prevalence of occupational exposure of healthcare workers to HIV in the past 12 months was 153 (45.0%), and 96 (63.3%) experienced such exposure more than once. Contacts with potentially infectious body fluid accounted for the largest proportion 51 (33.3%); followed by needle stick prick 49 (32.6%). About 189 (56.1%) had safety information at their disposal and this serves as a reminder on safety precautions. The likelihood of occupational exposure was significantly higher among doctors (AOR = 2.22, 95% C.I = 1.16-4.25,) but lower among environmental health workers (AOR = 0.10, 95% C.I = 0.02-0.46,) than nurses/midwives when other factors were included in the model. CONCLUSION: Occupational exposure to blood and body fluids remains a frequent occurrence among healthcare workers; highest among doctors in PMTCT sites in the study area. Provision of protective safety materials, training and enforcement of adherence to universal precaution strategies are highly recommended.

Reemergence of Human Monkeypox in Nigeria, 2017.

In Nigeria, before 2017 the most recent case of human monkeypox had been reported in 1978. By mid-November 2017, a large outbreak caused by the West African clade resulted in 146 suspected cases and 42 laboratory-confirmed cases from 14 states. Although the source is unknown, multiple sources are suspected.

Mortality Among Confirmed Lassa Fever Cases During the 2015-2016 Outbreak in Nigeria.

OBJECTIVES: To determine factors associated with mortality among confirmed Lassa fever cases. METHODS: We reviewed line lists and clinical records of laboratory-confirmed cases of Lassa fever during the 2016 outbreak in Nigeria to determine factors associated with mortality. We activated an incident command system to coordinate response. RESULTS: We documented 47 cases, 28 of whom died (case fatality rate [CFR] = 59.6%; mean age 31.4 years; SD = ±18.4 years). The youngest and the oldest were the most likely to die, with 100% mortality in those aged 5 years or younger and those aged 55 years or older. Patients who commenced ribavirin were more likely to survive (odds ratio [OR] = 0.1; 95% confidence interval [CI] = 0.03, 0.50). Fatality rates went from 100% (wave 1) through 69% (wave 2) to 31% (wave 3; χ2 for linear trend: P < .01). Patients admitted to a health care center before incident command system activation were more likely to die (OR = 4.4; 95% CI = 1.1, 17.6). The only pregnant patient in the study died postpartum. CONCLUSIONS: Effective, coordinated response reduces mortality from public health events. Attention to vulnerable groups during disasters is essential. Public Health Implications. Activating an incident command system improves the outcome of disasters in resource-constrained settings.

Large Outbreak of Neisseria meningitidis Serogroup C - Nigeria, December 2016-June 2017.

On February 16, 2017, the Ministry of Health in Zamfara State, in northwestern Nigeria, notified the Nigeria Centre for Disease Control (NCDC) of an increased number of suspected cerebrospinal meningitis (meningitis) cases reported from four local government areas (LGAs). Meningitis cases were subsequently also reported from Katsina, Kebbi, Niger, and Sokoto states, all of which share borders with Zamfara State, and from Yobe State in northeastern Nigeria. On April 3, 2017, NCDC activated an Emergency Operations Center (EOC) to coordinate rapid development and implementation of a national meningitis emergency outbreak response plan. After the outbreak was reported, surveillance activities for meningitis cases were enhanced, including retrospective searches for previously unreported cases, implementation of intensified new case finding, and strengthened laboratory confirmation. A total of 14,518 suspected meningitis cases were reported for the period December 13, 2016-June 15, 2017. Among 1,339 cases with laboratory testing, 433 (32%) were positive for bacterial pathogens, including 358 (82.7%) confirmed cases of Neisseria meningitidis serogroup C. In response, approximately 2.1 million persons aged 2-29 years were vaccinated with meningococcal serogroup C-containing vaccines in Katsina, Sokoto, Yobe, and Zamfara states during April-May 2017. The outbreak was declared over on June 15, 2017, after high-quality surveillance yielded no evidence of outbreak-linked cases for 2 consecutive weeks. Routine high-quality surveillance, including a strong laboratory system to test specimens from persons with suspected meningitis, is critical to rapidly detect and confirm future outbreaks and inform decisions regarding response vaccination.

Descriptive characterization of the 2010 cholera outbreak in Nigeria.

BACKGROUND: In 2010, 18 States of Nigeria reported cholera outbreaks with a total of 41,787 cases including 1,716 deaths (case-fatality rate [CFR]: 4.1%). This exceeded the mean overall CFR of 2.4% reported in Africa from 2000-2005 and the WHO acceptable rate of 1%. We conducted a descriptive analysis of the 2010 cholera outbreak to determine its epidemiological and spatio-temporal characteristics. METHODS: We conducted retrospective analysis of line lists obtained from 10 of the 18 states that submitted line lists to the Federal Ministry of Health (FMOH). We described the outbreak by time, place and person and calculated the attack rates by state as well as the age- and sex-specific CFR from cholera cases for whom information on age, sex, place of residence, onset of symptoms and outcome were available. RESULTS: A total of 21,111 cases were reported with an overall attack rate and CFR of 47.8 cases /100,000 population and 5.1%, respectively. The CFR ranged in the states between 3.8% and 8.9%. The age-specific CFR was highest among individuals 65 years and above (14.6%). The epidemiological curve showed three peaks with increasing number of weekly reported cases. A geographical clustering of LGAs reporting cholera cases could be seen in all ten states. During the third peak which coincided with flooding in five states the majority of newly affected LGAs were situated next to LGAs with previously reported cholera cases, only few isolated outbreaks were seen. CONCLUSION: Our study showed a cholera outbreak that grew in magnitude and spread to involve the whole northern part of the country. It also highlights challenges of suboptimal surveillance and response in developing countries as well as potential endemicity of cholera in the northern part of Nigeria. There is the need for a harmonized, coordinated approach to cholera outbreaks through effective surveillance and response with emphasis on training and motivating front line health workers towards timely detection, reporting and response. Findings from the report should be interpreted with caution due to the high number of cases with incomplete information, and lack of data from eight states.

Dissecting the oncogenic properties of essential RNA-modifying enzymes: a focus on NAT10.

Chemical modifications of ribonucleotides significantly alter the physicochemical properties and functions of RNA. Initially perceived as static and essential marks in ribosomal RNA (rRNA) and transfer RNA (tRNA), recent discoveries unveiled a dynamic landscape of RNA modifications in messenger RNA (mRNA) and other regulatory RNAs. These findings spurred extensive efforts to map the distribution and function of RNA modifications, aiming to elucidate their distribution and functional significance in normal cellular homeostasis and pathological states. Significant dysregulation of RNA modifications is extensively documented in cancers, accentuating the potential of RNA-modifying enzymes as therapeutic targets. However, the essential role of several RNA-modifying enzymes in normal physiological functions raises concerns about potential side effects. A notable example is N-acetyltransferase 10 (NAT10), which is responsible for acetylating cytidines in RNA. While emerging evidence positions NAT10 as an oncogenic factor and a potential target in various cancer types, its essential role in normal cellular processes complicates the development of targeted therapies. This review aims to comprehensively analyze the essential and oncogenic properties of NAT10. We discuss its crucial role in normal cell biology and aging alongside its contribution to cancer development and progression. We advocate for agnostic approaches to disentangling the intertwined essential and oncogenic functions of RNA-modifying enzymes. Such approaches are crucial for understanding the full spectrum of RNA-modifying enzymes and imperative for designing effective and safe therapeutic strategies.

NAT10, an RNA Cytidine Acetyltransferase, Regulates Ferroptosis in Cancer Cells.

Recently, we reported that N-acetyltransferase 10 (NAT10) regulates fatty acid metabolism through ac4C-dependent RNA modification of key genes in cancer cells. During this work, we noticed ferroptosis as one of the most negatively enriched pathways among other pathways in NAT10-depleted cancer cells. In the current work, we explore the possibility of whether NAT10 acts as an epitranscriptomic regulator of the ferroptosis pathway in cancer cells. Global ac4C levels and expression of NAT10 with other ferroptosis-related genes were assessed via dotblot and RT-qPCR, respectively. Flow cytometry and biochemical analysis were used to assess oxidative stress and ferroptosis features. The ac4C-mediated mRNA stability was conducted using RIP-PCR and mRNA stability assay. Metabolites were profiled using LC-MS/MS. Our results showed significant downregulation in expression of essential genes related to ferroptosis, namely SLC7A11, GCLC, MAP1LC3A, and SLC39A8 in NAT10-depleted cancer cells. Further, we noticed a reduction in cystine uptake and reduced GSH levels, along with elevated ROS, and lipid peroxidation levels in NAT10-depleted cells. Consistently, overproduction of oxPLs, as well as increased mitochondrial depolarization and decreased activities of antioxidant enzymes, support the notion of ferroptosis induction in NAT10-depleted cancer cells. Mechanistically, a reduced ac4C level shortens the half-life of GCLC and SLC7A11 mRNA, resulting in low levels of intracellular cystine and reduced GSH, failing to detoxify ROS, and leading to increased cellular oxPLs, which facilitate ferroptosis induction. Collectively, our findings suggest that NAT10 restrains ferroptosis by stabilizing the SLC7A11 mRNA transcripts in order to avoid oxidative stress that induces oxidation of phospholipids to initiate ferroptosis.

BTYNB, an inhibitor of RNA binding protein IGF2BP1 reduces proliferation and induces differentiation of leukemic cancer cells.

Leukemia is a group of diseases characterized by altered growth and differentiation of lymphoid or myeloid progenitors of blood. The existence of specific clusters of cells with stemness-like characteristics like differentiation, self-renewal, detoxification, and resistance to apoptosis in Leukemia makes them difficult to treat. It was recently reported that an oncofetal RNA binding protein, insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), maintains leukemic stem cell properties. BTYNB is an inhibitor of IGF2BP1 that was shown to affect the biological functions of IGF2BP1 however, the effect of BTYNB in Leukemia is not properly established. In this study, we assessed the effect of BTYNB on leukemic cell differentiation and proliferation. We performed cell viability assay to assess the effect of BTYNB in leukemic cells. We then assessed cell morphology of the leukemic cells treated with BTYNB. Further, we conducted an apoptosis assay and cell cycle assay. We found the cell viability of leukemic cells was significantly decreased post treatment with BTYNBs. Further, a noticeable morphological change was observed in BTYNB treated leukemic cells. BTYNB treated leukemic cells showed increased cell death and cell cycle arrest at S-phase. Evidence from the upregulation of BAK and p21 further confirmed apoptosis and cycle arrest. The gene expression of differentiation genes such as CD11B, ZFPM1, and KLF5 were significantly upregulated in BTYNB treated leukemic cells, therefore, confirming cell differentiation. Collectively, our study showed inhibition of IGF2BP1 function using BTYNB promotes differentiation in leukemic cells.

Availability, accessibility and use of antivenom for snakebite envenomation in Africa with proposed strategies to overcome the limitations.

Africa remains one of the regions with the highest incident and burden of snakebite. The goal of the World Health Organization to halve the global burden of snakebite by 2030 can only be achieved if sub-optimal access to antivenoms in the most affected regions is addressed. We identified upstream, midstream, and downstream factors along the antivenom value chain that prevent access to antivenoms in the African region. We identified windows of opportunities that could be utilized to ensure availability, accessibility, and affordability for snakebite endemic populations in Africa. These include implementation of multicomponent strategies such as intensified advocacy, community engagement, healthcare worker trainings, and leveraging the institutional and governance structure provided by African governments to address the challenges identified.

Epidemiology and psychosocial assessment of COVID-19 among workers of the Nigeria Centre for Disease Control infected with COVID-19.

Background: COVID-19 is a global health crisis. By 2021, Nigeria had 230,000 cases. As the national public health institute, NCDC leads the COVID-19 response. Due to constant contact with infected patients, agency employees are a t high-risk. Here, we describe the transmission and psychosocial effects of COVID- 19 among infected NCDC workers as a learning curve for minimizing occupational transmission among frontline public health workers in future outbreaks. Methods: We approved and enrolled all NCDC COVID-19- infected personnel from November to December 2020. We collected data using SurveyMonkey. STATA 14 analyzed the data. Results: 172 of 300 afflicted NCDC staff participated in this study. One-third were between 30 and 39; most were male (104, 60.5%). Most participants worked in the lab (30%) or surveillance (24%). Only 19% (33/172) of participants confirmed pandemic deployment. Most reported interaction with a confirmed case (112/65.1%). Most people (78, 45.3%) felt unhappy when diagnosed. Anger, worry, and low motivation also ranked high (19). The majority reported adequate financial, moral, or psychosocial assistance (26, 70.6%). Conclusions: NCDC staff had a high SARS-CoV-2 infection rate and emotional damage. We urge stricter infection control methods when sending staff for outbreaks response to prevent additional transmission, as well as ongoing psychosocial and economic assistance for afflicted workers.

Mpox (monkeypox) risk and mortality associated with HIV infection: a national case-control study in Nigeria.

INTRODUCTION: Recent outbreaks of mpox are characterised by changes in the natural history of the disease, the demographic and clinical characteristics of the cases, and widening geographical distribution. We investigated the role of HIV and other sexually transmitted infections (STIs) coinfection among cases in the re-emergence of mpox to inform national and global response. METHODS: We conducted a national descriptive and case-control study on cases in the 2017-2019 Nigerian mpox outbreak. Mpox cases were age, sex and geographical area matched each with two randomly selected controls from a representative national HIV/AIDS survey. Logistic regression was used to investigate the association between HIV infection and the risk of mpox acquisition and death. RESULTS: Among 204 suspected mpox cases, 86 were confirmed (median age 31 years (IQR 27-38 years), mostly males (61 cases, 70.9%). Three-fifths of mpox cases had serological evidence of one or more STIs with 27.9% (24/86) coinfected with HIV. The case fatality rate was 9.4% (8/86) and 20.8% (5/24) overall and in HIV positive cases respectively. Mpox cases were more likely to have HIV coinfection compared with an age, gender and geography-matched control group drawn from the general population (OR 45 (95% CI 6.1 to 333.5, p=0.002) and when compared with non mpox rash cases (7.29 (95% CI 2.6 to 20.5, p<0.0001)). HIV coinfection and young age were associated with mortality among mpox cases (aOR 13.66 (95% CI 1.88 to 98.95, p=0.010) and aOR 0.90 (0.82-0.97, p=0.008), respectively). CONCLUSION: HIV infection was associated with a higher risk of contracting and dying from mpox. Children are also at high risk of death. STIs in mpox cases may be suggestive of high-risk sexual behaviours among these individuals.

Predictors of Lassa fever diagnosis in suspected cases reporting to health facilities in Nigeria.

Lassa fever (LF) remains endemic in Nigeria with the country reporting the highest incidence and mortality globally. Recent national data suggests increasing incidence and expanding geographic spread. Predictors of LF case positivity in Nigeria have been sparsely studied. We thus sought to determine the sociodemographic and clinical determinants of LF positivity amongst suspected cases presenting to health facilities from 2018 to 2021. A secondary analysis of the national LF surveillance data between January 2018 and December 2021. Socio-demographic and clinical data of 20,027 suspected LF cases were analysed using frequencies and Chi-square statistics with significant p-value set at p < 0.05. The outcome variable was LF case status (positive or negative). Predictors of LF case positivity were assessed using multiple logistic regression models with 95% confidence intervals (CI). Case positivity rate (CPR) for the four years was 15.8% with higher odds of positivity among age group 40-49 years (aOR = 1.40; 95% CI 1.21-1.62), males (aOR = 1.11; 95% CI 1.03-1.20), those with formal education (aOR = 1.33; 95% CI 1.13-1.56), artisans (aOR = 1.70; 95% CI 1.28-2.27), religious leaders (aOR = 1.62; 95% CI 1.04-2.52), farmers (aOR = 1.48; 95% CI 1.21-1.81), and symptomatic individuals (aOR = 2.36; 95% CI 2.09-2.68). Being a health worker (aOR = 0.69; 95% CI 0.53-0.91), a teacher (aOR = 0.69; 95% CI 0.53-0.89) and cases reporting in the 3rd quarter (aOR = 0.79; 95% CI 0.69-0.92) had lower odds. In a sex-disaggregated analysis, female farmers had higher odds of positivity (aOR = 2.43; 95% CI 1.76-3.38; p < 0.001) than male farmers (aOR = 1.52; 95% CI 1.19-1.96; p < 0.01). Fever (aOR = 2.39; 95% CI 2.00-2.84) and gastrointestinal (GI) symptoms (aOR = 2.15; 95% CI 1.94-2.37) had the highest odds among symptoms. Combination of fever and GI symptoms (aOR = 2.15; 95% CI 1.50-3.10), fever and neurological symptoms (aOR = 6.37; 95% CI 1.49-27.16), fever and musculo-skeletal symptoms (aOR = 2.95; 95% CI 1.37-6.33), fever and cardiopulmonary symptoms (aOR = 1.81; 95% CI 1.24-2.64), and cardiopulmonary and general symptoms (aOR = 1.50; 95% CI 1.19-1.89) were also predictive. Cumulative LF CPR appears high with clearly identified predictors. Targeted interventions with heightened index of suspicion for sociodemographic categories predictive of LF in suspected cases are recommended. Ethnographic and further epidemiological studies could aid better understanding of these associations.

Clinical characteristics and predictors of human mpox outcome during the 2022 outbreak in Nigeria: a cohort study.

BACKGROUND: Research from sub-Saharan Africa that contributes to our understanding of the 2022 mpox (formerly known as monkeypox) global outbreak is insufficient. Here, we describe the clinical presentation and predictors of severe disease among patients with mpox diagnosed between Feb 1, 2022, and Jan 30, 2023 in Nigeria. METHODS: We did a cohort study among laboratory-confirmed and probable mpox cases seen in 22 mpox-treatment centres and outpatient clinics across Nigeria. All individuals with confirmed and probable mpox were eligible for inclusion. Exclusion criteria were individuals who could not be examined for clinical characterisation and those who had unknown mortality outcomes. Skin lesion swabs or crust samples were collected from each patient for mpox diagnosis by PCR. A structured questionnaire was used to document sociodemographic and clinical data, including HIV status, complications, and treatment outcomes from the time of diagnosis to discharge or death. Severe disease was defined as mpox associated with death or with a life-threatening complication. Two logistic regression models were used to identify clinical characteristics associated with severe disease and potential risk factors for severe disease. The primary outcome was the clinical characteristics of mpox and disease severity. FINDINGS: We enrolled 160 people with mpox from 22 states in Nigeria, including 134 (84%) adults, 114 (71%) males, 46 (29%) females, and 25 (16%) people with HIV. Of the 160 patients, distinct febrile prodrome (n=94, 59%), rash count greater than 250 (90, 56%), concomitant varicella zoster virus infection (n=48, 30%), and hospital admission (n=70, 48%) were observed. Nine (6%) of the 160 patients died, including seven (78%) deaths attributable to sepsis. The clinical features independently associated with severe disease were a rash count greater than 10 000 (adjusted odds ratio 26·1, 95% CI 5·2-135·0, p<0·0001) and confluent or semi-confluent rash (6·7, 95% CI 1·9-23·9). Independent risk factors for severe disease were concomitant varicella zoster virus infection (3·6, 95% CI 1·1-11·5) and advanced HIV disease (35·9, 95% CI 4·1-252·9). INTERPRETATION: During the 2022 global outbreak, mpox in Nigeria was more severe among those with advanced HIV disease and concomitant varicella zoster virus infection. Proactive screening, management of co-infections, the integration and strengthening of mpox and HIV surveillance, and preventive and treatment services should be prioritised in Nigeria and across Africa. FUNDING: None.

Thermosensitive Hydrogels Loaded with Resveratrol Nanoemulsion: Formulation Optimization by Central Composite Design and Evaluation in MCF-7 Human Breast Cancer Cell Lines.

The second most common cause of mortality among women is breast cancer. A variety of natural compounds have been demonstrated to be beneficial in the management of various malignancies. Resveratrol is a promising anticancer polyphenolic compound found in grapes, berries, etc. Nevertheless, its low solubility, and hence its low bioavailability, restrict its therapeutic potential. Therefore, in our study, we developed a thermosensitive hydrogel formulation loaded with resveratrol nanoemulsion to enhance its bioavailability. Initially, resveratrol nanoemulsions were formulated and optimized utilizing a central composite-face-centered design. The independent variables for optimization were surfactant level, homogenization speed, and time, while the size and zeta potential were the dependent variables. The optimized nanoemulsion formulation was converted into a sensitive hydrogel using poloxamer 407. Rheological studies proved the formation of gel consistency at physiological temperature. Drug loading efficiency and in vitro drug release from gels were also analyzed. The drug release mechanisms from the gels were assessed using various mathematical models. The effect of the optimized thermosensitive resveratrol nanoemulsion hydrogel on the viability of human breast cancer cells was tested using MCF-7 cancer cell lines. The globule size of the selected formulation was 111.54 ± 4.16 nm, with a zeta potential of 40.96 ± 3.1 mV. Within 6 h, the in vitro release profile demonstrated a release rate of 80%. According to cell line studies, the produced hydrogel of resveratrol nanoemulsion was cytotoxic to breast cancer cells. Overall, the results proved the developed nanoemulsion-loaded thermosensitive hydrogel is a promising platform for the effective delivery of resveratrol for the management of breast cancer.

Butin Mitigates Memory Impairment in Streptozotocin-Induced Diabetic Rats by Inhibiting Oxidative Stress and Inflammatory Responses.

It has been reported from the previous literature that butin restores mitochondrial dysfunction by modulation of oxidative stress and glutamate-induced neurotoxicity in mouse hippocampus HT22 cells. Butin also possesses an anti-Huntington's effect in rats. Considering the current background, this study was designed to evaluate the neuroprotective effect of butin against memory loss caused by streptozotocin (STZ). STZ (40 mg/kg) was intraperitoneally injected into rats. Three days later, diabetic rats were identified and included in the study. A total of 30 rats (12 nondiabetic and 18 diabetics) were grouped as Group A (control-non-diabetic rats) and Group B (STZ diabetic control) were treated with 1 mL of sodium CMC (0.5% w/v). Group C (STZ+ butin 25) were treated with butin 25 mg/kg. Group D (STZ+ butin 50) and Group E (butin per se) were administered with butin 50 mg/kg. Each therapy was administered orally once each day for 15-day. The Morris water maze and the Y-maze behavioural tests were run throughout the experimental programme. Animals were put to death on day 15 and their brains were removed for biochemical assays (CAT, SOD, GSH, MDA, nitrite, acetylcholinesterase (AchE), IL-1, and mitochondrial enzyme complexes). Rats with neurobehavioral impairments brought on by STZ have less spontaneous movement, learning capacity, and memory. Additionally, STZ decreased endogenous antioxidants and increased pro-inflammatory cytokines, nitrite, MDA, and AchE. Neurobehavioral deficits and metabolic markers were dramatically improved by butin.

NAT10: An RNA cytidine transferase regulates fatty acid metabolism in cancer cells.

BACKGROUND: N-4 cytidine acetylation (ac4C) is an epitranscriptomics modification catalyzed by N-acetyltransferase 10 (NAT10); important for cellular mRNA stability, rRNA biogenesis, cell proliferation and epithelial to mesenchymal transition (EMT). However, whether other crucial pathways are regulated by NAT10-dependent ac4C modification in cancer cells remains unclear. Therefore, in this study, we explored the impact of NAT10 depletion in cancer cells using unbiased RNA-seq. METHODS: High-throughput sequencing of knockdown NAT10 in cancer cells was conducted to identify enriched pathways. Acetylated RNA immunoprecipitation-seq (acRIP-seq) and RIP-PCR were used to map and determine ac4C levels of RNA. Exogenous palmitate uptake assay was conducted to assess NAT10 knockdown cancer cells using Oil Red O staining and lipid content analysis. Gas-chromatography-tandem mass spectroscopy (GC/MS) was used to perform untargeted lipidomics. RESULTS: High-throughput sequencing of NAT10 knockdown in cancer cells revealed fatty acid (FA) metabolism as the top enriched pathway through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis in differentially downregulated genes. FA metabolic genes such as ELOLV6, ACSL1, ACSL3, ACSL4, ACADSB and ACAT1 were shown to be stabilised via NAT10-dependent ac4C RNA acetylation. Additionally, NAT10 depletion was shown to significantly reduce the levels of overall lipid content, triglycerides and total cholesterol. Further, NAT10 depletion in palmitate-loaded cancer cells showed decrease in ac4C levels across the RNA transcripts of FA metabolic genes. In untargeted lipidomics, 496 out of 2 279 lipids were statistically significant in NAT10 depleted cancer cells, of which pathways associated with FA metabolism are the most enriched. CONCLUSIONS: Conclusively, our results provide novel insights into the impact of NAT10-mediated ac4C modification as a crucial regulatory factor during FA metabolism and showed the benefit of targeting NAT10 for cancer treatment.

Impact of a Newly Established Revolving Outbreak Investigation Fund on Timeliness of Response to Public Health Emergencies in Nigeria.

Timely access to emergency funding has been identified as a bottleneck for outbreak response in Nigeria. In February 2019, a new revolving outbreak investigation fund (ROIF) was established by the Nigeria Centre for Disease Control (NCDC). We abstracted the date of NCDC notification, date of verification, and date of response for 25 events that occurred prior to establishing the fund (April 2017 to August 2019) and for 8 events that occurred after establishing the fund (February to October 2019). The median time to notification (1 day) and to verification (0 days) did not change after establishing the ROIF, but the median time to response significantly decreased, from 6 days to 2 days (P = .003). Response to disease outbreaks was accelerated by access to emergency funding with a clear approval process. We recommend that the ROIF should be financed by the national government through budget allocation. Finally, development partners can provide financial support for the existing fund and technical assistance for protocol development toward financial accountability and sustainability.