A novel test and treat program for hepatitis C virus infection utilizing HCV core antigen testing, among police and general population, Islamabad, Pakistan, 2022.

Hepatitis C virus core antigen (HCVcAg) testing can simplify and decrease costs of HCV infection confirmation compared to molecular testing (nucleic acid testing). We piloted HCVcAg testing for the confirmation of active infection. The study was conducted during June through December 2022 among the police and the general population of Islamabad, Pakistan age 18 years and older. Initial screening for HCV antibody was conducted using a rapid diagnostic test (RDT) for all consenting participants. Those who tested positive had venous blood samples tested for HCVcAg, platelets and aspartate aminotransferase (AST). Persons with HCVcAg values ≥3 fmol/L were defined as viremic, and they were offered treatment with direct acting antiviral (DAA) medications, sofosbuvir and daclatasvir. Aspartate aminotransferase to platelet ratio index (APRI) was calculated for each HCV infected person, and those with an APRI score <1.5 received treatment for 12 weeks, while those with APRI ≥ to 1.5 received 24 weeks of treatment. A total of 15,628 persons were screened for anti-HCV using RDT and 643 (4.1%) tested positive. HCVcAg values of ≥3 fmol/L was found in 399/643 (62.1%), and all were offered and accepted treatment. Of those treated, 273/399 (68.4%) returned for a follow-up SVR and HCVcAg was not detected in 261/273, a 95.6% cure rate. The pilot study demonstrated the effectiveness of reaching and treating an urban population using RDT for screening and HCVcAg for confirmation of infection and test of cure.

Context-dependent accuracy of the cobas plasma separation card for HCV RNA viral load measurement.

Collection and preservation of plasma are challenging in remote or under-resourced settings. The cobas® Plasma Separation Card (PSC) is an alternative specimen type for blood-borne pathogen nucleic acid quantitation. We assessed PSC as a specimen type for HCV RNA quantitation in Pakistan. Plasma from venous blood and PSC from finger prick blood were prepared at two sites: Site 1 (in Lahore, n = 199) consisted of laboratory-based outpatient clinics. Specimens were prepared in the same facility and stored frozen. Site 2 was a catchment area within a resource-limited, semi-urban locality of Islamabad with limited access to healthcare services (n = 151). Community public health outreach staff collected blood and prepared the PSC in the participants' homes. Specimens were transported to the central hepatitis laboratory in Lahore to be stored frozen until tested. HCV RNA testing was performed using the cobas HCV RNA test in a central laboratory. Concordance with respect to RNA detectability was high at Site 1 (97.4%), but lower at Site 2 (82.4%). At Site 1, HCV viral load in plasma and PSC were well correlated across the linear range with a 0.21 log10 IU/mL mean bias toward higher concentrations in PSC. At Site 2, HCV viral load in plasma and PSC were poorly correlated. There was a 0.11 log10 IU/mL mean bias toward higher concentrations in PSC. PSC performance can be excellent in underserved settings where refrigerated transport of traditional specimens is difficult. In very challenging field settings, extra support must be provided to ensure correct specimen collection and handling.

Understanding the socio-demographic and programmatic factors associated with adolescent motherhood and its association with child undernutrition in Bangladesh.

BACKGROUND: Worldwide, a significant number of girls become mothers during adolescence. In Bangladesh, adolescent childbirth is highly prevalent and has adverse effects on children's health and undernutrition. We aimed to identify the relationship between the undernutrition of children and adolescent motherhood, the factors associated with adolescent mothers' age at first birth, and to examine the programmatic factors and gaps influencing children's undernutrition in Bangladesh. METHODS: We analysed the 'Bangladesh Demographic and Health Survey' BDHS-17-18 data and desk review. To examine the factors associated with adolescent motherhood and its impact on child undernutrition, data from 7,643 mother-child pairs were selected. Child stunting, wasting, and underweight were measured according to the World Health Organisation (WHO) median growth guidelines based on z-scores - 2. Univariate, bivariate, simple, and multiple logistic regressions were used for analyse. We followed the systematic procedures for the literature review. RESULTS: Approximately, 89% of adolescents aged ≤ 19 years were married and 71% of them gave their first childbirth. Children of adolescent mothers (≤ 19 years) were significantly 1.68 times more wasted (aOR: 1.68; 95% CI: 1.08 to 2.64), 1.37 times more underweight (aOR: 1.37; 95% CI: 1.01 to 1.86) and either form 1.32 times more stunting, wasting or underweight (aOR:1.32; 95% Cl: 1.05 to 1.66) compared to the children of adult mothers (> 19 years) after adjusting potential confounders. The factors associated with mothers' first childbirth during adolescence were the age gap between husband and wife 5-10 years (aOR: 1.81; 95% Cl: 1.57-2.10) and age gap > 10 years (aOR: 2.41; 95% Cl: 1.96-2.97) compared with the age group < 5 years, and husbands' education (aOR: 1.29; 95% Cl: 1.04-1.61) compared with the uneducated husbands. In the literature review, we found potential gaps in focusing on the Adolescent Sexual and Reproductive Health (ASRH) program in Bangladesh, from thirty-two programmes only half of them focused on adolescents aged 10-19 years, and eleven programmes focused only on girls. CONCLUSION: Children of adolescent mothers are at risk of wasting, underweight, and any form of undernutrition. For effective policies and interventions in Bangladesh, it is important to emphasise delaying adolescent pregnancy and prioritising child undernutrition.

Examining the implementation of facility-based integrated management of childhood illness and insecticide treated nets in Bangladesh: lessons learned through implementation research.

BACKGROUND: Bangladesh significantly reduced under-5 mortality (U5M) between 2000 and 2015, despite its low economic development and projected high mortality rates in children aged under 5 years. A portion of this success was due to implementation of health systems-delivered evidence-based interventions (EBIs) known to reduce U5M. This study aims to understand how Bangladesh was able to achieve this success between 2000 and 2015. Implementation science studies such as this one provide insights on the implementation process that are not sufficiently documented in existing literature. METHODS: Between 2017 and 2020, we conducted mixed methods implementation research case studies to examine how six countries including Bangladesh outperformed their regional and economic peers in reducing U5M. Using existing data and reports supplemented by key informant interviews, we studied key implementation strategies and associated implementation outcomes for selected EBIs and contextual factors which facilitated or hindered this work. We used facility-based integrated management of childhood illnesses and insecticide treated nets as examples of two EBIs that were implemented successfully and with wide reach across the country to understand the strategies put in place as well as the facilitating and challenging contextual factors. RESULTS: Strategies which contributed to the successful implementation and wide coverage of the selected EBIs included community engagement, data use, and small-scale testing, important to achieving implementation outcomes such as effectiveness, reach and fidelity, although gaps persisted including in quality of care. Key contextual factors including a strong community-based health system, accountable leadership, and female empowerment facilitated implementation of these EBIs. Challenges included human resources for health, dependence on donor funding and poor service quality in the private sector. CONCLUSION: As countries work to reduce U5M, they should build strong community health systems, follow global guidance, adapt their implementation using local evidence as well as build sustainability into their programs. Strategies need to leverage facilitating contextual factors while addressing challenging ones.

Barriers and Strategies for Hepatitis B and C Elimination in Pakistan.

BACKGROUND: Pakistan has a high hepatitis burden for both hepatitis C virus (HCV) and hepatitis B virus (HBV). To achieve World Health Organization (WHO) 2030 targets for hepatitis elimination, there is a need to constitute progress in the country, find the barriers and strategies for HCV elimination, and take actions to address the gaps. METHODS: We collected data from (1) WHO estimates in 2020, (2) midterm review questionnaire of the WHO regional action plan, and (3) WHO estimates on immunization. We analyzed these data to inform (1) the burden defined as prevalence and mortality and (2) response in 3 thematic areas: governance, policy, and finance; strategic information; and service delivery. RESULTS: The prevalence of hepatitis B in the general population is 1.6% with 12 000 deaths/year. The prevalence of hepatitis C in the general population is 7.5% with 19 000 deaths and 545 000 new cases (incidence)/year. The selected indicators to monitor progress on viral hepatitis in Pakistan were governance and financing, policies and guidelines, and strategic information. The overall governance indicators are good with a focal point, a national hepatitis strategy, an operational plan, strategy for price reduction, and involvement of civil society but the costed action plan and the advocacy strategy are missing. The indicators on policies and guidelines are also adequately addressed. The hepatitis B and C testing and treatment guidelines are available, there is a policy to screen all blood donations, and there is an injection safety policy, but the policy for timely hepatitis B vaccine birth dose and hepatitis B vaccination for the vulnerable is missing. Both indicators regarding strategic information, that is measures of key hepatitis indicators and regular data review, are missing. The status of 5 key interventions in Pakistan show that the hepatitis B vaccination coverage is 74% and only 3% of newborn children are given the hepatitis B vaccine birth dose. Only 22% of HCV cases have been diagnosed and 2% have received treatment. Treatment response is 96%. Same-day testing and treatment of hepatitis C reduced the overall dropout rate and improved the cascade of care. Decentralization and task shifting are important tools to improve service delivery and reach communities. Finances to implement hepatitis elimination is a major barrier. CONCLUSIONS: Pakistan has the highest hepatitis disease burden. With the current pace, hepatitis elimination appears impossible. Introduction of the birth dose of hepatitis B vaccine and improving access and affordability of testing can improve the testing and treatment numbers. Finances need to be mobilized from within the country and outside to support disease elimination.

Hepatitis C prevalence and elimination planning in Pakistan, a bottom-up approach accounting for provincial variation.

In Pakistan, substantial changes to hepatitis C virus (HCV) programming and treatment have occurred since the 2008 nationwide serosurvey estimated a 4.8% anti-HCV prevalence. In the absence of an updated national study, this analysis uses provincial data to estimate a national prevalence and the interventions needed to achieve elimination. Using a Delphi process, epidemiologic HCV data for the four provinces of Pakistan (accounting for 97% of the population) were reviewed with 21 subject-matter experts in Pakistan. Province-level estimates were inputted into a mathematical model to estimate the national HCV disease burden in the absence of intervention (Base), and if the World Health Organization (WHO) elimination targets are achieved by 2030 (80% reduction in new infections, 90% diagnosis coverage, 80% treatment coverage, and 65% reduction in mortality: WHO Elimination). An estimated 9,746,000 (7,573,000-10,006,000) Pakistanis were living with viraemic HCV as of January 1, 2021; a viraemic prevalence of 4.3% (3.3-4.4). WHO Elimination would require an annual average of 18.8 million screens, 1.1 million treatments, and 46,700 new infections prevented anually between 2022 and 2030. Elimination would reduce total infections by 7,045,000, save 152,000 lives and prevent 104,000 incident cases of hepatocellular carcinoma from 2015 to 2030. Blood surveys, programmatic data, and expert panel input uncovered more HCV infections and lower treatment numbers in the provinces than estimated using national extrapolations, demonstrating the benefits of a bottom-up approach. Screening and treatment must increase 20 times and 5 times, respectively, to curb the HCV epidemic in Pakistan and achieve elimination by 2030.

Engineering carbon nanotubes for sensitive viral detection.

Viral infections have been proven a severe threat to human beings, and the pandemic of Coronavirus Disease 2019 (COVID-19) has become a societal health concern, including mental distress and morbidity. Therefore, the early diagnosis and differentiation of viral infections are the prerequisite for curbing the local and global spread of viruses. To this end, carbon nanotubes (CNTs) based virus detection strategies are developed that provide feasible alternatives to conventional diagnostic techniques. Here in this review, an overview of the design and engineering of CNTs-based sensors for virus detection is summarized, followed by the nano-bio interactions used in developing biosensors. Then, we classify the viral sensors into covalently engineered CNTs, non-covalently engineered CNTs, and size-tunable CNTs arrays for viral detection, based on the type of CNTs-based nano-bio interfaces. Finally, the current challenges and prospects of CNTs-based sensors for virus detection are discussed.

Black phosphorus nanosheets/poly(allylamine hydrochloride) based electrochemical immunosensor for the selective detection of human epididymis protein 4.

In this work, an electrochemical immunosensor based on black phosphorus nanosheets (BPNS)/poly(allylamine hydrochloride) (PAH) nanocomposite modified glassy carbon electrode was developed for the detection of ovarian cancer biomarker HE4. PAH has been applied to retain BPNS in its original honeycomb structure and to anchor biomolecules electrostatically on the transducer surface. The as synthesized nanocomposite was characterized by zeta potential analysis, scanning electron microscopy, x-ray photoelectron spectroscopy, transmission electron microscopy, high-resolution transmission electron microscopy. Subsequently, the performance of the electrochemical immunosensor was evaluated through cyclic voltammetry, differential pulse voltammetry and electrochemical impedance spectroscopy. Under the optimal condition, the developed electrochemical immunosensor permitted to detect HE4 with a linear range of 0.1-300 ng ml-1and a detection limit of 0.01 ng ml-1. The developed sensor exhibited good selectivity and specificity to HE4 with negligible interference effect from common biomolecules like bovine serum albumin, lysozyme, protamine, glucose, fructose, hemoglobin and fetal bovine serum. Further, practical application of developed electrochemical immunosensor was demonstrated in spiked human serum which showed satisfactory recovery percentages.

Girl child marriage and the social context of displacement: a qualitative comparative exploration of Syrian refugees in Jordan and Rohingya refugees in Bangladesh.

BACKGROUND: There is growing global evidence that girl child marriage (CM) increases during humanitarian crises. Norms, attitudes, and policies that sustain CM are deeply entrenched within families and communities, and may be further exacerbated by conflict and displacement. The purpose of this study is to understand how the social and normative environment influences attitudes and practices related to CM in two diverse humanitarian settings. METHODS: We held a total of eight focus group discussions, four in each country, with Syrian refugees in Jordan and Rohingya Refugees in Bangladesh. FGDs were conducted with fathers, mothers, and adolescent boys and girls. RESULTS: Similar themes emerged from both settings. Participants discussed a desire to hold onto tradition in displacement and how norms are reinforced across generations. Social influence emerged in positive and negative ways, including peer pressure and conformity and the positive influence of host communities. In both settings, girls themselves described having little agency. Participants described resistance to change, which was exacerbated by conflict and displacement, though they discussed how social influence could be an effective way to challenge existing norms that drive the practice of girl child marriage. CONCLUSIONS: Our findings represent a more robust understanding of how norms operate within the social ecological system, and how they are reinforced across social relationships, offering an opportunity to more effectively challenge norms that sustain the practice of girl child marriage.

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.

A mechanistic evaluation of the traditional uses of Nepeta ruderalis in gastrointestinal and airway disorders.

CONTEXT: Nepeta ruderalis Buch.-Ham. (Lamiaceae), locally known as Badranj Boya, is an aromatic herb used traditionally as an antispasmodic, antidiarrhoeal, and anti-asthamatic remedy. OBJECTIVE: Aqueous methanolic extract of N. ruderalis was studied to investigate its traditional uses. MATERIALS AND METHODS: Study was conducted from September 2015 to February 2016. In vitro spasmolytic and broncho-relaxant activity of crude extract of N. ruderalis (whole plant) was evaluated at 0.01-10 mg/mL final bath concentration in isolated rabbit jejunum and tracheal tissues, using PowerLab data acquisition system (Transonic Systems Inc., Ithaca, NY). In vivo antidiarrhoeal activity was evaluated in castor oil-induced diarrhoeal mice at the dose of 300 and 500 mg of crude extract orally. RESULTS: Crude extract of N. ruderalis completely relaxed spontaneously contracting, high K+ (80 mM) and carbachol (1 µM) induced contracted jejunum with an EC50 value of 5.85 (5.45-6.27), 4.0 (3.80-4.23) and 2.86 (2.48-3.29), similar to verapamil. Nr.Cr relaxed high K+ and carbachol induced contractions, at 5 and 10 mg/mL with an EC50 value of 2.37 (2.11-2.67) and 3.26 (2.9-3.67), respectively, and also displaced calcium concentration-response curves toward right at 0.1 and 0.3 mg/mL. Nr.Cr exhibited antidiarrhoeal protection at a dose of 300 and 500 mg/kg, similar to verapamil, whereas no acute toxicity signs were seen up to 5 g/kg in healthy mice. DISCUSSION AND CONCLUSION: Results suggest the presence of spasmolytic and broncho-relaxant effects in the crude extract of N. ruderalis, possibly mediated through calcium channel-blocking activity, providing the pharmacological basis for its traditional uses in gastrointestinal and airway disorders.

Antioxidant, antibacterial and antiproliferative activities of pumpkin (cucurbit) peel and puree extracts - an in vitro study.

Natural resources right from the beginning of the human civilization has paved the way to human being to combat different challenges. The big challenge was to safe the human being from diseases and shortage of food. Plants helped the man in both areas very efficiently. No doubt when plants are used as food actually we are also taking lot of compounds of medicinal values in an excellent combination which naturally reduce the risk of diseases. Extraction and purification of several medicinally important compounds also gave the way to develop pharmaceutical industry in addition to its own therapeutic effects against different lethal diseases. Pumpkin is one of the several medicinal important vegetables used in different way on the behalf of its admirable power to combat different diseases. Antioxidant and biological studies showed very important results. A good coherence was found among extraction yield (10.52 to 18.45%), total phenolics (1.13 to 6.78 mg GAE/100g), total flavonoids (0.23 to 0.72mg CE/100g) and antioxidant potential (≻70%). Antibacterial assays of peel and puree extracts advocated good potential to stop the growth and division of pathogenic bacteria. Further biological activity study was carried out using MDBK cancer cell line. The growth inhibitory effect on cancer cell line using MTT assay showed methanol extracts of peel and puree both remained efficient to inhibit growth (≻35%) and cell division of cancer cells. Our results showed that extracts of pumpkin puree and its waste, peel, may be utilize to prepare functional food against pathogenic born diseases and most active compounds may also be extracted, concentrated and converted into tablets or suspension form for therapeutic purposes.

Basic neonatal resuscitation, knowledge assessment at primary health care centers of district Sheikhupura in Pakistan -- a cross-sectional study.

OBJECTIVE: To assess the knowledge of lady health visitors and midwives working at primary healthcare facilities about neonatal resuscitation. METHODS: The cross-sectional survey was conducted in District Sheikhupura of Pakistan's Punjab province from September to November 2013, and comprised lady health visitors and midwives at primary level healthcare facilities. Datas was gathered using a close-ended questionnaire. SPSS 16 was used for statistical analysis. RESULTS: Of the 103 health workers interviewed, 54(52.4%) were lady health visitors and 49(47.5%) were midwives. Overall, 71(69.90%) health workers had received training on neonatal resuscitation, while 32(30.10%) had no formal training. Basic neonatal resuscitative arrangements were available at all the 54(100%) basic health units and 7(100%) rural health centres. Basic neonatal care knowledge was found adequate but the knowledge of midwives on the subject was poor as only 24(49%) answered correctly. CONCLUSIONS: There is a need for regular in-service trainings of lady health visitors and midwives regarding Basic Neonatal Resuscitation.

Optimizing lornoxicam-loaded poly(lactic-co-glycolic acid) and (polyethylene glycol) nanoparticles for transdermal delivery: ex vivo/in vivo inflammation evaluation.

Aim: This study focused on developing a topical gel incorporating lornoxicam-loaded poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) blend nanoparticles to mitigate gastrointestinal (GIT) side effects and enhance therapeutic efficacy. Materials & methods: Synthesized nanoparticles were subjected to in vitro characterization, ex vivo permeation studies, and acute oral toxicity analysis post-incorporation into the gel using a S/O/W double emulsion solvent. Results & conclusion: The nanoparticles displayed a smooth, spherical morphology (170-321 nm) with increased entrapment efficiency (96.2%). LOX exhibited a permeation rate of 70-94% from the nanoparticle-infused gel, demonstrating favorable biocompatibility at the cellular level. The formulated gel, enriched with nanoparticles, holds promising prospects for drug-delivery systems and promising improved therapeutic outcomes for LOX.

[Box: see text].

pH-sensitive docetaxel-loaded chitosan/thiolated hyaluronic acid polymeric nanoparticles for colorectal cancer.

Aim: This study aimed to develop and evaluate pH-sensitive docetaxel-loaded thiolated hyaluronic acid (HA-SH) nanoparticles (NPs) for targeted treatment of colon cancer. Materials & methods: HA-SH, synthesized via oxidation and subsequent covalent linkage to cysteamine, served as the precursor for developing HA-SH NPs through polyelectrolyte complexation involving chitosan and thiol-bearing HA. Results & conclusion: HA-SH NPs displayed favorable characteristics, with small particle sizes (184-270 nm), positive zeta potential (15.4-18.6 mV) and high entrapment efficiency (91.66-95.02%). In vitro, NPs demonstrated potent mucoadhesion and enhanced cytotoxicity compared with free docetaxel. In vivo assessments confirmed safety and biocompatibility, suggesting HA-SH NPs as promising pH-sensitive drug carriers with enhanced antitumor activity for colorectal cancer treatments.

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.

J-Aggregation induced NIR-II fluorescence: an aza-BODIPY luminogen for efficient phototheranostics.

The development of organic dyes with emission peaks in the second near-infrared window (NIR-II 1000-1700 nm) is highly desirable for in vivo imaging and imaging-guided phototheranostics. However, the lack of appropriate molecular frameworks and the challenges associated with complex synthesis critically hinder the development of new candidate fluorophores. J-Aggregation is considered as a smart and straightforward way to construct such a therapeutic agent with NIR-II fluorescence imaging properties. Here, we present the design and synthesis of an aza-BODIPY probe (TA). Upon encapsulation within the amphiphilic polymer DSPEG-PEG2000-NH2, TA underwent self-assembly and formed J-aggregates (TAJ NPs), which showed emission at 1020 nm. High spatial resolution and adequate signal-to-noise ratio of the TAJ NPs are demonstrated for noninvasive bioimaging of the vasculature, lymph nodes and bones of mice in the NIR-II region. Moreover, the TAJ NPs exhibited good tumor enrichment efficiency with reduced liver accumulation and significant imaging-guided phototherapy performance against lung cancer cells. Taken together, this work not only introduces a new NIR-II imaging and phototheranostic agent based on J-aggregates, but also provides insight into the development of versatile organic dyes for future clinical implementation.