Effect of degree of substitution of octenyl succinate on starch micelles for synthesis and stability of selenium nanoparticles: Towards selenium supplements.

To develop a promising selenium supplement that overcomes the instability and poor water dispersibility of selenium nanoparticles (SeNPs), we synthesized a series of amphiphilic octenyl succinic anhydride starch (OSAS) through esterification. As the degree of substitution (DS) increased, the particle size of OSAS micelles and the critical micelle concentration (CMC) decreased. FTIR and XRD analyses confirmed the successful introduction of octenyl succinic anhydride groups onto starch. Subsequently, OSAS micelles were used as carriers to synthesize SeNPs via in situ chemical reduction, forming SeNPs-loaded self-assembled starch nano-micelles (OSAS-SeNPs). The OSAS-SeNPs exhibited spherical dispersion in water with an average diameter of 116.1 ±â€¯2.3 nm, contributed to enhanced hydrophobic interactions. TEM images showed a core-shell structure with SeNPs as the core and OSAS as the shell. FTIR results indicated hydrogen bonding interactions between OSAS and SeNPs. Due to the negatively charged OSAS shell and hydrogen bonding (OH⋯Se), OSAS-SeNPs remained non-aggregated for one month at room temperature, demonstrating remarkable stability. This study suggests that using OSAS can address the synthesis and stability issues of SeNPs, making it a potential selenium supplement candidate for further evaluation as an anticancer agent.

Influence of agro-wastes derived biochar and their composite on reducing the mobility of toxic heavy metals and their bioavailability in industrial contaminated soils.

The agro-waste derived valuable products are prime interest for effective management of toxic heavy metals (THMs). The present study investigated the efficacy of biochars (BCs) on immobilization of THMs (Cr, Zn, Pb, Cu, Ni and Cd), bioaccumulation and health risk. Agro-wastes derived BCs including wheat straw biochar (WSB), orange peel biochar (OPB), rice husk biochar (RHB) and their composite biochar (CB) were applied in industrial contaminated soil (ICS) at 1% and 3% amendments rates. All the BCs significantly decreased the bioavailable THMs and significantly (p < 0.001) reduced bioaccumulation at 3% application with highest efficiency for CB followed by OPB, WSB and RHB as compared to control treatment. The bioaccumulation factor (BAF), concentration index (CI) and ecological risk were decreased with all BCs. The hazard quotient (HQ) and hazard index (HI) of all THMs were <1, except Cd, while carcer risk (CR) and total cancer risk index (TCRI) were decreased through all BCs. The overall results depicted that CB at 3% application rate showed higher efficacy to reduce significantly (p < 0.001) the THMs uptake and reduced health risk. Hence, the present study suggests that the composite of BCs prepared from agro-wastes is eco-friendly amendment to reduce THMs in ICS and minimize its subsequent uptake in vegetables.

The present study has a scientific research scope, based on reduction of bioavailability and bioaccumulation of toxic heavy metals (THMs) by the addition of biochars derived from agro-wastes and their composite biochar (CB), thereby decreasing the potential health risk. Limited study has been conducted, especially on the impact of CB in THMs-contaminated soil. This study could fill the scientific research gap and provides useful information for mitigation of THMs present in contaminated soil, which could be followed by the Environmental Protection Agency, Ministry of Agriculture and farmers in degraded lands.

Multitarget Mechanisms of Monocarbonyl Curcuminoid Analogues against HL-60 Cancer Cells: In Vitro and Network Pharmacology-Based Approach.

This study addressed the cytotoxic potential of four compounds: monocarbonyl curcuminoid, ethyl (2E)-2-benzylidene-3-oxobutanoate 1, 1,2-dimethoxy-12-methyl-13H- [1,3] benzodioxolo[5,6-c] phenanthridine 2, 3,5-dibenzyloxybenzyl bromide 3, and (E)-4-(4-chlorobenzylidene)-1-(4-nitrophenyl)hexan-3-one 4. In vitro cytotoxic assays were carried out in HL-60 and BJ cells using the MTT assay along with analysis of apoptosis with the annexin V detection kit. Additional network pharmacology and docking analyses were carried out. In the in vitro assays, compounds 2 and 4 displayed significant antiproliferative effects in HL-60 cells, exhibiting IC50 values of 5.02 and 9.50 µM, respectively. Compound 1 showed no activity, and compound 3 displayed toxicity in BJ cells. In addition, both compounds 2 and 4 induced apoptosis in HL-60 cells. Network pharmacology and docking analyses indicated that compounds 2 and 4 had synergistic effects targeting the CASP3 and PARP1 proteins. Notably, these proteins play pivotal roles in cancer-related pathways. Thus, by modulating these proteins, monocarbonyl curcuminoid has the potential to influence various cancer-related pathways. In summary, our novel findings provide valuable insights into the potential of these compounds to serve as novel anticancer therapeutic agents, warranting further mechanistic studies and clinical exploration.

Toward function starch nanogels by self-assembly of polysaccharide and protein: From synthesis to potential for polyphenol delivery.

Nanogels formed by self-assembly of natural proteins and polysaccharides have attracted great interest as potential carriers of bioactive molecules. Herein, we reported that carboxymethyl starch-lysozyme nanogels (CMS-Ly NGs) were prepared using carboxymethyl starch and lysozyme by green and facile electrostatic self-assembly, and the nanogels served as epigallocatechin gallate (EGCG) delivery systems. The dimensions and structure of the prepared starch-based nanogels (i.e., CMS-Ly NGs) were characterized by dynamic light scattering (DLS), ζ-potential, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and thermal gravimetric analyzer (TGA). FT-IR and 1H NMR spectra together confirmed the formation of CMS; FT-IR spectra confirmed the formation of CMS-Ly NGs; XRD spectra confirmed the disruption of the crystal structure of lysozyme after electrostatic self-assembly with CMS, and further confirmed the formation of nanogels. TGA demonstrated the thermal stability of nanogels. More importantly, the nanogels showed a high EGCG encapsulation rate of 80.0 ± 1.4 %. The CMS-Ly NGs encapsulated with EGCG exhibited regular spherical structure and stable particle size. Under the simulated gastrointestinal environmental conditions, CMS-Ly NGs encapsulated with EGCG showed the controlled release potential, which increased its utilization. Additionally, anthocyanins can also be encapsulated in CMS-Ly NGs and showed slow-release properties during gastrointestinal digestion in the same way. Cytotoxicity assay also demonstrated good biocompatibility between CMS-Ly NGs and CMS-Ly NGs encapsulated with EGCG. The findings of this research suggested the potential application of protein and polysaccharides-based nanogels in the delivery system of bioactive compounds.

Dibenzylideneacetone Induces Apoptosis in Cervical Cancer Cells through Ros-Mediated Mitochondrial Damage.

Cervical cancer is a health problem among women worldwide. Considering the limitations of prevention and antineoplastic chemotherapy against cervical cancer, research is needed to discover new, more effective, and safe antitumor agents. In the present study, we investigated the in vitro cytotoxicity of a new synthetic dibenzylideneacetone derived from 1,5-diaryl-3-oxo-1,4-pentadienyl (A3K2A3) against cervical cancer cells immortalized by HPV 16 (SiHa), and 18 (HeLa) by MTT assay. Furthermore, we performed spectrofluorimetry, flow cytometry, and Western blot analyzes to explore the inhibitory mechanism of A3K2A3 in cervical cancer cells. A3K2A3 showed cytotoxic activity against both cell lines. Mitochondrial depolarization and reduction in intracellular ATP levels were observed, which may be dependent on the redox imbalance between increased ROS and reduced levels of the antioxidant defense. In addition, damage to the cell membrane and DNA, and effective blocking of cell division in the G2/M phase were detected, which possibly led to the induction of apoptosis. This result was further confirmed by the upregulation of apoptosis-related proteins Bax, cytochrome C, and caspases 9 and 3. Our results provided the first evidence that A3K2A3 contributes to the suppression of cervical cancer in vitro, showing promise as a possible alternative for the treatment of this cancer.

Contamination level, source identification and health risk assessment of potentially toxic elements in drinking water sources of mining and non-mining areas of Khyber Pakhtunkhwa, Pakistan.

Accelerated mining activities have increased water contamination with potentially toxic elements (PTEs) and their associated human health risk in developing countries. The current study investigated the distribution of PTEs, their potential sources and health risk assessment in both ground and surface water sources in mining and non-mining areas of Khyber Pakhtunkhwa, Pakistan. Water samples (n = 150) were taken from selected sites and were analyzed for six PTEs (Ni, Cr, Zn, Cu, Pb and Mn). Among PTEs, Cr showed a high mean concentration (497) µg L-1, followed by Zn (414) µg L-1 in the mining area, while Zn showed the lowest mean value (4.44) µg L-1 in non-mining areas. Elevated concentrations of Ni, Cr and a moderate level of Pb in ground and surface water of Mohmand District exceeded the permissible limits set by WHO. Multivariate statistical analyses showed that the pollution sources of PTEs were mainly from mafic-ultramafic rocks, acid mine drainage, open dumping of mine wastes and mine tailings. The hazard quotient (HQ) was the highest for children relative to that for adults, but not higher than the USEPA limits. The hazard index (HI) for ingestions of all selected PTEs was lower than the threshold value (HIing < 1), except for Mohmand District, which showed a value of HI >1 in mining areas through ingestion. Moreover, the carcinogenic risk (CR) values exceeded the threshold limits for Ni and Cr set by the USEPA (1.0E-04-1.0E-06). In order to protect the drinking water sources of the study areas from further contamination, management techniques and policy for mining operations need to be implemented.

Breast Cancer Awareness and Associated Factors Amongst Women in Peshawar, Pakistan: A Cross-Sectional Study.

BACKGROUND: Breast cancer is the most common cancer in women, and the second overall, following lung cancer. Breast cancer can occur at any age, with an increased incidence in women 40 years and above. Worldwide the incidence is around 1 million cases per year, 60% of the cases reported from low- and middle-income countries. The current study was conducted to determine knowledge, attitude, and practices related to breast cancer, the associated risk factors, and screening methods in women presenting to a health care facility from resource-poor settings in Pakistan. METHODS: A cross-sectional study design was used, and participants were recruited phase-wise from three major outpatient departments (OPDs) (Gynecology and Obstetrics OPD, Medical OPD, and Surgical OPD). Data were collected through the validated "Breast Cancer Awareness Measure" developed by Cancer Research UK, King's College London, and University College London in 2009. Data were analyzed through Statistical Package for Social Sciences software (SPSS) version 23.0. Students's T-Test, ANOVA, and linear regression analysis were conducted. RESULTS: A total of 430 women were invited for participation in the study from the 3 main OPDs, and 400 took part in the study (response rate = 93.02%). The mean age of the women was 33.62 years ± 12.3 years, and the mean years of formal education were 5.05 ± 6.3 years. Less than a quarter of the participants were aware of the breast cancer warning signs, and 23.3% recognized the pain in the armpit or one of the breasts as a sign of breast cancer. The proportion of women aware of age-related and lifetime risk of getting breast cancer was 15.0%. Furthermore, only 2.5% performed breast self-examination at least once a month. Women identified many barriers like embarrassment, transport, and confidentiality issues in seeking medical help. CONCLUSION: Overall, women had poor knowledge of breast cancer, related warning signs, breast self-examination, risk factors, and screening methods.

Starch/tea polyphenols nanofibrous films for food packaging application: From facile construction to enhance mechanical, antioxidant and hydrophobic properties.

Starch based food packaging has been receiving increasing attention. However, the inherent poor properties of starch restrict its practical applications in the versatile material science field. In this study, a fast, simple, and environmentally friendly route to construct polyfunctional starch/tea polyphenols nanofibrous films (STNFs) by one-step temperature-assisted electrospinning was developed. The effects of introduction of tea polyphenols (TP) on the mechanical and antioxidant activity of STNFs were comprehensively investigated. Results of ABTS·+ free radical scavenging assay showed that the antioxidant activity of STNFs was endowed by addition of TP with optimum mechanical properties confirmed by tensile test. More interestingly, the hydrophobicity of STNFs was improved dramatically with increasing cross-linking time as indicated by water contact angle (WCA) measurement showing no effect on the antioxidant activity of the films. The results of this work offer a major step forward to promote functional starch-based materials for sustainable application in food packaging.

Clinical and serological characteristics of systemic sclerosis: Experience of a tertiary care center in Pakistan.

Objectives: This study aims to evaluate the clinical and serological characteristics of systemic sclerosis (SSc) in Pakistani population. Patients and methods: This prospective, cross-sectional study included a total of 38 patients (6 males, 32 females; mean age: 34.5±1.5 years; range, 16 to 60 years) with SSc who were admitted to our rheumatology clinic between November 2019 and January 2020. We evaluated the clinical, serological, and radiological features of SSc patients. Results: Thirty-four (89.5%) patients developed Raynaud phenomenon at the time of disease onset, while sclerodactyly was found in 34 (89.5%), digital ulcers in 25 (65.8%), and tendon friction rub in 12 (31.6%) patients. Interstitial lung disease was present in 30 (78.9%) patients with a higher prevalence in diffuse scleroderma (100%) than in limited scleroderma (70%) (p=0.01). Pulmonary hypertension was present in 18 patients with a significantly higher prevalence in diffuse disease (57.1%) than limited disease (11.8%) (p<0.01). Thirty (78.9%) patients had impaired pulmonary function tests. Fibromyalgia was present in seven (18.4%) patients, and depression was present in 10 (26.3%) patients. Antinuclear antibody (ANA) was positive in 30 (78.9%) patients. Anti-Scl-70 antibodies were present in 24 (63.2%) patients with a significant association with diffuse disease (85% vs. 35.3%, respectively; p<0.01). The anti-centromere antibodies (ACA) were present in 20 (52.6%) patients with a significantly higher rate in limited disease (94.2% vs. 19.0%, respectively; p<0.01). Conclusion: Scleroderma has a female preponderance. Raynaud phenomenon is the most initial clinical feature followed by other manifestations of a variable course and disease severity.

The antioxidant N-(2-mercaptopropionyl)-glycine (tiopronin) attenuates expression of neuropathic allodynia and hyperalgesia.

The current pharmacotherapy of neuropathic pain is inadequate as neuropathic pain involves varied clinical manifestations with multifactorial etiology, modulated by a cascade of physical and molecular events leading to different clinical presentations of pain. There is an accumulating evidence of the involvement of oxidative stress in neuropathy, and antioxidants have shown promise in mitigating neuropathic pain syndromes. To explore the evidence supporting this beneficial proclivity of antioxidants, this study investigated the antinociceptive effectiveness of N-(2-mercaptopropionyl)glycine or tiopronin, a well-recognized aminothiol antioxidant, in a refined chronic constriction injury (CCI) rat model of neuropathic pain. Tiopronin (10, 30, and 90 mg/kg, i.p.) and pregabalin (30 mg/kg, i.p.) were administered daily after CCI surgery. The neuropathic paradigms of mechanical/cold allodynia and mechanical/heat hyperalgesia were assessed on days 3, 7, 14, and 21 post-nerve ligation. At the end of study, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were estimated in the sciatic nerve, dorsal root ganglion, and spinal cord for assessing the extent of oxidative stress. The expression of neuropathic nociception was attenuated by tiopronin which was observed as a significant attenuation of CCI-induced allodynia and hyperalgesia. Tiopronin reversed the neuronal oxidative stress by significantly reducing MDA, and increasing SOD, CAT, and GSH levels. Pregabalin also showed similar beneficial propensity on CCI-induced neuropathic aberrations. These findings suggest prospective neuropathic pain attenuating efficacy of tiopronin and further corroborated the notion that antioxidants are effective in mitigating the development and expression of neuropathic pain and underlying neuronal oxidative stress.

Activity and Cell-Death Pathway in Leishmania infantum Induced by Sugiol: Vectorization Using Yeast Cell Wall Particles Obtained From Saccharomyces cerevisiae.

Visceral leishmaniasis, caused by Leishmania infantum, is a neglected tropical disease, to which efforts in the innovation of effective and affordable treatments remain limited, despite the rising incidence in several regions of the world. In this work, the antileishmanial effects of sugiol were investigated in vitro. This compound was isolated from the bark of Cupressus lusitanica and showed promising activity against L. infantum. In spite of the positive results, it is known that the compound is a poorly water-soluble diterpene molecule, which hinders further investigation, especially in preclinical animal studies. Thus, in an alternative delivery method, sugiol was entrapped in glucan-rich particles obtained from Saccharomyces cerevisiae yeast cell walls (YCWPs). To evaluate the activity of sugiol, the experiments were divided into two parts: (i) the in vitro investigation of antileishmanial activity of free sugiol against L. infantum promastigotes after 24, 48, and 72 h of treatment and (ii) the evaluation of antileishmanial activity of sugiol entrapped in glucan-rich particles against intracellular L. infantum amastigotes. Free sugiol induced the cell-death process in promastigotes, which was triggered by enhancing cytosolic calcium level and promoting the autophagy up to the first 24 h. Over time, the presence of autophagic vacuoles became rarer, especially after treatment with lower concentrations of sugiol, but other cellular events intensified, like ROS production, cell shrinkage, and phosphatidylserine exposure. Hyperpolarization of mitochondrial membrane potential was found at 72 h, induced by the mitochondria calcium uptake, causing an increase in ROS production and lipid peroxidation as a consequence. These events resulted in the cell death of promastigotes by secondary necrosis. Sugiol entrapped in glucan-rich particles was specifically recognized by dectin-1 receptor on the plasma membrane of macrophages, the main host cell of Leishmania spp. Electron micrographs revealed particles containing sugiol within the infected macrophages and these particles were active against the intracellular L. infantum amastigotes without affecting the host cell. Therefore, the YCWPs act like a Trojan horse to successfully deliver sugiol into the macrophage, presenting an interesting strategy to deliver water-insoluble drugs to parasitized cells.

Computational and pharmacological investigation of novel 1,5-diaryl-1,4-pentadien-3-one derivatives for analgesic, anti-inflammatory and anticancer potential.

OBJECTIVES: The novel 1,5-diaryl-1,4-pentadien-3-one derivatives were studied for analgesic, anti-inflammatory and anticancer potential to establish their role in pain, inflammatory disorders and cancer. MATERIALS AND METHODS: Two 1,5- diaryl-1,4-pentadien-3-one derivatives: (1E,4E)- 5-(4-fluoro phenyl)-1-(4-methoxyphenyl)- 2-methylpenta-1,4-dien-3-one (A2K2A17) and (1E,4E)-5-(4-nitrophenyl)-1-(4-nitrophenyl)-2-ethylhexa-1,4-dien-3-one (A11K3A11) were synthesized and characterized via 1H NMR and 13C NMR techniques. Molecular docking, anti-inflammatory, analgesic and anticancer activities were performed using Auto Doc Vina, carrageenan mediated paw edema and formalin induced chronic inflammation, acetic acid induced writhings and hotplate assay and brine-shrimp lethality assay. RESULTS: A2K2A17 and A11K3A11 showed high computational affinities (binding energy > -9.0 Kcal/mol) against COX-1, kappa receptor and braf kinase domain. A2K2A17 and A11K3A11 exhibited moderate docking affinities (binding energy > -8.0 Kcal/mol) against COX-2, human capsaicin receptor, tumor necrosis factor, lipoxygenase, colony stimulating factor, delta receptor, cyclin dependent protein kinase-2, mitogen activated kinase, mu receptor and kit kinase domain. A2K2A17 and A11K3A11 possess low docking affinities (binding energy > -7.0 Kcal/mol) against purinoceptor, platelets-derived growth Factor-1 and vascular-endothelial growth factor. In analgesic activity, A2K2A17 (1-30 mg/kg) and A11K3A11 (1-10 mg/kg) decreased acetic acid induced writhes and prolonged the latency time (P<0.01, P<0.001 vs saline group) respectively. A2K2A17 (10-30 mg/kg) and A11K3A11 (1-10 mg/kg) reduced carrageenan as well as formalin mediated edema (P<0.01, P<0.001). A2K2A17 found effective for cytotoxicity assay with LC50 value 1.5 µg/ml. CONCLUSION: The in silico, in vitro and in vivo studies on A2K2A17 and A11K3A11 reports their computational binding affinities against targets as well as the analgesic, anti-inflammatory and the anticancer effects.

A3K2A3-induced apoptotic cell death of Leishmania amazonensis occurs through caspase- and ATP-dependent mitochondrial dysfunction.

Leishmaniasis is a neglected tropical disease that affects millions of people worldwide. Current therapies mainly rely on antimonial drugs that are inadequate because of their high toxicity and increased drug resistance. An urgent need exists to discover new, more effective, more affordable, and more target-specific drugs. Pathways that are associated with apoptosis-like cell death have been identified in unicellular eukaryotes, including protozoan parasites. In the present study, we studied the mechanism of cell death that is induced by A3K2A3 against L. amazonensis. A3K2A3 is a dibenzylideneacetone that has an acyclic dienone that is attached to aryl groups in both ß-positions, which is similar to curcuminoids and chalcone structures. This compound was previously shown to be safe with regard to cytotoxicity and active against the parasite. Biochemical and morphological approaches were used in the present study. The results suggested that A3K2A3 caused mitochondrial dysfunction in L. amazonensis promastigotes, leading to mechanisms of cell death that share some common phenotypic features with metazoan apoptosis, such as an increase in reactive oxygen species production, a decrease in the adenosine triphosphate ratio, phosphatidylserine exposure, a decrease in cell volume, caspase production, and DNA fragmentation. Altogether, these findings indicate that apoptosis can indeed be triggered by chemotherapeutic agents.