Physicochemical properties, pharmacokinetic studies, DFT approach, and antioxidant activity of nitro and chloro indolinone derivatives.

The process of developing of new drugs is greatly hampered by their inadequate physicochemical, pharmacokinetic, and intrinsic characteristics. In this regard, the selected chloro indolinone, (Z)-6-chloro-3-(2-chlorobenzylidene)indolin-2-one (C1), and nitro indolinone, (Z)-6-chloro-3-(2-nitrobenzylidene)indolin-2-one (C2), were subjected to SwissADME and density function theory (DFT) analysis. For compounds C1 and C2, the BOILED-Egg pharmacokinetic model predicted intestinal absorption, blood-brain barrier (BBB) penetration, and p-glycoprotein interaction. According to the physicochemical analysis, C1 has exceptional drug-like characteristics suitable for oral absorption. Despite only being substrates for some of the major CYP 450 isoforms, compounds C1 and C2 were anticipated to have strong plasma protein binding and efficient distribution and block these isoforms. The DFT study using the B3LYP/6-311G(d,p) approach with implicit water effects was performed to assess the structural features, electronic properties, and global reactivity parameters (GRP) of C1 and C2. The DFT results provided further support for other studies, implying that C2 is more water-soluble than C1 and that both compounds can form hydrogen bonds and (weak) dispersion interactions with other molecules, such as solvents and biomolecules. Furthermore, the GRP study suggested that C1 should be more stable and less reactive than C2. A concentration-dependent 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity was shown by both C1 and C2. In brief, this finding has provided a strong foundation to explore further the therapeutic potential of these molecules against a variety of human disorders.

Gentisic acid prevents colorectal cancer metastasis via blocking GPR81-mediated DEPDC5 degradation.

BACKGROUND: Metastasis driven by epithelial-mesenchymal transition (EMT) remains a significant contributor to the poor prognosis of colorectal cancer (CRC), and requires more effective interventions. GPR81 signaling has been linked to tumor metastasis, while lacks an efficient specific inhibitor. PURPOSE: Our study aimed to investigate the effect and mechanism of Gentisic acid on colorectal cancer (CRC) metastasis. STUDY DESIGN: A lung metastasis mouse model induced by tail vein injection and a subcutaneous graft tumor model were used. Gentisic acid (GA) was administered by an intraperitoneal injection. HCT116 was treated with lactate to establish an in vitro model. METHODS: MC38 cells with mCherry fluorescent protein were injected into tail vein to investigate lung metastasis ability in vivo. GA was administered by intraperitoneal injection for 3 weeks. The therapeutic effect was evaluated by survival rates, histochemical analysis, RT-qPCR and live imaging. The mechanism was explored using small interfering RNA (siRNA), Western blotting, RT-qPCR and immunofluorescence. RESULTS: GA had a therapeutic effect on CRC metastasis and improved survival rates and pathological changes in dose-dependent manner. GA emerged as an GPR81 inhibitor, effectively suppressed EMT and mTOR signaling in CRC induced by lactate both in vivo and in vitro. Mechanistically, GA halted lactate-induce degradation of DEPDC5 through impeding the activation of Chaperone-mediated autophagy (CMA). CONCLUSION: CMA-mediated DEPDC5 degradation is crucial for lactate/GPR81-induced CRC metastasis, and GA may be a promising candidate for metastasis by inhibiting GPR81 signaling.

Alkaloids as drug leads in Alzheimer's treatment: Mechanistic and therapeutic insights.

Alzheimer's disease (AD) has few effective treatment options and continues to be a major global health concern. AD is a neurodegenerative disease that typically affects elderly people. Alkaloids have potential sources for novel drug discovery due to their diverse chemical structures and pharmacological activities. Alkaloids, natural products with heterocyclic nitrogen-containing structures, are considered potential treatments for AD. This review explores the neuroprotective properties of alkaloids in AD, focusing on their ability to regulate pathways such as amyloid-beta aggregation, oxidative stress, synaptic dysfunction, tau hyperphosphorylation, and neuroinflammation. The FDA has approved alkaloids such as acetylcholinesterase inhibitors like galantamine and rivastigmine. This article explores AD's origins, current market medications, and clinical applications of alkaloids in AD therapy. This review explores the development of alkaloid-based drugs for AD, focusing on pharmacokinetics, blood-brain barrier penetration, and potential adverse effects. Future research should focus on the clinical evaluation of promising alkaloids, developing recently discovered alkaloids, and the ongoing search for novel alkaloids for medical treatment. A pharmaceutical option containing an alkaloid may potentially slow down the progression of AD while enhancing its symptoms. This review highlights the potential of alkaloids as valuable drug leads in treating AD, providing a comprehensive understanding of their mechanisms of action and therapeutic implications.

Therapeutic potential of proteases in acute lung injury and respiratory distress syndrome via TLR4/Nrf2/NF-kB signaling modulation.

The COVID-19 pandemic has drawn attention to acute lung injury and respiratory distress syndrome as major causes of death, underscoring the urgent need for effective treatments. Protease enzymes possess a wide range of beneficial effects, including antioxidant, anti-inflammatory, antifibrotic, and fibrinolytic effects. This study aimed to evaluate the potential therapeutic effects of bacterial protease and chymotrypsin in rats in mitigating acute lung injury induced by lipopolysaccharide. Molecular docking was employed to investigate the inhibitory effect of bacterial protease and chymotrypsin on TLR-4, the receptor for lipopolysaccharide. Bacterial protease restored TLR-4, Nrf2, p38 MAPK, NF-kB, and IKK-ß levels to normal levels, while chymotrypsin normalized TLR-4, IKK-ß, IL-6, and IL-17 levels. The expression of TGF-ß, caspase-3, and VEGF in the bacterial protease- and chymotrypsin-treated groups was markedly reduced. Our results suggest that both therapies ameliorate LPS-induced acute lung injury and modulate the TLR4/Nrf2/NF-k signaling pathway. Each protease exhibited distinct mechanisms, with bacterial protease showing a better response to oxidative stress, edema, and fibrosis, whereas chymotrypsin provided a better response in the acute phase and innate immunity. These findings highlight the potential of each protease as a promising therapeutic option for acute lung injury and respiratory distress syndrome.

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.

Assessing the health risks of heavy metals and seasonal minerals fluctuations in Camellia sinensis cultivars during their growth seasons.

The risk assessment of heavy metals in tea is extremely imperative for the health of tea consumers. However, the effects of varietal variations and seasonal fluctuations on heavy metals and minerals in tea plants remain unclear. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used to evaluate the contents of aluminum (Al), manganese (Mn), magnesium (Mg), boron (B), calcium (Ca), copper (Cu), cobalt (Co), iron (Fe), sodium (Na), zinc (Zn), arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), and antimony (Sb) in the two categories of young leaves (YL) and mature leaves (ML) of tea (Camellia sinensis) cultivars throughout the growing seasons. The results showed significant variations in the contents of the investigated nutrients both among the different cultivars and growing seasons as well. Furthermore, the average concentrations of Al, Mn, Mg, B, Ca, Cu, Co, Fe, Na, Zn, As, Cd, Cr, Ni, and Sb in YL ranged, from 671.58-2209.12, 1260.58-1902.21, 2290.56-2995.36, 91.18-164.68, 821.95-5708.20, 2.55-3.80, 3.96-25.22, 37.95-202.84, 81.79-205.05, 27.10-69.67, 0.028-0.053, 0.065-0.127, 2.40-3.73, 10.57-12.64, 0.11-0.14 mg kg-1, respectively. In ML, the concentrations were 2626.41-7834.60, 3980.82-6473.64, 3335.38-4537.48, 327.33-501.70, 9619.89-13153.68, 4.23-8.18, 17.23-34.20, 329.39-567.19, 145.36-248.69, 40.50-81.42, 0.089-0.169, 0.23-0.27, 5.24-7.89, 18.51-23.97, 0.15-0.19 mg kg-1, respectively. The contents of all analyzed nutrients were found to be higher in ML than in YL. Target hazard quotients (THQ) of As, Cd, Cr, Ni, and Sb, as well as the hazard index (HI), were all less than one, suggesting no risk to human health via tea consumption. This research might provide the groundwork for essential minerals recommendations, as well as a better understanding and management of heavy metal risks in tea.

Unleashing the potential of fNIRS with machine learning: classification of fine anatomical movements to empower future brain-computer interface.

In this study, we explore the potential of using functional near-infrared spectroscopy (fNIRS) signals in conjunction with modern machine-learning techniques to classify specific anatomical movements to increase the number of control commands for a possible fNIRS-based brain-computer interface (BCI) applications. The study focuses on novel individual finger-tapping, a well-known task in fNIRS and fMRI studies, but limited to left/right or few fingers. Twenty-four right-handed participants performed the individual finger-tapping task. Data were recorded by using sixteen sources and detectors placed over the motor cortex according to the 10-10 international system. The event's average oxygenated Δ HbO and deoxygenated Δ HbR hemoglobin data were utilized as features to assess the performance of diverse machine learning (ML) models in a challenging multi-class classification setting. These methods include LDA, QDA, MNLR, XGBoost, and RF. A new DL-based model named "Hemo-Net" has been proposed which consists of multiple parallel convolution layers with different filters to extract the features. This paper aims to explore the efficacy of using fNRIS along with ML/DL methods in a multi-class classification task. Complex models like RF, XGBoost, and Hemo-Net produce relatively higher test set accuracy when compared to LDA, MNLR, and QDA. Hemo-Net has depicted a superior performance achieving the highest test set accuracy of 76%, however, in this work, we do not aim at improving the accuracies of models rather we are interested in exploring if fNIRS has the neural signatures to help modern ML/DL methods in multi-class classification which can lead to applications like brain-computer interfaces. Multi-class classification of fine anatomical movements, such as individual finger movements, is difficult to classify with fNIRS data. Traditional ML models like MNLR and LDA show inferior performance compared to the ensemble-based methods of RF and XGBoost. DL-based method Hemo-Net outperforms all methods evaluated in this study and demonstrates a promising future for fNIRS-based BCI applications.

Phytostilbenes in lymphoma: Focuses on the mechanistic and clinical prospects of resveratrol, pterostilbene, piceatannol, and pinosylvin.

Lymphoma is a cancer affecting the lymphatic system that fights infections and diseases. In addition to surgery, radiotherapy, and chemotherapy, novel approaches have recently been investigated, such as phytostilbenes in treating lymphoma. Phytostilbenes are natural compounds present in various plants and have been shown to have different therapeutic effects, including anticancer properties. Resveratrol is a main phytostilbene with various derivates followed by pterostilbene and piceatannol. Studies have revealed that phytostilbenes can suppress the growth and proliferation of lymphoma cells by inducing apoptosis and inhibiting specific enzyme activity in cancer cell survival. The compounds also have antiinflammatory effects contributing to reducing lymphoma-associated inflammation. Additionally, phytostilbenes have been shown to increase the immune system's ability to fight cancer cells by activating immune cells (T-cells and natural killer cells). This review investigates the potential therapeutic effects of phytostilbenes, including resveratrol, pterostilbene, piceatannol, and pinosylvin, against lymphoma.

3,4',5-Trimethoxy-trans-stilbene ameliorates hepatic insulin resistance and oxidative stress in diabetic obese mice through insulin and Nrf2 signaling pathways.

Resveratrol has profound benefits against diabetes. However, whether its methylated derivative 3,4',5-trimethoxy-trans-stilbene (3,4',5-TMS) also plays a protective role in glucose metabolism is not characterized. We aimed to study the anti-diabetic effects of 3,4',5-TMS in vitro and in vivo. Insulin-resistant HepG2 cells (IR-HepG2) were induced by high glucose plus dexamethasone whilst six-week-old male C57BL/6J mice received a 60 kcal% fat diet for 14 weeks to establish an obese diabetic model. 3,4',5-TMS did not reduce the cell viability of IR-HepG2 cells at concentrations of 0.5 and 1 µM, which enhanced the capability of glycogen synthesis and glucose consumption in IR-HepG2 cells. Four-week oral administration of 3,4',5-TMS at 10 mg kg-1 day-1 ameliorated insulin sensitivity and glucose tolerance of diet-induced obese (DIO) mice. 3,4',5-TMS activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway by inhibiting phosphorylation of insulin receptor substrate (IRS)-1 at Ser307 and increasing the protein levels of IRS-1 and IRS-2 to restore the insulin signaling pathway in diabetes. 3,4',5-TMS also upregulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) at Ser9. 3,4',5-TMS suppressed oxidative stress by increasing the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H : quinone oxidoreductase 1 (NQO1) and antioxidant enzyme activity. In summary, 3,4',5-TMS alleviated hepatic insulin resistance in vitro and in vivo, by the activation of the insulin signaling pathway, accomplished by the suppression of oxidative stress.

A feasibility study investigating cortical hemodynamic changes during infinity walk with fNIRS.

This study seeks to explore the correlation between cortical activation and the Infinity Walk pattern, examining how the influence of foot overpronation and footwear may impact motor control. Functional near-infrared spectroscopy (fNIRS), a portable and user-friendly neuroimaging technique, was used to measure hemodynamical changes in six individuals with non-critical pronation degrees. Participants perform the Infinity Walk under various footwear conditions while wearing an fNIRS portable imaging device. Results indicate a consistent hemodynamic pattern in both hemispheres during the Infinity Walk, with no significant differences observed across subjects and footwear conditions in the prefrontal cortex (PFC), pre-motor area, the supplementary motor cortex (PMA & SMC), the primary motor cortex (PMC), and Wernicke's area (WA). The impact of pronation and footwear on motor control remains inconclusive due to inconsistent hemodynamic patterns. Notably, the activation patterns in Broca's area (BA) and the temporal gyrus (TG) differ significantly from other brain regions. The balanced hemodynamic responses in the bilateral hemispheres may be attributed to the Infinity Walk's inherent walking pattern. These findings indicate a need for further investigation into the Infinity Walk to examine the similarities and distinctions in activation patterns within specific brain regions. Additionally, the impact of pronation necessitates more substantial experimental research to establish a correlation between pronation and cortical hemodynamics.

Mitigation of sciatica injury-induced neuropathic pain through active metabolites derived from medicinal plants.

Sciatica characterized by irritation, inflammation, and compression of the lower back nerve, is considered one of the most common back ailments globally. Currently, the therapeutic regimens for sciatica are experiencing a paradigm shift from the conventional pharmacological approach toward exploring potent phytochemicals from medicinal plants. There is a dire need to identify novel phytochemicals with anti-neuropathic potential. This review aimed to identify the potent phytochemicals from diverse medicinal plants capable of alleviating neuropathic pain associated with sciatica. This review describes the pathophysiology of sciatic nerve pain, its cellular mechanisms, and the pharmacological potential of various plants and phytochemicals using animal-based models of sciatic nerve injury-induced pain. Extensive searches across databases such as Medline, PubMed, Web of Science, Scopus, ScienceDirect, and Google Scholar were conducted. The findings highlights 39 families including Lamiaceae, Asteraceae, Fabaceae, and Apocyanaceae and Cucurbitaceae, effectively treating sciatic nerve injury-induced pain. Flavonoids made up 53% constituents, phenols and terpenoids made up 15%, alkaloids made up 13%, and glycosides made up 6% to be used in neuorpathic pain. Phytochemicals derived from various medicinal plants can serve as potential therapeutic targets for both acute and chronic sciatic injury-induced neuropathic pain.

Neuroprotective potentials of Lead phytochemicals against Alzheimer's disease with focus on oxidative stress-mediated signaling pathways: Pharmacokinetic challenges, target specificity, clinical trials and future perspectives.

BACKGROUND: Alzheimer's diseases (AD) and dementia are among the highly prevalent neurological disorders characterized by deposition of beta amyloid (Aß) plaques, dense deposits of highly phosphorylated tau proteins, insufficiency of acetylcholine (ACh) and imbalance in glutamatergic system. Patients typically experience cognitive, behavioral alterations and are unable to perform their routine activities. Evidence also suggests that inflammatory processes including excessive microglia activation, high expression of inflammatory cytokines and release of free radicals. Thus, targeting inflammatory pathways beside other targets might be the key factors to control- disease symptoms and progression. PURPOSE: This review is aimed to highlight the mechanisms and pathways involved in the neuroprotective potentials of lead phytochemicals. Further to provide updates regarding challenges associated with their use and their progress into clinical trials as potential lead compounds. METHODS: Most recent scientific literature on pre-clinical and clinical data published in quality journals especially on the lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin was collected using SciFinder, PubMed, Google Scholar, Web of Science, JSTOR, EBSCO, Scopus and other related web sources. RESULTS: Literature review indicated that the drug discovery against AD is insufficient and only few drugs are clinically approved which have limited efficacy. Among the therapeutic options, natural products have got tremendous attraction owing to their molecular diversity, their safety and efficacy. Research suggest that natural products can delay the disease onset, reduce its progression and regenerate the damage via their anti-amyloid, anti-inflammatory and antioxidant potentials. These agents regulate the pathways involved in the release of neurotrophins which are implicated in neuronal survival and function. Highly potential lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin regulate neuroprotective signaling pathways implicated in neurotrophins-mediated activation of tropomyosin receptor kinase (Trk) and p75 neurotrophins receptor (p75NTR) family receptors. CONCLUSIONS: Phytochemicals especially phenolic compounds were identified as highly potential molecules which ameliorate oxidative stress induced neurodegeneration, reduce Aß load and inhibit vital enzymes. Yet their clinical efficacy and bioavailability are the major challenges which need further interventions for more effective therapeutic outcomes.

Understanding the Therapeutic Approaches for Neuroprotection.

The term "neurodegenerative disorders" refers to a group of illnesses in which deterioration of nerve structure and function is a prominent feature. Cognitive capacities such as memory and decision-making deteriorate as a result of neuronal damage. The primary difficulty that remains is safeguarding neurons since they do not proliferate or regenerate spontaneously and are therefore not substituted by the body after they have been damaged. Millions of individuals throughout the world suffer from neurodegenerative diseases. Various pathways lead to neurodegeneration, including endoplasmic reticulum stress, calcium ion overload, mitochondrial dysfunction, reactive oxygen species generation, and apoptosis. Although different treatments and therapies are available for neuroprotection after a brain injury or damage, the obstacles are inextricably connected. Several studies have revealed the pathogenic effects of hypothermia, different breathed gases, stem cell treatments, mitochondrial transplantation, multi-pharmacological therapy, and other therapies that have improved neurological recovery and survival outcomes after brain damage. The present review highlights the use of therapeutic approaches that can be targeted to develop and understand significant therapies for treating neurodegenerative diseases.

LDMRes-Net: A Lightweight Neural Network for Efficient Medical Image Segmentation on IoT and Edge Devices.

In this study, we propose LDMRes-Net, a lightweight dual-multiscale residual block-based convolutional neural network tailored for medical image segmentation on IoT and edge platforms. Conventional U-Net-based models face challenges in meeting the speed and efficiency demands of real-time clinical applications, such as disease monitoring, radiation therapy, and image-guided surgery. In this study, we present the Lightweight Dual Multiscale Residual Block-based Convolutional Neural Network (LDMRes-Net), which is specifically designed to overcome these difficulties. LDMRes-Net overcomes these limitations with its remarkably low number of learnable parameters (0.072M), making it highly suitable for resource-constrained devices. The model's key innovation lies in its dual multiscale residual block architecture, which enables the extraction of refined features on multiple scales, enhancing overall segmentation performance. To further optimize efficiency, the number of filters is carefully selected to prevent overlap, reduce training time, and improve computational efficiency. The study includes comprehensive evaluations, focusing on the segmentation of the retinal image of vessels and hard exudates crucial for the diagnosis and treatment of ophthalmology. The results demonstrate the robustness, generalizability, and high segmentation accuracy of LDMRes-Net, positioning it as an efficient tool for accurate and rapid medical image segmentation in diverse clinical applications, particularly on IoT and edge platforms. Such advances hold significant promise for improving healthcare outcomes and enabling real-time medical image analysis in resource-limited settings.

Spatiotemporal variation in the vegetation cover of Peshawar Basin in response to climate change.

Climate factors like temperature, precipitation, humidity, and sunshine time exert a profound influence on vegetation. The intricate interplay between the two is crucial to understand in the face of changing climate to develop mitigation strategies. In the current exploration, we delve how climate variability (CV) has impacted the vegetation in the Peshawar Basin (PB) using remote sensing data tools. The trend of climatic variability was investigated using the modified Mann-Kendall test and Sen's slope statistics. The changing climatic parameters were regressed on the Moderate Resolution Imaging Spectroradiometer (MODIS) normalized difference vegetation index (NDVI). The NDVI was further analyzed for spatiotemporal variability under land surface temperature (LST) influence. Results revealed that among the climate factors, average annual temperature and solar radiation have a significant (p < 0.05) negative impact on vegetation while precipitation and relative humidity significantly (p < 0.05) influence NDVI positively. The overall positive trend shows that vegetation improved between 2001 and 2020 with time, however some years (2010, 2012, 2014, 2016, and 2017) with low NDVI. NDVI varied in space considerably due to climatic extremes brought on by CV and the urbanization of agricultural land. NDVI regressed on LST showed that there was no or very little vegetation in the grids with high LST. The study concluded that the region is significantly impacted by both CV-related extreme weather events and anthropogenic activities. The vegetation is improving, but it is in danger of being destroyed by deforestation due to CV and human activities that exacerbate the risk of future calamities. To protect vegetation and avoid disasters, there is an immense need for adaptation and mitigation measures to deal with the region's fast-changing environment. The study urges local authorities to create climate-resilient governmental policies and supports regional sustainable development and vegetation restoration.

Is Early Childhood Development Care at Public Health Facilities in Pakistan Effective? A Cluster Randomized Controlled Trial.

BACKGROUND: Significant brain development in children occurs from birth to 2 years, with environment playing an important role. Stimulation interventions are widely known to be effective in enhancing early childhood development (ECD). This study aims to assess the feasibility and effectiveness of integrating ECD care delivered by lady health visitors (LHVs) at public health facilities in rural Pakistan. METHOD: A cluster randomized controlled trial was conducted through public health facilities in 2 districts of Punjab, Pakistan. A total of 22 clusters (rural health centers and subdistrict hospitals) were randomly allocated to receive routine care (control: n=11 clusters, 406 mother-child pairs) or counseling (intervention: n=11 clusters, 398 mother-child pairs). All children aged 11-12 months without any congenital abnormality were eligible for enrollment. The intervention was delivered by the LHVs to mothers with children aged 12-24 months in 3 quarterly sessions. RESULTS: The primary outcome was the prevention of ECD delays in children aged 24 months (assessed with the Ages and Stages Questionnaire-3). Analysis was done on an intention-to-treat basis. A total of 804 mother-child pairs were registered in the study, of which 26 (3.3%) pairs were lost to follow-up at the endpoint. The proportion of children with 2 or more developmental delays was significantly less in the intervention arm (13%) as compared to the control arm (41%) at an endpoint (odds ratio=0.21; 95% confidence interval=0.11, 0.42). Children in the intervention arm also had significantly better anthropometric measurements when aged 24 months than the children in the control arm. CONCLUSION: The integrated ECD care intervention for children aged 12-24 months at public health facilities was found to be effective in enhancing ECD and reducing the proportion of children with global development delays.

Managing Weed-Crop Interactions Enhances Chickpea (Cicer arietinum L.) Chemical Components.

Chickpea (Cicer arietinum L.) is a major pulse crop worldwide, renowned for its nutritional richness and adaptability. Weeds are the main biotic factor deteriorating chickpea yield and nutritional quality, especially Asphodelus tenuifolius Cav. The present study concerns a two-year (2018-19 and 2019-20) field trial aiming at evaluating the effect of weed management on chickpea grain quality. Several weed management practices have been here implemented under a factorial randomized complete block design, including the application of four herbicides [bromoxynil (C7H3Br2NO) + MCPA (Methyl-chlorophenoxyacetic acid) (C9H9ClO3), fluroxypyr + MCPA, fenoxaprop-p-ethyl (C18H16ClNO5), pendimethalin (C13H19N3O4)], the extracts from two allelopathic weeds (Sorghum halepense and Cyperus rotundus), two mulches (wheat straw and eucalyptus leaves), a combination of A. tenuifolius extract and pendimethalin, and an untreated check (control). Chickpea grain quality was measured in terms of nitrogen, crude protein, crude fat, ash, and oil content. The herbicides pendimethalin (Stomp 330 EC (emulsifiable concentrate) in pre-emergence at a rate of 2.5 L ha-1) and fenoxaprop-p-ethyl (Puma Super 7.5 EW (emulsion in water) in post-emergence at a rate of 1.0 L ha-1), thanks to A. tenuifolius control, showed outstanding performance, providing the highest dietary quality of chickpea grain. The herbicides Stomp 330 EC, Buctril Super 40 EC, Starane-M 50 EC, and Puma Super 7.5 EW provided the highest levels of nitrogen. Outstanding increases in crude protein content were observed with all management strategies, particularly with Stomp 330 EC and Puma Super 7.5 EW (+18% on average). Ash content was highly elevated by Stomp 330 EC and Puma Super 7.5 EW, along with wheat straw mulching, reaching levels of 2.96% and 2.94%. Crude fat content experienced consistent elevations across all treatments, with the highest improvements achieved by Stomp 330 EC, Puma Super 7.5 EW, and wheat straw mulching applications. While 2018-19 displayed no significant oil content variations, 2019-20 revealed the highest oil content (5.97% and 5.96%) with herbicides Stomp 330 EC and Puma Super 7.5 EW, respectively, followed by eucalyptus leaves mulching (5.82%). The results here obtained are of key importance in the agricultural and food sector for the sustainable enhancement of chickpea grain's nutritional quality without impacting the environment.

Synthesis, in-vitro inhibition of cyclooxygenases and in silico studies of new isoxazole derivatives.

Isoxazole belongs to the class of five-membered heterocyclic compounds. The process of developing new drugs has significantly gained attention due to inadequate pharmacokinetic and safety attributes of the available drugs. This study aimed to design a new diverse array of ten novel isoxazole derivatives via Claisen Schmidt condensation reaction. In vitro COX-1/2 anti-inflammatory assay, in silico molecular docking of potent compounds, Molecular docking simulation, and SwissADME pharmacokinetic profile were investigated in this research. The in vitro COX-1 and COX-2 enzyme inhibitory assay showed that almost all the tested compounds exhibited anti-inflammatory effects whereas C6, C5, and C3 were found to be the most potent COX-2 enzyme inhibitors among the tested compounds and are good candidates for selective COX-2 inhibitors. In silico molecular docking studies coupled with molecular dynamic simulation has been done to rationalize the time-evolved mode of interaction of selected inhibitor inside the active pockets of target COX-2. The binding orientations and binding energy results also showed the selectivity of compounds towards COX-2. Physicochemical properties, pharmacokinetic profile, lipophilicity, water solubility, drug metabolism, drug-likeness properties, and medicinal chemistry of the synthesized isoxazole derivatives were assessed. The SwissADME (absorption, distribution, metabolism, and excretion) database was used to assess the physicochemical properties and drug-likeness properties of the synthesized isoxazole derivatives. All the compounds were shown high GI absorption except Compound 7 (C7). Compound 1 (C1) and Compound 2 (C2) were found to cross the blood-brain barrier (BBB). Lipinski's rule of five is not violated by any of the ten synthesized isoxazole derivatives. It was predicted with the SwissADME database that C2, C5, C6, C7, and C8 are potent inhibitors of cytochrome (CYP) subtype CYP-2C19. A subtype of CYP-2C9 was inhibited by C4 and C7. The medicinal chemistry of all the compounds C1-C10 showed no PAIN (Pan assay interference compounds) alerts. The improved gastrointestinal (GI) absorption and BBB permeability of C1 and C2 can provide a future prospective for new researchers in the medicinal field to investigate the compounds for the management of chronic diseases. The synthesized isoxazole compounds showed excellent in vitro COX-1/2 enzymes anti-inflammatory investigations, in silico studies, good physicochemical properties, and improved pharmacokinetic profile which will be further investigated via in vivo anti-inflammatory activities. Moreover, to further support our findings of the computational research and in vitro studies, an in-vivo pharmacokinetic profile is suggested in the future.

An electronic health record system implementation in a resource limited country-lessons learned.

Electronic health records have revolutionized the medical world by improving medical care, refining provider documentation, standardizing care, and minimizing sentinel events. Successful implementation of electronic health records remains a daunting task and requires careful strategic planning and buy-in from key stakeholders. Much has been published in resource-rich settings and high-income countries about implementations of electronic health records. However, little is known about the experience in resource-limited settings where challenges remain unique and distinct from other parts of the world. Our intention is to share lessons learned during implementation of a web-based electronic health record at a tertiary care center in Kenya.