Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis.

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

Analysis of Gastrointestinal and Hepatic Manifestations of SARS-CoV-2 Infection in 892 Patients in Queens, NY.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus responsible for coronavirus disease 2019 (COVID-19).1,2 The virus enters cells via the angiotensin-converting enzyme 2 receptor, which is present in enterocytes in the ileum and colon.3 Gastrointestinal (GI) manifestations include diarrhea, nausea, vomiting, and abdominal pain, and the prevalence of GI symptoms varies greatly, with a range between 2% and 57%.4 In addition, abnormal liver chemistries are reported commonly.4 As a medical center at the forefront of the early epidemic in the United States, we seek to contribute to the growing body of literature that outlines the gastrointestinal and hepatic manifestations of COVID-19.

Acquisition of Spatial Search Strategies and Reversal Learning in the Morris Water Maze Depend on Disparate Brain Functional Connectivity in Mice.

Learning has been proposed to coincide with changes in connections between brain regions. In the present study, we used resting-state fMRI (rsfMRI) to map brain-wide functional connectivity (FC) in mice that were trained in the hidden-platform version of the Morris water maze. C57BL6 mice were investigated in a small animal MRI scanner following 2, 10, or 15 days of acquisition learning, or 5 days of reversal learning. Spatial learning coincided with progressive and changing FC between telencephalic regions that have been implemented in spatial learning (such as hippocampus, cingulate, visual, and motor cortex). Search strategy assessment demonstrated that the use of cognitively advanced spatial strategies correlated positively with extensive telencephalic connectivity, whereas non-spatial strategies correlated negatively with connectivity. FC patterns were different and more extensive after reversal learning compared with after extended acquisition learning, which could explain why reversal learning has been shown to be more sensitive to subtle functional defects.

Bottom-up sensory processing can induce negative BOLD responses and reduce functional connectivity in nodes of the default mode-like network in rats.

The default mode network is a large-scale brain network that is active during rest and internally focused states and deactivates as well as desynchronizes during externally oriented (top-down) attention demanding cognitive tasks. However, it is not sufficiently understood if salient stimuli, able to trigger bottom-up attentional processes, could also result in similar reduction of activity and functional connectivity in the DMN. In this study, we investigated whether bottom-up sensory processing could influence the default mode-like network (DMLN) in rats. DMLN activity was examined using block-design visual functional magnetic resonance imaging (fMRI) while its synchronization was investigated by comparing functional connectivity during a resting versus a continuously stimulated brain state by unpredicted light flashes. We demonstrated that the BOLD response in DMLN regions was decreased during visual stimulus blocks and increased during blanks. Furthermore, decreased inter-network functional connectivity between the DMLN and visual networks as well as decreased intra-network functional connectivity within the DMLN was observed during the continuous visual stimulation. These results suggest that triggering of bottom-up attention mechanisms in sedated rats can lead to a cascade similar to top-down orienting of attention in humans and is able to deactivate and desynchronize the DMLN.

Dynamic resting state fMRI analysis in mice reveals a set of Quasi-Periodic Patterns and illustrates their relationship with the global signal.

Time-resolved 'dynamic' over whole-period 'static' analysis of low frequency (LF) blood-oxygen level dependent (BOLD) fluctuations provides many additional insights into the macroscale organization and dynamics of neural activity. Although there has been considerable advancement in the development of mouse resting state fMRI (rsfMRI), very little remains known about its dynamic repertoire. Here, we report for the first time the detection of a set of recurring spatiotemporal Quasi-Periodic Patterns (QPPs) in mice, which show spatial similarity with known resting state networks. Furthermore, we establish a close relationship between several of these patterns and the global signal. We acquired high temporal rsfMRI scans under conditions of low (LA) and high (HA) medetomidine-isoflurane anesthesia. We then employed the algorithm developed by Majeed et al. (2011), previously applied in rats and humans, which detects and averages recurring spatiotemporal patterns in the LF BOLD signal. One type of observed patterns in mice was highly similar to those originally observed in rats, displaying propagation from lateral to medial cortical regions, which suggestively pertain to a mouse Task-Positive like network (TPN) and Default Mode like network (DMN). Other QPPs showed more widespread or striatal involvement and were no longer detected after global signal regression (GSR). This was further supported by diminished detection of subcortical dynamics after GSR, with cortical dynamics predominating. Observed QPPs were both qualitatively and quantitatively determined to be consistent across both anesthesia conditions, with GSR producing the same outcome. Under LA, QPPs were consistently detected at both group and single subject level. Under HA, consistency and pattern occurrence rate decreased, whilst cortical contribution to the patterns diminished. These findings confirm the robustness of QPPs across species and demonstrate a new approach to study mouse LF BOLD spatiotemporal dynamics and mechanisms underlying functional connectivity. The observed impact of GSR on QPPs might help better comprehend its controversial role in conventional resting state studies. Finally, consistent detection of QPPs at single subject level under LA promises a step forward towards more reliable mouse rsfMRI and further confirms the importance of selecting an optimal anesthesia regime.

Interleukin-13 immune gene therapy prevents CNS inflammation and demyelination via alternative activation of microglia and macrophages.

Detrimental inflammatory responses in the central nervous system are a hallmark of various brain injuries and diseases. With this study we provide evidence that lentiviral vector-mediated expression of the immune-modulating cytokine interleukin 13 (IL-13) induces an alternative activation program in both microglia and macrophages conferring protection against severe oligodendrocyte loss and demyelination in the cuprizone mouse model for multiple sclerosis (MS). First, IL-13 mediated modulation of cuprizone induced lesions was monitored using T2 -weighted magnetic resonance imaging and magnetization transfer imaging, and further correlated with quantitative histological analyses for inflammatory cell influx, oligodendrocyte death, and demyelination. Second, following IL-13 immune gene therapy in cuprizone-treated eGFP+ bone marrow chimeric mice, we provide evidence that IL-13 directs the polarization of both brain-resident microglia and infiltrating macrophages towards an alternatively activated phenotype, thereby promoting the conversion of a pro-inflammatory environment toward an anti-inflammatory environment, as further evidenced by gene expression analyses. Finally, we show that IL-13 immune gene therapy is also able to limit lesion severity in a pre-existing inflammatory environment. In conclusion, these results highlight the potential of IL-13 to modulate microglia/macrophage responses and to improve disease outcome in a mouse model for MS. GLIA 2016;64:2181-2200.

Resting-state functional MRI and [18F]-FDG PET demonstrate differences in neuronal activity between commonly used mouse strains.

The existence of numerous interesting mouse models of neurological disorders enables the investigation of causal relations between pathological events and the effect of treatment regimes. However, mouse models of a specific neurological disease are often generated using different background strains, which raises the question whether the observed effects are specific to pathology or depend on the used strain. This study used two independent in vivo functional imaging techniques to evaluate whether mouse strain differences exist in functional connectivity (FC) and brain glucose metabolism i.e. indirect measures of neuronal activity. For this purpose, C57BL/6, BALB/C and SJL mice (N=15/group, male) were evaluated using resting-state functional MRI (rsfMRI) and static [18F]-fluorodeoxyglucose Positron Emission Tomography ([18F]-FDG PET). RsfMRI and [18F]-FDG PET data were analyzed with independent component analysis (ICA). FC was quantified by calculating the mean network-specific FC strength and [18F]-FDG uptake was quantified by calculating the mean network-specific standard uptake value corrected for plasma glucose levels and body weight (SUVglu). The ICA results showed spatially similar neurological components in the rsfMRI and [18F]-FDG PET data, suggesting that patterns of metabolic covariance in the mouse brain reflect FC networks. Comparing FC and [18F]-FDG data showed that strain-dependent differences in brain activity exist for several brain networks i.e. the frontal, cingulate, (hypo)thalamus, striatum, and sensorimotor networks. The results of this study have implications for the interpretation of in vivo functional imaging data in mouse models of neurological disorders generated on different background strains.

Early pathologic amyloid induces hypersynchrony of BOLD resting-state networks in transgenic mice and provides an early therapeutic window before amyloid plaque deposition.

INTRODUCTION: In Alzheimer's disease (AD), pathologic amyloid-beta (Aß) is synaptotoxic and impairs neuronal function at the microscale, influencing brain networks at the macroscale before Aß deposition. The latter can be detected noninvasively, in vivo, using resting-state functional MRI (rsfMRI), a technique used to assess brain functional connectivity (FC). METHODS: RsfMRI was performed longitudinally in TG2576 and PDAPP mice, starting before Aß deposition to determine the earliest FC changes. Additionally, the role of pathologic Aß on early FC alterations was investigated by treating TG2576 mice with the 3D6 anti-Aß-antibody. RESULTS: Both transgenic models showed hypersynchronized FC before Aß deposition and hyposynchronized FC at later stages. Early anti-Aß treatment in TG2576 mice prevented hypersynchronous FC and the associated synaptic impairments and excitatory/inhibitory disbalances. DISCUSSION: Hypersynchrony of FC may be used as a new noninvasive read out of early AD and can be recovered by anti-Aß treatment, encouraging preventive treatment strategies in familial AD.

Acute modulation of the cholinergic system in the mouse brain detected by pharmacological resting-state functional MRI.

INTRODUCTION: The cholinergic system is involved in learning and memory and is affected in neurodegenerative disorders such as Alzheimer's disease. The possibility of non-invasively detecting alterations of neurotransmitter systems in the mouse brain would greatly improve early diagnosis and treatment strategies. The hypothesis of this study is that acute modulation of the cholinergic system might be reflected as altered functional connectivity (FC) and can be measured using pharmacological resting-state functional MRI (rsfMRI). MATERIAL AND METHODS: Pharmacological rsfMRI was performed on a 9.4T MRI scanner (Bruker BioSpec, Germany) using a gradient echo EPI sequence. All mice were sedated with medetomidine. C57BL/6 mice (N = 15/group) were injected with either saline, the cholinergic antagonist scopolamine, or methyl-scopolamine, after which rsfMRI was acquired. For an additional group (N = 8), rsfMRI scans of the same mouse were acquired first at baseline, then after the administration of scopolamine and finally after the additional injection of the cholinergic agonist milameline. Contextual memory was evaluated with the same setup as the pharmacological rsfMRI using the passive avoidance behavior test. RESULTS: Scopolamine induced a dose-dependent decrease of FC between brain regions involved in memory. Scopolamine-induced FC deficits could be recovered completely by milameline for FC between the hippocampus-thalamus, cingulate-retrosplenial, and visual-retrosplenial cortex. FC between the cingulate-rhinal, cingulate-visual and visual-rhinal cortex could not be completely recovered by milameline. This is consistent with the behavioral outcome, where milameline only partially recovered scopolamine-induced contextual memory deficits. Methyl-scopolamine administered at the same dose as scopolamine did not affect FC in the brain. CONCLUSION: The results of the current study are important for future studies in mouse models of neurodegenerative disorders, where pharmacological rsfMRI may possibly be used as a non-invasive read-out tool to detect alterations of neurotransmitter systems induced by pathology or treatment.

Different anesthesia regimes modulate the functional connectivity outcome in mice.

PURPOSE: The use of resting-state functional MRI (rsfMRI) in preclinical research is expanding progressively, with the majority of resting-state imaging performed in anesthetized animals. Since anesthesia may change the physiology and, in particular, the neuronal activity of an animal considerably, it may also affect rsfMRI findings. Therefore, this study compared rsfMRI data from awake mice with rsfMRI results obtained from mice anesthetized with α-chloralose (120 mg/kg), urethane (2.5 g/kg), or isoflurane (1%). METHODS: Functional connectivity (FC) was estimated using both independent component analysis (40 components) and ROI-based analysis to zoom in on the effect of different anesthetics on inter-hemispheric FC. RESULTS: The data revealed an important diminishment of cortical interhemispheric FC in both the α-chloralose and urethane groups in comparison with the isoflurane and awake groups. CONCLUSION: When performing FC analysis in anesthetized mice, the impact of anesthetics must be taken into account. The required doses for stable anesthesia during MRI significantly decrease interhemispheric FC.

d-α-tocopheryl polyethylene glycol 1000 succinate surface scaffold polysarcosine based polymeric nanoparticles of enzalutamide for the treatment of colorectal cancer: In vitro, in vivo characterizations.

In this study, Enzalutamide (ENZ) loaded Poly Lactic-co-Glycolic Acid (PLGA) nanoparticles coated with polysarcosine and d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared using a three-step modified nanoprecipitation method combined with self-assembly. A three-factor, three-level Box-Behnken design was implemented with Design-Expert® software to evaluate the impact of three independent variables on particle size, zeta potential, and percent entrapment efficiency through a numeric optimization approach. The results were corroborated with ANOVA analysis, regression equations, and response surface plots. Field emission scanning electron microscopy and transmission electron microscope images revealed nanosized, spherical polymeric nanoparticles (NPs) with a size distribution ranging from 178.9 ± 2.3 to 212.8 ± 0.7 nm, a zeta potential of 12.6 ± 0.8 mV, and entrapment efficiency of 71.2 ± 0.7 %. The latter increased with higher polymer concentration. Increased polymer concentration and homogenization speed also enhanced drug entrapment efficiency. In vitro drug release was 85 ± 22.5 %, following the Higuchi model (R2 = 0.98) and Fickian diffusion (n < 0.5). In vitro cytotoxicity assessments, including Mitochondrial Membrane Potential Estimation, Apoptosis analysis, cell cycle analysis, Reactive oxygen species estimation, Wound healing assay, DNA fragmentation assay, and IC50 evaluation with Sulforhodamine B assay, indicated low toxicity and high efficacy of polymeric nanoparticles compared to the drug alone. In vivo studies demonstrated biocompatibility and target specificity. The findings suggest that TPGS surface-scaffolded polysarcosine-based polymer nanoparticles of ENZ could be a promising and safe delivery system with sustained release for colorectal cancer treatment, yielding improved therapeutic outcomes.

Biogenic metallic nanoparticles: from green synthesis to clinical translation.

Biogenic metallic nanoparticles (NPs) have garnered significant attention in recent years due to their unique properties and various applications in different fields. NPs, including gold, silver, zinc oxide, copper, titanium, and magnesium oxide NPs, have attracted considerable interest. Green synthesis approaches, utilizing natural products, offer advantages such as sustainability and environmental friendliness. The theranostics applications of these NPs hold immense significance in the fields of medicine and diagnostics. The review explores intricate cellular uptake pathways, internalization dynamics, reactive oxygen species generation, and ensuing inflammatory responses, shedding light on the intricate mechanisms governing their behaviour at a molecular level. Intriguingly, biogenic metallic NPs exhibit a wide array of applications in medicine, including but not limited to anti-inflammatory, anticancer, anti-diabetic, anti-plasmodial, antiviral properties and radical scavenging efficacy. Their potential in personalized medicine stands out, with a focus on tailoring treatments to individual patients based on these NPs' unique attributes and targeted delivery capabilities. The article culminates in emphasizing the role of biogenic metallic NPs in shaping the landscape of personalized medicine. Harnessing their unique properties for tailored therapeutics, diagnostics and targeted interventions, these NPs pave the way for a paradigm shift in healthcare, promising enhanced efficacy and reduced adverse effects.

An Insight on Microfluidic Organ-on-a-Chip Models for PM2.5-Induced Pulmonary Complications.

Pulmonary diseases like asthma, chronic obstructive pulmonary disorder, lung fibrosis, and lung cancer pose a significant burden to global human health. Many of these complications arise as a result of exposure to particulate matter (PM), which has been examined in several preclinical and clinical trials for its effect on several respiratory diseases. Particulate matter of size less than 2.5 µm (PM2.5) has been known to inflict unforeseen repercussions, although data from epidemiological studies to back this are pending. Conventionally utilized two-dimensional (2D) cell culture and preclinical animal models have provided insufficient benefits in emulating the in vivo physiological and pathological pulmonary conditions. Three-dimensional (3D) structural models, including organ-on-a-chip models, have experienced a developmental upsurge in recent times. Lung-on-a-chip models have the potential to simulate the specific features of the lungs. With the advancement of technology, an emerging and advanced technique termed microfluidic organ-on-a-chip has been developed with the aim of identifying the complexity of the respiratory cellular microenvironment of the body. In the present Review, the role of lung-on-a-chip modeling in reproducing pulmonary complications has been explored, with a specific emphasis on PM2.5-induced pulmonary complications.

Disabled-2, a versatile tissue matrix multifunctional scaffold protein with multifaceted signaling: Unveiling its potential in the cancer battle.

A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/ß-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-ß) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas.

Disable 2, A Versatile Tissue Matrix Multifunctional Scaffold Protein with Multifaceted Signaling: Unveiling Role in Breast Cancer for Therapeutic Revolution.

The Disabled-2 (DAB2) protein, found in 80-90% of various tumors, including breast cancer, has been identified as a potential tumor suppressor protein. On the contrary, some hypothesis suggests that DAB2 is associated with the modulation of the Ras/MAPK pathway by endocytosing the Grb/Sos1 signaling complex, which produces oncogenes and chemoresistance to anticancer drugs, leading to increased tumor growth and metastasis. DAB2 has multiple functions in several disorders and is typically under-regulated in several cancers, making it a potential target for treatment of cancer therapy. The primary function of DAB2 is the modulation of transforming growth factor- ß (TGF-ß) mediated endocytosis, which is involved in several mechanisms of cancer development, including tumor suppression through promoting apoptosis and suppressing cell proliferation. In this review, we will discuss in detail the mechanisms through which DAB2 leads to breast cancer and various advancements in employing DAB2 in the treatment of breast cancer. Additionally, we outlined its role in other diseases. We propose that upregulating DAB2 could be a novel approach to the therapeutics of breast cancer.

Role of natural P-gp inhibitor in the effective delivery for chemotherapeutic agents.

Multi-drug resistance has shown to be one of the leading threats faced currently in many chemotherapeutic agents. Permeability glycoprotein (P-gp) is an efflux transporter in membrane, an integral part of ATP-binding cassette (ABC) transporters widely distributed in the body for cellular uptake. It is present enormously in cancerous cells and is in charge of generating transporter mediated resistance to treatments of tumorous cells in addition to blocking the entry of chemotherapeutic drugs into the cell. Natural P-gp inhibitors are derived from natural plant sources possessing basic structures like alkaloids, flavonoids, phenolics, terpenoids, saponins, sapogenins, sterols, coumarins and miscellaneous structures acting on P-gp substrate for inhibition of multi-drug resistance via inhibiting the efflux pump. They do not depict their action on the healthy cells and thus it is proven to be more effective and less toxic than synthetic P-gp inhibitor leading to enhancement in bioavailability of chemotherapeutic drugs. The significant objective of the present review is surfing through the impact of natural P-gp inhibitors having basic structures derived from the plant sources and how it inhibits the resistance of chemotherapeutic drugs together with how well it delivers chemotherapy medicines.

CD44 targeted delivery of hyaluronic acid-coated polymeric nanoparticles against colorectal cancer.

Aim: To develop hyaluronic acid (HA)-coated poly-lactic-co-glycolic acid (PLGA)-polysarcosine (PSAR) coupled sorafenib tosylate (SF) polymeric nanoparticles for targeted colon cancer therapy. Materials & methods: PLGA-PSAR shells were encapsulated with SF via nanoprecipitation. Interactions were examined with transmission electron microscopy, revealing formulation component interactions. Results: The optimized HA-coated polymeric nanoparticles (238.8 nm, -6.1 mV, 68.361% entrapment) displayed enhanced controlled release of SF. These formulations showed superior cytotoxicity against HCT116 cell lines compared with free drug (p < 0.05). In vivo tests on male albino Wistar rats demonstrated improved pharmacokinetics, targeting and biocompatibility. HA-coated PLGA-PSAR-coupled SF polymeric nanoparticles hold potential for effective colorectal therapy. Conclusion: Colon cancer may be precisely targeted by HA-coated PLGA-PSA-coupled SF polymeric nanoparticles.

Combating relapsed and refractory Mantle cell lymphoma with novel therapeutic armamentarium: Recent advances and clinical prospects.

Mantle cell lymphoma (MCL) is a rare, aggressive subtype of non-Hodgkin's lymphoma (NHL), accounting for 5% of all cases. Due to its virulence factor, it is an incurable disease and keeps relapsing despite an intensive treatment regimen. Advancements in research and drug discovery have shifted the treatment strategy from conventional chemotherapy to targeted agents and immunotherapies. The establishment of the role of Bruton tyrosine kinase led to the development of ibrutinib, a first-generation BTK inhibitor, and its successors. A conditioning regimen based immunotherapeutic agent like ibritumumob, has also demonstrated a viable response with a favorable toxicity profile. Brexucabtagene Autoleucel, the only approved CAR T-cell therapy, has proven advantageous for relapsed/refractory MCL in both children and adults. This article reviews certain therapies that could help update the current approach and summarizes a few miscellaneous agents, which, seldom studied in trials, could alleviate the regression observed in traditional therapies. DATA AVAILABILITY: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Harnessing three-dimensional (3D) cell culture models for pulmonary infections: State of the art and future directions.

Pulmonary infections have been a leading etiology of morbidity and mortality worldwide. Upper and lower respiratory tract infections have multifactorial causes, which include bacterial, viral, and rarely, fungal infections. Moreover, the recent emergence of SARS-CoV-2 has created havoc and imposes a huge healthcare burden. Drug and vaccine development against these pulmonary pathogens like respiratory syncytial virus, SARS-CoV-2, Mycobacteria, etc., requires a systematic set of tools for research and investigation. Currently, in vitro 2D cell culture models are widely used to emulate the in vivo physiologic environment. Although this approach holds a reasonable promise over pre-clinical animal models, it lacks the much-needed correlation to the in vivo tissue architecture, cellular organization, cell-to-cell interactions, downstream processes, and the biomechanical milieu. In view of these inadequacies, 3D cell culture models have recently acquired interest. Mammalian embryonic and induced pluripotent stem cells may display their remarkable self-organizing abilities in 3D culture, and the resulting organoids replicate important structural and functional characteristics of organs such the kidney, lung, gut, brain, and retina. 3D models range from scaffold-free systems to scaffold-based and hybrid models as well. Upsurge in organs-on-chip models for pulmonary conditions has anticipated encouraging results. Complexity and dexterity of developing 3D culture models and the lack of standardized working procedures are a few of the setbacks, which are expected to be overcome in the coming times. Herein, we have elaborated the significance and types of 3D cell culture models for scrutinizing pulmonary infections, along with the in vitro techniques, their applications, and additional systems under investigation.

Fabrication of D-α-tocopheryl polyethylene glycol 1000 succinates and human serum albumin conjugated chitosan nanoparticles of bosutinib for colon targeting application; in vitro-in vivo investigation.

For more effective chemotherapy and targeted treatment of colorectal cancer, this study seeks to develop chitosan (CH)-human serum albumin (HAS)-D-α-tocopheryl polyethylene glycol 1000 (TPGS) nanoparticles (BOS-CH-HSA-TPGS-NPs) coated with Bosutinib (BOS). Nuclear magnetic resonance (NMR) indicated that chitosan's structure was modified by carbodiimide coupling with HSA. We used a Box-Behnken design to find the ideal region for particle size, zeta potential, and entrapment efficiency, eventually emerging at a formulation with these values: 187.14 ± 3.2 nm, 76.2 ± 0.96 %, and 21.1 ± 2.3 mV. Differential scanning calorimetry (DSC), Transmission electron microscopy (TEM), X-ray diffraction (XRD), Atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), High-performance liquid chromatography (HPLC) were all used to characterize the sample in detail. At a phosphate buffer pH of 7.4, in vitro drug release tests showed both Higuchi model release (0.954) and Fickian diffusion (n = 0.5). Compared to free BOS, HCT116 cell lines showed considerably higher cytotoxicity in in vitro cytotoxicity assays. In male albino Wistar rats, the BOS-CH-HSA-TPGS-NPs also showed enhanced pharmacokinetics, targeting efficiency, and biocompatibility. When used to the treatment of colorectal cancer, the BOS-CH-HSA-TPGS NPs show promise as a sustained-release therapy with improved therapeutic effects by addressing the challenges of poor solubility, poor permeability, and toxic side effects.