Emerging Trends in Nanotechnology for Endometriosis: Diagnosis to Therapy.

Endometriosis, an incurable gynecological disease that causes abnormal growth of uterine-like tissue outside the uterine cavity, leads to pelvic pain and infertility in millions of individuals. Endometriosis can be treated with medicine and surgery, but recurrence and comorbidities impair quality of life. In recent years, nanoparticle (NP)-based therapy has drawn global attention, notably in medicine. Studies have shown that NPs could revolutionize conventional therapeutics and imaging. Researchers aim to enhance the prognosis of endometriosis patients with less invasive and more effective NP-based treatments. This study evaluates this potential paradigm shift in endometriosis management, exploring NP-based systems for improved treatments and diagnostics. Insights into nanotechnology applications, including gene therapy, photothermal therapy, immunotherapy, and magnetic hyperthermia, offering a theoretical reference for the clinical use of nanotechnology in endometriosis treatment, are discussed in this review.

Promising Combinatorial Therapeutic Strategies against Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) presents a complex and diverse disease, exhibiting variations at individuals' cellular and histological levels. This complexity gives rise to different subtypes and genetic mutations, posing challenges for accurate diagnosis and effective treatment. Nevertheless, continuous progress in medical research and therapies is continually shaping the landscape of NSCLC diagnosis and management. The treatment of NSCLC has undergone significant advancements in recent years, especially with the emergence of targeted therapies that have shown remarkable efficacy in patients with actionable mutations. This has ushered in the era of personalized medicine in NSCLC treatment, with improvements in molecular and immunohistochemical techniques contributing to enhanced progression-free survival. This review focuses on the latest progress, challenges, and future directions in developing targeted therapies for NSCLC, including tyrosine kinase inhibitors (TKIs), DNA-damaging agents, immunotherapy regimens, natural drug therapy, and nanobodies. Furthermore, recent randomized studies have demonstrated enhanced overall survival in patients receiving different targeted and natural drug therapies.

Nanodiamonds: Next generation nano-theranostics for cancer therapy.

Cancer remains a leading global cause of mortality, demanding early diagnosis and effective treatment. Traditional therapeutic methods often fall short due to their need for more specificity and systemic toxicity. In this challenging landscape, nanodiamonds (ND) emerge as a potential solution, mitigating the limitations of conventional approaches. ND are tiny carbon particles that mimic traditional diamonds chemical stability and hardness and harness nanomaterials' advantages. ND stands out for the unique properties that make them promising nanotheranostics candidates, combining therapeutic and imaging capabilities in one platform. Many of these applications depend on the design of the particle's surface, as the surface's role is crucial in transporting bioactive molecules, preventing aggregation, and building composite materials. This review delves into ND's distinctive features, structural and optical characteristics, and their profound relevance in advancing cancer diagnosis and treatment methods. The report delves into how these exceptional ND properties drive the development of state-of-the-art techniques for precise tumor targeting, boosting the effectiveness of chemotherapy as a chemosensitizer, harnessing immunotherapy strategies, facilitating precision medicine, and creating localized microfilm devices for targeted therapies.

Epinephrine facilitates the growth of T cell lymphoma by altering cell proliferation, apoptosis, and glucose metabolism.

In recent years, studies have reported the role of stress-regulatory hormones, including epinephrine, in regulating the progression of a few cancers. However, the tumor-promoting action of epinephrine is not yet investigated in T cell malignancy, a rare and complicated neoplastic disorder. More so, very little is known regarding the implication of epinephrine in the glucose metabolic rewiring in tumor cells. The present investigation showed that epinephrine enhanced the proliferation of T lymphoma cells through up- and down-regulating the expression of PCNA, cyclin D, and p53, respectively. In addition, epinephrine inhibited apoptosis in T lymphoma cells possibly by increasing the level of BCL2 (an anti-apoptotic protein) and decreasing PARP level (a pro-apoptotic protein). Intriguingly, epinephrine is reported to stimulate glycolysis in T lymphoma cells by increasing the expression of crucial glycolysis regulatory molecules, namely HKII and PKM2, in a HIF-1α-dependent manner. Moreover, augmented production of ROS has been observed in T lymphoma cells, which might be a central player in epinephrine-mediated T cell lymphoma growth. Taken together, our study demonstrates that epinephrine might have a significant role in the progression of T cell lymphoma.

Understanding the significance of biological clock and its impact on cancer incidence.

The circadian clock is an essential timekeeper that controls, for humans, the daily rhythm of biochemical, physiological, and behavioral functions. Irregular performance or disruption in circadian rhythms results in various diseases, including cancer. As a factor in cancer development, perturbations in circadian rhythms can affect circadian homeostasis in energy balance, lead to alterations in the cell cycle, and cause dysregulation of chromatin remodeling. However, knowledge gaps remain in our understanding of the relationship between the circadian clock and cancer. Therefore, a mechanistic understanding by which circadian disruption enhances cancer risk is needed. This review article outlines the importance of the circadian clock in tumorigenesis and summarizes underlying mechanisms in the clock and its carcinogenic mechanisms, highlighting advances in chronotherapy for cancer treatment.

Optimum health and inhibition of cancer progression by microbiome and resveratrol.

Resveratrol (RES) is a naturally occurring polyphenol found in fruits, green leafy vegetables, and peanuts. This versatile compound, which has potent regenerative, anti-oxidative, and cancer-fighting properties, is produced in plants, particularly in response to stress stimuli. By various mechanisms, including regulation of genes and proteins, RES inhibits the growth of pathogenic bacteria and the development of cancers. The gut has a prominent role in nutrient assimilation, metabolism, immunity, and cancer regression, and the endogenous microbiome protects the host from invasive bacteria that facilitate the progression of various diseases. Short-chain fatty acids (SFCAs) are the byproducts of microbial fermentation in the gastrointestinal tract. Native microflora regulates internal homeostasis, influence the activity of host immune cells, and regress some cancers via the action of SCFAs produced from a plant-based diet. This review shows the relevance of dietary constituents and gut microbial activity in ensuring optimal health of the host.

Aging-Exacerbated Acute Axon and Myelin Injury Is Associated with Microglia-Derived Reactive Oxygen Species and Is Alleviated by the Generic Medication Indapamide.

Age is a critical risk factor for many neurologic conditions, including progressive multiple sclerosis. Yet the mechanisms underlying the relationship are unknown. Using lysolecithin-induced demyelinating injury to the mouse spinal cord, we characterized the acute lesion and investigated the mechanisms of increased myelin and axon damage with age. We report exacerbated myelin and axon loss in middle-aged (8-10 months of age) compared with young (6 weeks of age) female C57BL/6 mice by 1-3 d of lesion evolution in the white matter. Transcriptomic analysis linked elevated injury to increased expression of Cybb, the gene encoding the catalytic subunit of NADPH oxidase gp91phox. Immunohistochemistry in male and female Cx3cr1CreER/+:Rosa26tdTom/+ mice for gp91phox revealed that the upregulation in middle-aged animals occurred primarily in microglia and not infiltrated monocyte-derived macrophages. Activated NADPH oxidase generates reactive oxygen species and elevated oxidative damage was corroborated by higher malondialdehyde immunoreactivity in lesions from middle-aged compared with young mice. From a previously conducted screen for generic drugs with antioxidant properties, we selected the antihypertensive CNS-penetrant medication indapamide for investigation. We report that indapamide reduced superoxide derived from microglia cultures and that treatment of middle-aged mice with indapamide was associated with a decrease in age-exacerbated lipid peroxidation, demyelination and axon loss. In summary, age-exacerbated acute injury following lysolecithin administration is mediated in part by microglia NADPH oxidase activation, and this is alleviated by the CNS-penetrant antioxidant, indapamide.SIGNIFICANCE STATEMENT Age is associated with an increased risk for the development of several neurologic conditions including progressive multiple sclerosis, which is represented by substantial microglia activation. We demonstrate that in the lysolecithin demyelination model in young and middle-aged mice, the latter group developed greater acute axonal and myelin loss attributed to elevated oxidative stress through NADPH oxidase in lineage-traced microglia. We thus used a CNS-penetrant generic medication used in hypertension, indapamide, as we found it to have antioxidant properties in a previous drug screen. Following lysolecithin demyelination in middle-aged mice, indapamide treatment was associated with decreased oxidative stress and axon/myelin loss. We propose indapamide as a potential adjunctive therapy in aging-associated neurodegenerative conditions such as Alzheimer's disease and progressive multiple sclerosis.

Efficacy and safety of immune checkpoint blockade in self-identified Black patients with advanced non-small cell lung cancer.

BACKGROUND: To the authors' knowledge, race-based differences in efficacy for the treatment of patients with advanced non-small cell lung cancer (NSCLC) have not been studied to date due to the underrepresentation of patients of minority backgrounds in pivotal trials. In the current study, the authors examined real-world differences in outcome in a diverse patient population. METHODS: The authors retrospectively analyzed the clinical outcomes of patients with advanced NSCLC who were treated with single-agent immune checkpoint blockade (ICB) between 2013 and July 2018 at Winship Cancer Institute of Emory University in Atlanta, Georgia. Primary efficacy comparison between Black patients and White patients was performed using bivariate and multivariate analyses for overall survival (OS) and progression-free survival (PFS). RESULTS: Data from 257 patients were analyzed. The median age of the patients was 69 years; 50.6% of the patients were female, 63.4% were White, 29.5% were Black, and 7.1% of the patients were of "other" race. ICB was the first-line treatment in 51 patients (19.9%), the second-line treatment in 161 patients (62.6%), and the third-line treatment in 33 patients (12.9%). The most commonly used agents were nivolumab (49.0%), pembrolizumab (25.2%), and atezolizumab (21.3%). No differences with regard to OS (P = .839) and PFS (P = .235) were noted between Black and White patients. The sample overall response rate was 20.6% (15.2% in Black patients and 23.1% in White patients). No differences with regard to OS (P = .081) and PFS (P = .176) were observed between female and male patients. The rate of immune-related adverse events was found to be similar in Black and White patients (20.0% vs 29.9%; P = .148). On multivariate analysis, race was not found to be significantly associated with OS or PFS. CONCLUSIONS: Real-world analysis of the authors' institutional experience demonstrated similar efficacy and tolerability of ICB in Black versus White patients with advanced NSCLC. Larger multi-institutional studies including other US minority populations would make the findings of the current study more generalizable.

The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination.

BACKGROUND: Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of axonal regrowth and remyelination. More recently, they have also been highlighted as a modulator of macrophage infiltration into the central nervous system in experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. METHODS: We interrogated results from single nucleotide polymorphisms (SNPs) lying in or close to genes regulating CSPG metabolism in the summary results from two publicly available systematic studies of multiple sclerosis (MS) genetics. A demyelinating injury model in the spinal cord of exostosin-like 2 deficient  (EXTL2-/-) mice was used to investigate the effects of dysregulation of EXTL2 on remyelination. Cell cultures of bone marrow-derived macrophages and primary oligodendrocyte precursor cells and neurons were supplemented with purified CSPGs or conditioned media to assess potential mechanisms of action. RESULTS: The strongest evidence for genetic association was seen for SNPs mapping to the region containing the glycosyltransferase exostosin-like 2 (EXTL2), an enzyme that normally suppresses CSPG biosynthesis. Six of these SNPs showed genome-wide significant evidence for association in one of the studies with concordant and nominally significant effects in the second study. We then went on to show that a demyelinating injury to the spinal cord of EXTL2-/- mice resulted in excessive deposition of CSPGs in the lesion area. EXTL2-/- mice had exacerbated axonal damage and myelin disruption relative to wild-type mice, and increased representation of microglia/macrophages within lesions. In tissue culture, activated bone marrow-derived macrophages from EXTL2-/- mice overproduce tumor necrosis factor α (TNFα) and matrix metalloproteinases (MMPs). CONCLUSIONS: These results emphasize CSPGs as a prominent modulator of neuroinflammation and they highlight CSPGs accumulating in lesions in promoting axonal injury.

Biological and Clinical Significance of the CCR5/CCL5 Axis in Hepatocellular Carcinoma.

Despite the improvement in survival for patients with liver cancer (LCa) in recent decades, only one in five patients survive for 5 years after diagnosis. Thus, there is an urgent need to find new treatment options to improve patient survival. For various cancers, including LCa, the chemokine CCL5 (RANTES) facilitates tumor progression and metastasis. Since the function of the CCR5/CCL5 interaction in LCa cell proliferation and migration is poorly understood, the present study was undertaken to investigate the role of the CCR5/CCL5 axis in these processes. Flow cytometry, RT-PCR, Western blot, and immunofluorescence techniques were used to quantify the expression of CCR5 and CCL5 in LCa cells. To determine the biological significance of CCR5 expressed by LCa cell lines, a tissue microarray of LCas stained for CCR5 and CCL5 was analyzed. The results showed higher expression (p < 0.001) of CCR5 and CCL5 in hepatocellular carcinoma (HCC) tissues compared to non-neoplastic liver tissues. Furthermore, to delineate the role of the CCR5/CCL5 interaction in LCa cell proliferation and migration, various LCa cells were treated with maraviroc, a CCR5 antagonist, in the presence of CCL5. These data demonstrated the biological and clinical significance of the CCR5/CCL5 axis in LCa progression. The targeting of this axis is a promising avenue for the treatment of LCa.

Control of brain tumor growth by reactivating myeloid cells with niacin.

Glioblastomas are generally incurable partly because monocytes, macrophages, and microglia in afflicted patients do not function in an antitumor capacity. Medications that reactivate these macrophages/microglia, as well as circulating monocytes that become macrophages, could thus be useful to treat glioblastoma. We have discovered that niacin (vitamin B3) is a potential stimulator of these inefficient myeloid cells. Niacin-exposed monocytes attenuated the growth of brain tumor-initiating cells (BTICs) derived from glioblastoma patients by producing anti-proliferative interferon-α14. Niacin treatment of mice bearing intracranial BTICs increased macrophage/microglia representation within the tumor, reduced tumor size, and prolonged survival. These therapeutic outcomes were negated in mice depleted of circulating monocytes or harboring interferon-α receptor-deleted BTICs. Combination treatment with temozolomide enhanced niacin-promoted survival. Monocytes from glioblastoma patients had increased interferon-α14 upon niacin exposure and were reactivated to reduce BTIC growth in culture. We highlight niacin, a common vitamin that can be quickly translated into clinical application, as an immune stimulator against glioblastomas.

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

miRNA551b-3p Activates an Oncostatin Signaling Module for the Progression of Triple-Negative Breast Cancer.

Genomic amplification of 3q26.2 locus leads to the increased expression of microRNA 551b-3p (miR551b-3p) in triple-negative breast cancer (TNBC). Our results demonstrate that miR551b-3p translocates to the nucleus with the aid of importin-8 (IPO8) and activates STAT3 transcription. As a consequence, miR551b upregulates the expression of oncostatin M receptor (OSMR) and interleukin-31 receptor-α (IL-31RA) as well as their ligands OSM and IL-31 through STAT3 transcription. We defined this set of genes induced by miR551b-3p as the "oncostatin signaling module," which provides oncogenic addictions in cancer cells. Notably, OSM is highly expressed in TNBC, and the elevated expression of OSM associates with poor outcome in estrogen-receptor-negative breast cancer patients. Conversely, targeting miR551b with anti-miR551b-3p reduced the expression of the OSM signaling module and reduced tumor growth, as well as migration and invasion of breast cancer cells.

Fiber length and concentration: Synergistic effect on mechanical and cellular response in wet-laid poly(lactic acid) fibrous scaffolds.

In the area of biomaterials, fibers not only offer increased mechanical response, but also serve as an extracellular matrix mimicking morphology to direct cellular attachment and proliferation. While biologically similar in morphology, soft, and flexible hydrogel materials have low mechanical properties. For applications in tissue engineering, the lack of directional cues and attachment regions within the biogels is undesired as cells require a guide for adequate attachment and organized proliferation. In this work, we have investigated the role of poly(lactic acid) (PLA) fiber length and concentration as a reinforcement phase in a gelatin hydrogel matrix and the resultant mechanical and cellular responses. With increasing fiber length and concentration, the ultimate tensile strength, modulus, and toughness increased for the samples. Similarly, for shorter fiber lengths, the loss and storage modulus increased with fiber concentration. After seeding human mesenchymal stem cells (hMSCs) onto the neat fibrous scaffolds it was found that the fabrication process imparted no cytotoxicity. Furthermore, it was the concentrations and lengths of fiber both caused discernable differences in cell viability at the extreme values. Fibers of all lengths, when in a 4.0 wt % concentration, had a decrease in cell viability after 10 days while the 12.7 mm fibers showed a similar response at 2.0 wt %, but all stayed about 90% viability. With increased incubation time, hMSCs became elongated with increased proliferation. These results indicate that the wet-lay process is a rapid and scalable method by which fibrous 3D-scaffolds can be produced to reinforce hydrogel matrices. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 332-341, 2019.

Hsp70 and gama-Semino protein as possible prognostic marker of prostate cancer.

In the United States, Prostate Cancer (PCa) is the leading cause of cancer-related mortality in men. PCa resulted in abnormal growth and function of prostate gland such as secretion of high level of gamma-seminoprotein (gama-SM)/Prostate-Specific Antigen (PSA) which could be detected in the blood. Beside gama-SM protein, the levels of heat shock proteins (Hsp70) were also observed significantly high. Therefore, gama-SM and Hsp70 are unique proteins with high potential for PCa therapeutics and diagnostics. High level of Hsp70 suppresses apoptosis, thus allowing PCa cells to exist; however, depletion of Hsp70 induces apoptosis in PCa cells. Gama-SM is the most prominent biomarker for PCa screening; however, its accuracy is still questionable. Thus, a more suitable streamline biomarker for PCa screening is urgently needed. Hsp70 and gama-SM proteins could be used as a revolutionary biomarker for PCa, and could help to identify possible therapeutic target(s). In this review article we will discuss the relationship between the Hsp70 and gama-SM proteins with PCa, their potential as a dual biomarker, and the possibility for both proteins being used as therapeutic targets.

Differential role of CXCR3 in inflammation and colorectal cancer.

Chemokines (CXCR3) and their ligands (CXCL9, CXCL10, and CXCL11) exert exquisite control over T-cell trafficking and are critical for activation, differentiation and effector T cell function. CXCR3 is important for CD4 Th1 cells, CD8 effectors, memory cells, and for the function of natural killer and natural killer T cells. The presence of high cytotoxic CXCR3 ligand expression on CD8 T cells in colorectal cancerous tissue has been well documented in the past. CXCR3 and its ligands are differentially expressed at sites of inflammation and within the tumors. Further, the expression of CXCR3 and its ligands has been correlated with both the presence of effector T cells within tumor tissue and disease-free survival of patients. However, effector T cell infiltration into primary and metastatic tumors is highly variable and, in fact, often absent. Thus, understanding why T cells fail to infiltrate into tumors and determining the way to improve effector T cell entry into tumors would be important advances in efforts to harness the power of the immune system to fight cancer. To this end, the recent exciting discovery that CXCR3 is functionally expressed on regulatory T cells and also induces the differentiation of peripheral CD4 T cells into regulatory T cells, might address the novel clinically relevant question of the therapeutic potential of the CXCR3 system. This is also coupled with the fact that increases in CXCR3 expression also improves effector T cell function. This review describes the differential role of CXCR3 induction on peripheral and tumor microenvironment inflammation. Further, this review, tied with important findings from our laboratory, demonstrates that polyphenols induce CXCR3 expression on regulatory T cells and increases CXCR3 ligands in the tumor microenvironment, which act together to suppress colorectal cancer through a differential mechanism discussed herewith.

Pediatric oral formulation of dendrimer-N-acetyl-l-cysteine conjugates for the treatment of neuroinflammation.

N-Acetyl-l-cysteine (NAC) commonly used as an antidote in acetaminophen poisoning has shown promise in the treatment of neurological disorders such as cerebral palsy (CP). However, NAC suffers from drawbacks such as poor oral bioavailability and suboptimal blood-brain-barrier (BBB) permeability limiting its clinical success. It was previously demonstrated that intravenous administration of dendrimer-NAC (D-NAC) conjugates have shown significant promise in the targeted treatment of neuroinflammation, in multiple preclinical models. Development of an oral formulation of D-NAC may open new administrative routes for this compound. Here, we report the gastrointestinal stability, in vitro transepithelial permeability, and in vivo oral absorption and pharmacokinetics in rats of a pediatric formulation of D-NAC containing Capmul MCM (glycerol monocaprylate) as a penetration enhancer. D-NAC was stable for 6 h in all five simulated gastrointestinal fluids with no signs of chemical degradation. The apparent permeability (Papp) of D-NAC increased 9-fold in the formulation containing Capmul. The area under the curve [AUC]0-∞ of D-NAC with Capmul increased by 47% when compared to D-NAC alone. These results indicate that an oral pediatric formulation containing D-NAC and Capmul can be an effective option for the treatment of neuroinflammation.

Chondroitin sulfate proteoglycans as novel drivers of leucocyte infiltration in multiple sclerosis.

Multiple sclerosis presents with profound changes in the network of molecules involved in maintaining central nervous system architecture, the extracellular matrix. The extracellular matrix components, particularly the chondroitin sulfate proteoglycans, have functions beyond structural support including their potential interaction with, and regulation of, inflammatory molecules. To investigate the roles of chondroitin sulfate proteoglycans in multiple sclerosis, we used the experimental autoimmune encephalomyelitis model in a time course study. We found that the 4-sulfated glycosaminoglycan side chains of chondroitin sulfate proteoglycans, and the core protein of a particular family member, versican V1, were upregulated in the spinal cord of mice at peak clinical severity, correspondent with areas of inflammation. Versican V1 expression in the spinal cord rose progressively over the course of experimental autoimmune encephalomyelitis. A particular structure in the spinal cord and cerebellum that presented with intense upregulation of chondroitin sulfate proteoglycans is the leucocyte-containing perivascular cuff, an important portal of entry of immune cells into the central nervous system parenchyma. In these inflammatory perivascular cuffs, versican V1 and the glycosaminoglycan side chains of chondroitin sulfate proteoglycans were observed by immunohistochemistry within and in proximity to lymphocytes and macrophages as they migrated across the basement membrane into the central nervous system. Expression of versican V1 transcript was also documented in infiltrating CD45+ leucocytes and F4/80+ macrophages by in situ hybridization. To test the hypothesis that the chondroitin sulfate proteoglycans regulate leucocyte mobility, we used macrophages in tissue culture studies. Chondroitin sulfate proteoglycans significantly upregulated pro-inflammatory cytokines and chemokines in macrophages. Strikingly, and more potently than the toll-like receptor-4 ligand lipopolysaccharide, chondroitin sulfate proteoglycans increased the levels of several members of the matrix metalloproteinase family, which are implicated in the capacity of leucocytes to cross barriers. In support, the migratory capacity of macrophages in vitro in a Boyden chamber transwell assay was enhanced by chondroitin sulfate proteoglycans. Finally, using brain specimens from four subjects with multiple sclerosis with active lesions, we found chondroitin sulfate proteoglycans to be associated with leucocytes in inflammatory perivascular cuffs in all four patients. We conclude that the accumulation of chondroitin sulfate proteoglycans in the perivascular cuff in multiple sclerosis and experimental autoimmune encephalomyelitis boosts the activity and migration of leucocytes across the glia limitans into the central nervous system parenchyma. Thus, chondroitin sulfate proteoglycans represent a new class of molecules to overcome in order to reduce the inflammatory cascades and clinical severity of multiple sclerosis.

CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells.

Pancreatic cancer (PC) is one of the deadliest cancers and remains a major challenge due to its invasive and metastatic nature. Increased levels of CCR5 and CCL5 have established indicators for disease status in various cancers, including PC. However, their role in invasion and metastasis of PC is not known. Here we conducted immunohistochemistry of PC tissues and found elevated epithelial staining for CCR5 and CCL5 in metastatic PC tissues compared to non-neoplastic. In vitro experiments, such as flow cytometry, immunofluorescence and western blotting with human PC cell lines (AsPc-1, BxPc-3 and MIA PaCa-2), showed higher expression levels of CCR5. The CCL5 activation of PC cells expressing CCR5 increased their invasive potential, while treatment with CCR5 inhibitor maraviroc inhibited the CCL5 activation. CCL5 induced proliferation of PC cells was mediated through F-actin polymerization, while there was marked reduction when the cells were treated with maraviroc. The direct interaction of CCR5 with CCL5 was verified using a calcium mobilization assay. Taken together, our results demonstrate that CCR5 and CCL5 are potential markers for metastatic PC cancer, and their interaction leads to the increased PC cell invasion. Thus, blocking CCR5/CCL5 axis might prove beneficial to prevent metastasis and provide a more therapeutic strategy to control PC progression.

Enhanced hepatogenic differentiation of bone marrow derived mesenchymal stem cells on liver ECM hydrogel.

Bone marrow derived mesenchymal stem cells (BM-MSC) is a promising alternative cell source to primary hepatocytes because of their ability to differentiate into hepatocyte-like cells. However, their inability to differentiate efficiently and potential to turn into myofibroblasts restrict their applications. This study developed a plate coating from the liver extracellular matrix (ECM) and investigated its ability in facilitating the BM-MSCs proliferation, hepatic differentiation, and hepatocyte-specific functions during in vitro culture. After 28-day culture, BM-MSCs on the ECM coating showed hepatocyte-like morphology, and certain cells took up low-density lipoprotein. Synthesis of albumin, urea, and anti-alpha-fetoprotein, as well as expression of certain hepatic markers, in cells cultured on ECM were higher than cells cultured on non-coated and Matrigel-coated plates. mRNA levels of CYP3A4, albumin, CK18, and CYP7A1 in cells on ECM coating were significantly higher than cells cultured on the non-coating environment. In conclusion, viability and hepatogenic differentiation of BM-MSCs cultured on both Matrigel and ECM coating were significantly enhanced compared with those cultured on non-coated plates. Moreover, the liver ECM coating induced additional metabolic functions relative to the Matrigel coating. The liver ECM hydrogel preserves the natural composition, promotes simple gelling, induces efficient stem cell hepatogenic differentiation, and may have uses as an injectable intermedium for hepatocytes. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 829-838, 2018.