Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

Affinity-matured DLL4 ligands as broad-spectrum modulators of Notch signaling.

The Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, DeltaMAX, binds human and murine Notch receptors with 500- to 1,000-fold increased affinity compared with wild-type human Delta-like 4. DeltaMAX also potently activates Notch in plate-bound, bead-bound and cellular formats. When administered as a soluble decoy, DeltaMAX inhibits Notch in reporter and neuronal differentiation assays, highlighting its dual utility as an agonist or antagonist. Finally, we demonstrate that DeltaMAX stimulates increased proliferation and expression of effector mediators in T cells. Taken together, our data define DeltaMAX as a versatile tool for broad-spectrum activation or inhibition of Notch signaling.

An Organic Molecular Nanobarrel that Hosts and Solubilizes C60.

Organic cages have gained increasing attention in recent years as molecular hosts and porous materials. Among these, barrel-shaped cages or molecular nanobarrels are promising systems to encapsulate large hosts as they possess windows of the same size as their internal cavity. However, these systems have received little attention and remain practically unexplored despite their potential. Herein, we report the design and synthesis of a new trigonal prismatic organic nanobarrel with two large triangular windows with a diameter of 12.7 Šoptimal for the encapsulation of C60 . Remarkably, this organic nanobarrel shows a high affinity for C60 in solvents in which C60 is virtually insoluble, providing stable solutions of C60 .

Photocycloaddition as a Tool for Modulation of the Lower Critical Solution Temperature in a Molecular π-System to Control Transmission of Solar Radiation.

Diels-Alder photocycloaddition, a well-known textbook reaction, has not been explored in materials chemistry. Herein we describe how this classical photochemistry can be used to modulate the lower critical solution temperature (LCST) of a molecular π-system, which can further be exploited for the controlled transmission of solar radiation for the management of indoor heat and light. An amphiphilic anthracene derivative 9-PA-1 exhibited LCST behavior at 27-32 °C with a reversible transition from a transparent to an opaque phase in water (1-5 mM). Irradiation of a toluene solution of 9-PA-1 with 365 nm light resulted in a [4+2] photocycloadduct 9-PA-2, which exhibited a modulated LCST behavior at 25-27 °C, at a concentration as low as 6 µM. The photocycloaddition of 9-PA-1 was significantly retarded in water, making it a stable candidate for the design of sustainable smart windows. We also demonstrated 100 cm2 smart window prototypes (ΔTlum 82 %, ΔTIR 68 %, ΔTsol 73 %) with more than 1000 cycles of stable operation.

Supramolecular Gel Phase Controlled [4 + 2] Diels-Alder Photocycloaddition for Electroplex Mediated White Electroluminescence.

Diels-Alder photocycloaddition of 9-phenylethynylanthracene results in multiple [4 + 2] and [4 + 4] cycloaddition products in solution, which can be controlled to form specific products under a restricted environment. We have exploited the gel phase of a 9-phenylethynylanthracence derivative as a confined medium to specifically yield the [4 + 2] cycloadduct in >90% yield. The photocycloadduct ( anti-form) exhibited a blue emission with CIE chromaticity of x = 0.16/ y = 0.16. Construction of an organic light emitting device with the photocycloadduct, using a carbazole-based hole transporting host, resulted in white light emission with a CIE chromaticity of x = 0.33/ y = 0.32. This observation not only highlights the use of gel chemistry to achieve the otherwise difficult to obtain photoproducts but also underlines their potential in optoelectronic device fabrication.

Modulation of cell death in human colorectal and breast cancer cells through a manganese chelate by involving GSH with intracellular p53 status.

Chemotherapy is central to current treatment modality especially for advanced and metastatic colorectal and breast cancers. Targeting the key molecular events of the neoplastic cells may open a possibility to treat cancer. Although some improvements in understanding of colorectal and breast cancer treatment have been recorded, the involvement of glutathione (GSH) and dependency of p53 status on the modulation of GSH-mediated treatment efficacy have been largely overlooked. Herein, we tried to decipher the underlying mechanism of the action of Mn-N-(2-hydroxyacetophenone) glycinate (MnNG) against differential p53 status bearing Hct116, MCF-7, and MDA-MB-468 cells on the backdrop of intracellular GSH level and reveal the role of p53 status in modulating GSH-dependant abrogation of MnNG-induced apoptosis in these cancer cells. Present study discloses that MnNG targets specifically wild-type-p53 expressing Hct116 and MCF-7 cells by significantly depleting both cytosolic, mitochondrial GSH, and modulating nuclear GSH through Glutathione reductase and Glutamate-cysteine ligase depletion that may in turn induce p53-mediated intrinsic apoptosis in them. Thus GSH addition abrogates p53-mediated apoptosis in wild-type-p53 expressing cells. GSH addition also overrides MnNG-induced modulation of phase II detoxifying parameters in them. However, GSH addition partially replenishes the down-regulated or modulated GSH pool in cytosol, mitochondria, and nucleus, and relatively abrogates MnNG-induced intrinsic apoptosis in p53-mutated MDA-MB-468 cells. On the contrary, although MnNG induces significant cell death in p53-null Hct116 cells, GSH addition fails to negate MnNG-induced cell death. Thus p53 status with intracellular GSH is critical for the modulation of MnNG-induced apoptosis.

A Novel Approach of Synthesizing and Evaluating the Anticancer Potential of Silver Oxide Nanoparticles in vitro.

BACKGROUND: Development of novel strategies to kill cancer by sparing normal cells is of utmost importance. Apart from their known antimicrobial activity, only limited information has been recorded regarding the antitumor potential of biocompatible silver oxide nanoparticles (AgONPs). There is a need to evaluate the anticancer potential of biocompatible AgONPs in vitro. METHODS: A new approach of utilizing the leaf extract of Excoecaria agallocha was used to synthesize AgONPs. This was then characterized by ultraviolet-visible spectrophotometry, nanoparticle-tracking analysis, and ζ-potential analysis. Cytotoxicity and apoptotic potential were evaluated with an MTT assay and an annexin V-binding assay against the murine melanoma (B16F10), murine colon cancer (CT26), murine lung adenocarcinoma (3LL), and murine Ehrlich ascites carcinoma (EAC) cell lines. Cellular localization of AgONPs was evaluated on fluorescence microscopy. RESULTS: UV peaks at 270 and 330 nm indicated the formation of nanoparticles (NPs) and the NP-tracking analyzer revealed them to have a size of 228 nm. AgONPs exerted initial cytotoxicity, specifically against all the experimental malignant cells by sparing the normal cell lines. Moreover, AgONPs exert apoptosis equally on all the malignant cells in vitro and ex vivo. This cytotoxicity possibly occurs via the nuclear translocation of AgONPs as analyzed in B16F10 cells. CONCLUSIONS: AgONPs utilizing natural sources would be a new medicinal approach against a broad spectrum of malignancy.

In vitro and in vivo Anticancer Effects of a Novel 9-Phenyldibenzo[a,c]phenazin-9-ium Cation and Its Ligands.

BACKGROUND: Multidrug resistance (MDR) is a major problem in cancer treatment. Cu complexes possess the ability to overcome MDR in cancer. Therefore, the search for new Cu complexes is of great clinical significance and we address the anticancer effects of a previously synthesized novel 9-phenyldibenzo[a,c]phenazin-9-ium cation [1(+)] as [1] [CuCl2] and as [1] [I]. METHODS: The existence of the monovalent Cu(I) in [1] [CuCl2] was proven by electron paramagnetic resonance (EPR) studies and in vivo anticancer effects were studied in animals. RESULTS: The monovalent nature of the Cu ion in [1] [CuCl2] was determined through EPR. The mean survival time of mice bearing doxorubicin-resistant Ehrlich ascites carcinoma cells is longer when [1] [I] is injected intraperitoneally whereas [1] [CuCl2] does not significantly increase the median survival in tumor-bearing mice. Compounds do not follow the immunomodulatory route and only [1] [I] shows cytotoxic activity in both MDR and drug-sensitive leukemia cell lines. CONCLUSION: An organic iodide complex rather than a cupric complex possesses direct cytotoxic potential.

A copper chelate selectively triggers apoptosis in myeloid-derived suppressor cells in a drug-resistant tumor model and enhances antitumor immune response.

Myeloid-derived suppressor cells (MDSCs), one of the major orchestrators of immunosuppressive network are present in the tumor microenvironment suppress antitumor immunity by subverting Th1 response in tumor site and considered as a great obstacle for advancement of different cancer immunotherapeutic protocols. Till date, various pharmacological approaches have been explored to modulate the suppressive functions of MDSCs in vivo. The present study describes our endeavor to explore a possibility of eradicating MDSCs by the application of a copper chelate, namely copper N-(2-hydroxy acetophenone) glycinate (CuNG), previously found to be a potential immunomodulator that can elicit antitumorogenic Th1 response in doxorubicin-resistant EAC (EAC/Dox) bearing mice. Herein, we demonstrated that CuNG treatment could reduce Gr-1+CD11b+ MDSC accumulation in ascitic fluid and spleen of EAC/Dox tumor model. Furthermore, we found that CuNG mediated reduction in MDSCs is associated with induction of Th1 response and reduction in Treg cells. Moreover, we observed that CuNG could deplete MDSCs by inducing Fas-FasL mediated apoptotic cell death where death receptor Fas expression is enhanced in MDSCs and FasL is provided by activated T cells. However, MDSC expansion from bone marrow cells and their differentiation was not affected by CuNG. Altogether, these findings suggest that the immunomodulatory property of CuNG is attributed to, at least in part, by its selective cytotoxic action on MDSCs. So, this preclinical study unveils a new mechanism of regulating MDSC levels in drug-resistant cancer model and holds promise of translating the findings into clinical settings.

Identifying citrus limonoids as a potential fusion inhibitor of DENV-2 virus through its in silico study and FTIR analysis.

Dengue virus type 2 (DENV-2) is an arthropod-borne deadly RNA human pathogen transmitted through the mosquito Aedes. The DENV-2 roots viral infection by facilitating entry with its envelope glycoprotein to the receptor protein Dendritic-cell-specific ICAM3-grabbing non-integrin (DC-SIGN) through membrane fusion. Here, an organizational path is reported for inhibiting the transition due to fusion activation and by blocking the residues of the DC-SIGN-E-Glyco protein complex through citrus limonoids with its antiviral effect. Based on lower binding affinity obtained with E-glycoprotein, and based on ADMET and drug-likeness study, limonin was selected as having effective interaction with DC-SIGN-E-glycoprotein complex in comparison to other citrus limonoids. The FTIR spectra performed with the limonin-E-glycoprotein sample provide evidence of hydrogen bond formation that indicates the formation of a strong limonin-E-glycoprotein conjugate. Further, the strong physical interaction between DC-SIGN and small limonin molecules in comparison to that of E-glyco with DC-SIGN assures the development of immunity against DENV-2. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00207-2.

Rapid diagnosis of COVID-19 using disposal paper capacitive sensor.

Accurate and rapid detection and isolation become indispensable to restrict the spread of COVID-19. Since the start of COVID-19 pandemic in December 2019, many indisposal diagnostic tools are being developed incessantly. Out of all presently used tools, the gold standard rRT- PCR tool having very high sensitivity and specificity is a time consuming complicated molecular technique having requirements of special expensive equipment. Here, the main focus of this work is to develop rapid disposal paper capacitance sensor having simple and easy detection. We discovered a strong interaction between limonin and Spike-glycoprotein of SARS-COV-2 in comparison to its interaction with other similar viruses such as HCOV-OC43, HCOV-NL63, HCOV-HKU1, Influenza B and A viruses. The antibody free capacitive sensor having comb electrode structure was fabricated on whatman paper with drop coating of limonin (extracted using green method from pomelo seeds) and calibrated with known swab samples. The Blind test with unknown swab samples shows high sensitivity of 91.5% and high specificity of 88.37%. Requiring low sample volume and detection time and using biodegradable materials in the sensor fabrication assure the potential application as a point of care disposal diagnostic tool.

A novel electrochemical interdigitated electrodes sensor for limonin quantification and reduction in citrus limetta juice.

Limonin, a highly oxygenated triterpene biomolecule of citrus fruits is responsible for delayed bitterness of its juice lowering consumer's acceptability. Hence, limonin detection is essential for appropriate debittering intrusions. A novel interdigitated capacitive sensor using magnesium silicate-poly vinyl alcohol (MgSiO3.xH2O-PVA) composite has been introduced for quantification of limonin and debittering through selective adsorption of limonin from the citrus limetta juice. The sensor showed high sensitivity of 2.392 µF/ppm and fast response time of ∼6s. The sensor enables both quantification as well as measure debittering of citrus juice showing a reduction in limonin content from 5.77 ppm to 4.29 ppm with an exposure time of 60s to the sensing material making it distinctive in comparison to other methods. The sensor's results were validated with HPLC analysis. The device is simple, low-cost and reusable which promises easy, on-site and rapid quantification and reduction of limonin content in citrus juices without having toxicity.

Design and development of IDE sensor for naringin quantification in pomelo juice: An indicator of citrus maturity.

Maturity determination of pomelo fruits having health-benefiting attributes is an important issue to enhance the quality of harvesting. Here, an interdigitated electrode (IDE) based sensor is introduced to detect its maturity by determining the naringin content. The sensor was made by depositing amberlite IRA-400 as a sensing layer on IDE patterned PCB substrate at room temperature with hydrothermal and spin-coating techniques. The sensor exhibits excellent selectivity for naringin, high sensitivity of 0.008 µA for 10 ppb of naringin, and reusability up to 3-4 times for naringin quantification in maturity testing of fruits. The pomelo fruits start to mature when maximum values of current response and naringin content are found at 140 DAFS. The naringin content decreases as maturity progresses and maximum phytochemical attributes were obtained at 180-220 DAFS. The IDE sensor assures an appropriate period of plucking of pomelo fruits improving harvesting practices and trade of citrus fruits.

Structurally directed thienylenevinylene self-assembly for improved charge carrier mobility: 2D sheets vs. 1D fibers.

High charge carrier mobility is a prerequisite for organic electronics for which molecular arrangement and morphology play a vital role. Herein, we report how the self-assembly of thienylenevinylenes T1 and T2 can achieve morphologically distinct nanostructures with improved charge carrier mobility. Morphological analysis revealed that T1 forms 2D nanosheets that further extend to an array of hierarchical pseudo-1D assemblies, whereas T2 results in 1D nanofibers. Flash photolysis - time resolved microwave conductivity and transient absorption spectroscopy (FP-TRMC and TAS) revealed that 1D fibers of T2 show 1.75 fold higher charge carrier mobility (9.2 × 10-2 cm2 V-1 s-1) when compared to the array of 2D sheets obtained from T1 (5.0 × 10-2 cm2 V-1 s-1). This simple approach can be extended to design self-assembled organic photoconducting materials for optoelectronic applications.

Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.

Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61ß-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.

Risk of cardiovascular disease in HIV-infected patients.

The life expectancy of people living with HIV infection has improved dramatically since the use of highly active antiretroviral therapy (HAART). Now that patients with HIV infection are living longer, the focus of its treatment should shift to long-term management spanning decades. Diseases of ageing, including cardiovascular disease (CVD), have now become more important. The evidence of cardiovascular risk associated with HIV infection and antiretroviral therapy is explored and discussed in this article.

The Effect of Low Dose Oral Vitamin D on Bone Mineral Density Changes in HIV Patients: 36 Months Follow Up.

BACKGROUND: A high incidence of vitamin-D deficiency and abnormal bone mineral density (BMD) is reported among Human Immunodeficiency Virus (HIV) infected patients. The study highlighted the effect of oral low dose vitamin-D replacement in patients with a known vitamin- D deficiency on the levels of vitamin-D [25 (OH)D], parathyroid hormone (PTH) and Bone Mineral Density (BMD) of hip and spine. METHODS: Patients took a daily low dose of 800IU of vitamin-D. The following details were collected on all patients: demographics, CD-4 cell count, viral load, fracture risk factors, treatment history, corrected calcium, alkaline phosphatase (ALP), Parathyroid Hormone (PTH) (intact PTH), vitamin D 25(OH)D, inorganic phosphate and BMD of hip and spine at baseline, 12 and 36 months. RESULTS: Our Cohort consisted of 86 patients. Patient details included: mean age 42.8 (+/-7.7) years, 48 (55%) females 64, (74%) black African, CD-4 count 440.7 (+/-180.8) cells/dL, plasma VL 1.6 log (+/-2.3) copies/mL, duration of illness 80.9 (34.1) months, duration of exposure to antiretroviral 65.2 (+/-27.9) months. At baseline, no difference in BMD of hip or spine was observed, however, a higher PTH (0.001) in patients taking Tenofivir and a lower vitamin-D was noticed in patients taking Efavirenz. After 36 months, patients on vitamin D replacement (n=44) had a significant increase in vitamin- D level (15.4 +/-10.4 vs 104.1+/-29.1 p=0.0001), lower PTH (6.3 +/-3.4 vs 4.4 +/-1.4 p=0.0001) ALP (108.9+/-78.8 vs 90.6+/-45.8 p=0.05) but no change in corrected calcium (2.13 +/-0.1 vs 2.16 +/-0.34 p=0.5) and BMD of spine (1.039+/-0.226 vs.1.027+/-0.211, p=0.77), and BMD of hip (1.020 +/- 0.205 vs. 1.039, p=0.61). In a multivariate logistic regression analysis that included all significant variables, vitamin-D replacement independently was associated with increase in vitamin- D level (OR 2.08, CI 1.03, 4.12, p=0.005), decrease in PTH level (OR 0.53, CI 0.35, 0.82, p=0.04), but not with change in corrected calcium, alkaline phosphatase, BMD of hip or spine. CONCLUSION: After 36 months of follow up, the replacement of low dose once daily oral vitamin-D in the treatment experienced HIV infected patients with vitamin-D deficiency can increase vitamin- D level, reduce PTH level without any change in BMD of spine and hip.

Association of Low Vitamin D with Complications of HIV and AIDS: A literature Review.

With the advent of combination antiretroviral therapy (cART), the survival of HIV patients has improved dramatically, but the complications of the disease and treatment have become an important issue in the management of HIV patients. Vitamin-D deficiency is common in HIV patients. Low vitamin-D is associated with different comorbidities in the HIV uninfected general population. In this review, we first briefly describe vitamin D synthesis and mechanism of action and we focus on the epidemiological and clinical data dealing with the relationship between vitamin D deficiency in HIV infection with several comorbidities which has been found to be increasingly common in patients living with HIV infection. We searched the PubMed database using the keywords "HIV," "vitamin D" and other common disorders or conditions that are relatively common in HIV infection. The other conditions included in the search were osteoporosis and fracture, cardiovascular disease, diabetes and insulin resistance, active tuberculosis, hepatitis-C co-infection, and HIV disease progression. Articles presenting original data as well as systematic reviews and met analysis related to HIV population were included in our analysis. Vitamin-D deficiency seems to be associated with several adverse outcomes in HIV patients but a definite cause and effect relationship with vitamin-D is yet to be confirmed in most of the cases. However, the literature supporting the efficacy of vitamin-D supplementation is lacking.

Solution-processable and photopolymerisable TiO2 nanorods as dielectric layers for thin film transistors.

We report the fabrication of a solution-processed n-type Thin Film Transistor (TFT) with current on/off ratios of 104, a turn-on voltage (V ON) of 1.2 V and a threshold voltage (V T) of 6.2 V. The TFT incorporates an insoluble and intractable dielectric layer (k = 7-9) prepared in situ from solution-processed and then photopolymerised ligand-stabilised, inorganic/organic TiO2 nanorods. A solution processed zinc oxide (ZnO) layer acts as the semiconductor. The new surface-modified TiO2 nanorods were synthesised using a ligand replacement process with a monolayer coating of photopolymerisable 10-undecynylphosphonic acid (10UCYPA) to render them both soluble in common organic solvents and be photopolymerisable using UV-illumination after having been deposited on substrate surfaces from solution and drying.