Tuning Shortwave-Infrared J-aggregates of Aromatic Ring-Fused Aza-BODIPYs by Peripheral Substituents for Combined Photothermal and Photodynamic Therapies at Ultralow Laser Power.

Achieving photothermal therapy (PTT) at ultralow laser power density is crucial for minimizing photo-damage and allowing for higher maximum permissible skin exposure. However, this requires photothermal agents to possess not just superior photothermal conversion efficiency (PCE), but also exceptional near-infrared (NIR) absorptivity. J-aggregates, exhibit a significant redshift and narrower absorption peak with a higher extinction coefficient. Nevertheless, achieving predictable J-aggregates through molecular design remains a challenge. In this study, we successfully induced desirable J-aggregation (λabs max : 968 nm, ϵ: 2.96×105  M-1 cm-1 , λem max : 972 nm, ΦFL : 6.2 %) by tuning electrostatic interactions between π-conjugated molecular planes through manipulating molecular surface electrostatic potential of aromatic ring-fused aza-BODIPY dyes. Notably, by controlling the preparation method for encapsulating dyes into F-127 polymer, we were able to selectively generate H-/J-aggregates, respectively. Furthermore, the J-aggregates exhibited two controllable morphologies: nanospheres and nanowires. Importantly, the shortwave-infrared J-aggregated nanoparticles with impressive PCE of 72.9 % effectively destroyed cancer cells and mice-tumors at an ultralow power density of 0.27 W cm-2 (915 nm). This phototherapeutic nano-platform, which generates predictable J-aggregation behavior, and can controllably form J-/H-aggregates and selectable J-aggregate morphology, is a valuable paradigm for developing photothermal agents for tumor-treatment at ultralow laser power density.

Rhodium-Catalyzed Two-Fold, Regioselective and Enantioselective C-H Activation: an Efficient Strategy to Chiral Single-Benzene-Based Fluorophores.

A Rh-catalyzed two-fold, regioselective and enantioselective C-H activation via chiral transient directing group strategy has been demonstrated in moderate to good yields with commendable enantioselectivities. The newly synthesized chiral fluorophores exhibit favorable photophysical properties, including large Stokes shifts, good fluorescence quantum yields, aggregation-induced emission in aqueous solution, and intense emission and circularly polarized luminescence in the solid state, indicating great potential applications as chiral fluorescent probes or optoelectronic materials.

A phycoerythrin isolated from Rhodomonas salina induces apoptosis via ERK/Bak and JNK/Caspase-3 pathway in A549 cells.

Rhodomonas salina, Cryptophyta, Rhodomonas genus, is a valuable source for live feed in aquaculture and for the production of phycoerythrin (PE). In this study, PE was extracted from Rhodomonas salina and characterized as having a molecular weight of approximately 24 kDa, an absorbance at 545 nm, and a purity of up to 6.61 (which meets reagent grade requirements with an OD545/OD280 ratio >4). The effects of PE on anticancer activity and its underlying mechanisms were evaluated to assess the immunomodulatory potential on the human lung cancer A549 cell line. Biochemical assays and western blot analysis were applied to confirm the immune mechanisms. The results showed that after 24 h of exposure to PE, the proliferation of A549 cells was significantly and dose-dependently decreased. PE also caused the generation of reactive oxygen species (ROS) and a decrease in mitochondrial membrane potential (MMP). The further results showed that PE can remarkably enhance the protein levels of cleaved caspase-3 and p53. Simultaneously, the BCL-2 family was also affected and had some changes, such as the dramatically enhance of Bim and Bak and the decrease of Bcl-2 level. However, it is interesting to note that there was no apparent alteration in Bax expression during the experiment. Furthermore, the biological mechanism for the potential of PE to induce apoptosis showed that the ERK/Bak and the JNK/caspase-3 signaling pathway were activated. This study provides evidence that the anticancer activity of PE in Rhodomonas salina may have potential for preventing cancer and serving as a novel immunostimulant in the pharmaceutical industry.

Ribosome biogenesis in disease: new players and therapeutic targets.

The ribosome is a multi-unit complex that translates mRNA into protein. Ribosome biogenesis is the process that generates ribosomes and plays an essential role in cell proliferation, differentiation, apoptosis, development, and transformation. The mTORC1, Myc, and noncoding RNA signaling pathways are the primary mediators that work jointly with RNA polymerases and ribosome proteins to control ribosome biogenesis and protein synthesis. Activation of mTORC1 is required for normal fetal growth and development and tissue regeneration after birth. Myc is implicated in cancer development by enhancing RNA Pol II activity, leading to uncontrolled cancer cell growth. The deregulation of noncoding RNAs such as microRNAs, long noncoding RNAs, and circular RNAs is involved in developing blood, neurodegenerative diseases, and atherosclerosis. We review the similarities and differences between eukaryotic and bacterial ribosomes and the molecular mechanism of ribosome-targeting antibiotics and bacterial resistance. We also review the most recent findings of ribosome dysfunction in COVID-19 and other conditions and discuss the consequences of ribosome frameshifting, ribosome-stalling, and ribosome-collision. We summarize the role of ribosome biogenesis in the development of various diseases. Furthermore, we review the current clinical trials, prospective vaccines for COVID-19, and therapies targeting ribosome biogenesis in cancer, cardiovascular disease, aging, and neurodegenerative disease.

Aryl-Boron-Substituted BODIPYs: Direct Access via Aluminum-Chloride-Mediated Arylation from Arylstannanes and Tuning the Optoelectronic Properties.

An efficient procedure is presented for functionalization of BODIPYs at boron with arylstannanes as weak nucleophiles in the presence of aluminum chloride, providing new aryl-boron-substituted BODIPY and aza-BODIPY derivatives of singular importance. Most of these aryl-boron-substituted BODIPYs showed bright emission in the aqueous solution with significant aggregation-induced emission enhancement and high solid-state emission as a result of the restricted rotation of the meso-phenyl group and boron-substituted aryl groups as well as the formation of J-type aggregates.

Unique Double Intramolecular and Intermolecular Exciton Coupling in Ethene-Bridged aza-BODIPY Dimers for High-Efficiency Near-Infrared Photothermal Conversion and Therapy.

Spatial electronic communications of chromophores are both theoretically and practically fascinating. Despite intramolecular or intermolecular exciton coupling was observed in multichromophoric oligomers and J-aggregates, respectively, it is unusual that they both occur in the same molecule. Herein, ethene-bridged aza-BODIPY dimers with intramolecular exciton splitting have been developed. By encapsulating the dimer into F-127 polymer, J-type aggregated nanoparticles were produced, which showed obvious intermolecular exciton coupling and dramatically redshifted absorption and emission peaks at 936 and 1003 nm, respectively. The fabricated nanoagents have high photothermal conversion ability (η=60.3 %) and are ultra-photostable, leading to complete tumor ablation with 915 nm laser irradiation. This phototherapeutic nanoplatform through modulating both intra- and intermolecular exciton couplings is a valuable paradigm for developing photothermal agents for tumor treatment.

The Mechanisms Underlying the Beneficial Effects of Stem Cell-Derived Exosomes in Repairing Ischemic Tissue Injury.

Ischemic diseases are life-threatening, and the incidence increases as people's lifestyles change. Medications and surgical intervention offer limited benefit, and stem cell therapy has emerged as a potential approach for treating ischemic diseases. The exosomes secreted by stem cells have attracted more attention because they do not trigger the immune response and can be used as drug carriers. The non-coding RNA (ncRNA) carried by exosomes plays a key role in mediating exosome's beneficial effect, which can be further enhanced when combined with nanomaterials to improve its retention time. Here, we review the downstream target molecules and signal pathways of ncRNA and summarize recent advances of some nanomaterials used to encapsulate exosomes and promote ischemic tissue repair. We highlight the imprinting of exosomes from parent cells and discuss how the inflammasome pathway may be targeted for the development of novel therapy for ischemic diseases.

B2M mutation paves the way for immune tolerance in pathogenesis of Epstein-Barr virus positive diffuse large B-cell lymphomas.

This study focused genetic pathogenesis and tumor microenvironment of Epstein-Barr virus (EBV) positive diffuse large B-cell lymphomas (DLBCL) in patients without immunodeficiency. DNA samples from these cases were sequenced by next generation sequencing (NGS) using a selected gene panel. Results revealed that most gene mutations were not specific for EBV positive DLBCL. However, B2M (ß2-microglobulin) mutations were significantly increased and HLA-I or HLA-II expression was decreased in these cases, which was related to patient's poor outcome. B2M mutations and deregulation of B2M expression were further confirmed by Sanger sequencing and immunohistochemistry. Reducing the infiltration of CD8+ T lymphocytes, related to decreased expression of HLA-I or HLA-II was found in these patients. These results suggest that the mutations of B2M could cause the disruption of the expression and functions of this important subunit of HLA, leading to decreased expression of HLA-I or HLA-II and subsequently to reduce T lymphocyte infiltration in tumor tissues. The consequence of this event lessens the recognition and elimination of EBV+ tumor cells by host immunity and paves the way for the host immune tolerance to EBV+ tumor cells by evading immune recognition and escaping the T lymphocyte killing.

One-Pot Access to Ethylene-Bridged BODIPY Dimers and Trimers through Single-Electron Transfer Chemistry.

A Cu(I)-promoted oxidative dimerization of BODIPY dyes was developed to give a series of α,α- ethylene-bridged BODIPY dimers and trimers for the first time. This methodology does not need harsh conditions but relies on the singlet-electron-transfer process between alkylated BODIPYs and Cu(I) salt to generate BODIPY-based radical species, which undergo a selective radical homocoupling reaction. Moreover, these resultant dimers and trimers showed high attenuation coefficients, small line widths of the absorption and emission, and intense fluorescence.

Aggregative Perivascular Tumor Cell Growth Pattern of Primary Central Nervous System Lymphomas Is Associated with Hypoxia-Related Endoplasmic Reticulum Stress.

Primary central nervous system lymphomas (PCNSLs) often present a unique histopathological feature of aggregative perivascular tumor cells (APVT). Our previous studies showed that patients of PCNSL with APVTs exhibited poor long-term outcomes and increased expression of the endoplasmic reticulum stress (ERS) factor X-box-binding protein (XBP1). However, very little is known about molecular mechanism of the APVT formation in PCNSLs. The aim of this study is to determine if hypoxia-induced ERS is related to the APVT formation in PCNSLs. In this study, cell culture was used to observe the interplay between diffuse large B cell lymphoma (DLBCL) tumor cells and human brain microvascular endothelial cells (HBMECs) in different oxygen conditions. The expression of XBP1, CXCR and CD44 was manipulated by molecular cloning and siRNA technology. Mouse in vivo experiments and clinical studies were conducted to confirm our hypothesis. Our results showed that activated B-cell type-DLBCL cells easily migrated and invaded, and expressed high levels of XBP1 and stromal molecules CXCR4 and CD44 during hypoxia-induced ERS and dithiothreitol unfolded protein response (UPR). The gene upregulation (using overexpression vector) and downregulation (siRNA gene knock-out) in cultured cells and in mouse models further confirmed a close relation of the expression of XBP1, CXCR4, and CD44 with APVT formation, which is coincided with our clinical observation that increased expression of XBP1, CXCR4, and CD44 in the APVT cells in PCNSLs were associated with poor clinical outcomes. The results suggest that hypoxia-induced ERS and UPR might be associated with APVTs formation in PCNSL and its poor clinical outcomes. The results will help us better understand the progression of PCNSL with APVTs feature in daily pathological work and could be valuable for future target treatment of PCNSLs.

SAMHD1 Mutations and Expression in Mantle Cell Lymphoma Patients.

SAMHD1 (sterile alpha motif domain and histidine-aspartate domain-containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase regulating innate immune and modulating DNA damage signaling. It plays an important role in the development of some tumors. SAMHD1 was also reported as a barrier to cytarabine, a common chemotherapy drug for mantle cell lymphoma (MCL), and as a biomarker of grim prognosis for acute myelocytic leukemia (AML) patients. However, SAMHD1 expression and function in MCL have not been well-defined. In the present study, we evaluated SAMHD1 expression by immunohistochemistry and its gene structure by Sanger sequencing in MCL. Our results showed that SAMHD1 was positive in 36 (62.1%) patients. Importantly, SAMHD1-positive patients were associated with lower chemotherapy response rate (p = 0.023) and shorter overall survival (p = 0.039) than SAMHD1-negative cases. These results suggest that SAMHD1 is an adverse biomarker for MCL patients, which is due to the high expression of SAMHD1 and rapid cell proliferation. These findings were confirmed in an in vitro study using the siRNA technique. Silencing the SAMHD1 gene in the MCL cell line Jeko-1 significantly decreased cell proliferation and increased cell apoptosis. The MCL cell line with SAMHD1 knockdown showed lower Ki-67 proliferation index, higher caspase-3, and higher sensitivity to cytarabine. Furthermore, for the first time, four previously unreported missense mutations (S302Y, Y432C, E449G, and R451H) in exon 8 and exon 12 of the SAMHD1 gene were discovered by sequencing. The mutations had not been found to corelate with SAMHD1 protein expression detected by immunohistochemistry. The biological functions of this mutated SAMHD1 remain to be investigated.

Conjugated BODIPY Oligomers with Controllable Near-Infrared Absorptions as Promising Phototheranostic Agents through Excited-State Intramolecular Rotations.

Conjugated molecules with coplanar strong donor and acceptor (D-A) units have been widely used in the design of near-infrared (NIR) photothermal agents to increase an absorption band through intramolecular charge transfer and to control intramolecular motions in aggregated states. However, such conjugated D-A systems have strong dipolar moments and intermolecular interactions, which may inhibit other channels of photothermal conversion and are often susceptible to nucleophiles, especially in the presence of light irradiation. Now, we report a molecular guideline to develop novel NIR organic photothermal nanoagents based on conjugated boron dipyrromethene (BODIPY) oligomers. This oligomerization is helpful not only for their tunable NIR absorptions in the ground state with distinctly redshifted absorption maxima up to 1002 nm and high extinction coefficients but also for their highly efficient photothermal conversion because of the possible motion of the BODIPY motifs around the ethene linked group in the excited state. These oligomers were fabricated as ultra-photostable nanoagents for multiple imaging-guided phototherapies, which efficiently accumulated in tumors, and gave complete tumor ablation with NIR laser irradiation. This strategy of "ground-state conjugation, excited-state rotation" provides a novel guideline to develop advanced theranostic molecules with NIR absorption.

Estrogen and calcium handling proteins: new discoveries and mechanisms in cardiovascular diseases.

Estrogen deficiency is considered to be an important factor leading to cardiovascular diseases (CVDs). Indeed, the prevalence of CVDs in postmenopausal women exceeds that of premenopausal women and men of the same age. Recent research findings provide evidence that estrogen plays a pivotal role in the regulation of calcium homeostasis and therefore fine-tunes normal cardiomyocyte contraction and relaxation processes. Disruption of calcium homeostasis is closely associated with the pathological mechanism of CVDs. Thus, this paper maps out and summarizes the effects and mechanisms of estrogen on calcium handling proteins in cardiac myocytes, including L-type Ca2+ channel, the sarcoplasmic reticulum Ca2+ release channel named ryanodine receptor, sarco(endo)plasmic reticulum Ca2+-ATPase, and sodium-calcium exchanger. In so doing, we provide theoretical and experimental evidence for the successful design of estrogen-based prevention and treatment therapies for CVDs.

ß-AlkenylBODIPY Dyes: Regioselective Synthesis via Oxidative C-H Olefination, Photophysical Properties, and Bioimaging Studies.

A series of 2-alkenyl- and 2,6-dialkenylboron dipyrromethene (BODIPY) derivatives were synthesized through Pd(II)-catalyzed regioselective and stereoselective oxidative C-H olefination in one step. The 2-alkenyl BODIPY derivative further reacted with various amines regioselectively at the 5-position through direct oxidative nucleophilic substitution. The photophysical properties of the 2-alkenyl- and 2,6-dialkenyl-substituted BODIPYs were investigated, which showed great potential in fluorescent bioimaging.

High Singlet Oxygen Yield Photosensitizer Based Polypeptide Nanoparticles for Low-Power Near-Infrared Light Imaging-Guided Photodynamic Therapy.

NIR photosensitizer is attractive for photodynamic therapy (PDT). Low-power light irradiation and imaging-guided PDT makes it possible to increase tissue penetration depth. The pyrrole-substituted iodinated BODIPY (BDPI) molecule was designed and synthesized, and it possesses an intense NIR absorption and emission band, and exhibits a high singlet oxygen quantum yield (ΦΔ = 0.80) which leads remarkable cytotoxicity upon low power illumination (IC50 = 0.60 µg/mL, 6.1 mW/cm2). After being encapsulated with biocompatibility polypeptide PEG-PLys, polymeric micelles nanoparticles (PBDPI NPs) was obtained that are water-dispersed and passively tumor-targetable. Such enhanced accumulation in tumor area makes it easily traced in vivo due to its NIR fluorescence. In addition, such nanoparticles offer an unprecedented photodynamic therapeutic effect by using a low-power irradiation light, which makes it possible to kill cancer cells in deep tissue efficiently.

Syntheses and photophysical properties of BF2 complexes of curcumin analogues.

Stable tetracoordinated organoboron complexes as classic fluorescent molecules have found various applications in material and medical sciences. A new class of curcumin-BF2 complexes has been prepared from the condensation of 2,2-difluoro-1,3-dioxaborylpentadione with a variety of aldehydes and its photophysical properties were characterized. Systematic variations were observed in the absorption spectra of these curcumin-BF2 dyes in solutions, which are well correlated with their structural features, including characteristics of the aromatic groups and presence of a para electron-donating substituent. Strong fluorescence that is tunable from 500 to 800 nm via variation of the polarity of the solvent and a moderate to good fluorescence quantum yield ranging from 0.24 to 0.58 in dichloromethane were observed in curcumin-BF2 complexes 1. By contrast, their asymmetrical analogue, curcumin-BF2 complexes 3 exhibit much lower fluorescence quantum yields. Besides their excellent photostabilities, these curcumin-BF2 dyes also show singlet oxygen generating capabilities.

A nitroolefin functionalized BODIPY chemodosimeter for biothiols driven by an unexpected conjugated addition mechanism.

A weakly fluorescent nitroolefin functionalized BODIPY 1 was prepared and rapidly reacted with thiols through an unexpected conjugated addition to the azafulvene ring of BODIPY to generate highly fluorescent BODIPYs 4 and 5. This reaction was applied for the highly selective and sensitive detection of Cys in living cells.

Solvent dependent fluorescent properties of a 1,2,3-triazole linked 8-hydroxyquinoline chemosensor: tunable detection from zinc(II) to iron(III) in the CH3CN/H2O system.

A triazole-containing 8-hydroxyquinoline (8-HQ) ether 2 was efficiently synthesized in two steps from the "click" strategy. Compound 2 gave a strong fluorescence (Φ = 0.21) in nonprotic solvent like CH(3)CN, and a weak fluorescence (Φ = 0.06) in protic solvent like water. In water, a more than 100 nm red shift of the fluorescence maximum was observed for compound 2 in comparison with that in CH(3)CN. This fluorescence difference may be attributed to the intermolecular photoinduced proton transfer (PPT) process involving the protic solvent water molecules. Similarly, this intermolecular PPT process was also observed in the high-water-content CH(3)CN aqueous solution (e.g., CH(3)CN/H(2)O = 5/95, v/v). The water content in the CH(3)CN/H(2)O binary solvent mixture greatly affected the fluorescence intensity (e.g., Φ = 0.06 and 0.25 when CH(3)CN/H(2)O = 5/95 and 95/5, v/v, respectively) and emission wavelength. Using this interesting property, by simple variation of the water content in the CH(3)CN aqueous solution, compound 2 was tuned from a selective "turn-on" fluorescent sensor for Zn(2+) (CH(3)CN/H(2)O = 5/95, v/v) to a ratiometric one for Zn(2+) and a selective "turn-off" one for Fe(3+) (CH(3)CN/H(2)O = 95/5, v/v) over a wide range of pH value. In high-water-content (CH(3)CN/H(2)O = 5/95, v/v) aqueous solution compound 2 shows a selective "turn-on" response toward Zn(2+), with a 10-fold enhancement in the fluorescence intensity at 428 nm and a 62 nm blue shift of the emission maximum (490 to 428 nm) due to the inhibition of intermolecular PPT process upon chelating with Zn(2+). However, in a less polar solvent (CH(3)CN/H(2)O = 95/5, v/v) in which compound 2 has high fluorescence (quantum yield =0.25), it shows a ratiometric response toward Zn(2+), with a continuous decrease of the fluorescence intensity at 399 nm and an increase at 423 nm. More interestingly, in this case, it also exhibits a very sensitive, selective, and ratiometric fluorescence quenching in the presence of Fe(3+), with an 81 nm red shift of the emission maximum (399 to 480 nm) in a wide range of pH through a metal ligand charge transfer (MLCT) effect.

Long wavelength red fluorescent dyes from 3,5-diiodo-BODIPYs.

Amphiphilic and long wavelength red fluorescent dyes (4 and 7) were prepared from the Sonogashira coupling reactions of 3,5-diiodo-BODIPYs (1 and 6). One of these compounds, BODIPY 7, readily accumulated within human carcinoma HEp2 cells and was found to localize mainly within the endoplasmic reticulum (ER).