Alzheimer's disease linked Aß42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Amyloid ß (Aß) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aß42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aß42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We conducted kinetic analyses of γ-secretase activity in cell-free systems in the presence of Aß, as well as cell-based and ex vivo assays in neuronal cell lines, neurons, and brain synaptosomes to assess the impact of Aß on γ-secretases. We show that human Aß42 peptides, but neither murine Aß42 nor human Aß17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75, and pan-cadherin. Moreover, Aß42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aß42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aß toxicity in the context of γ-secretase-dependent homeostatic signaling.

Exploring the phototoxicity of GSH-resistant 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)quinoline-based Ir(III)-PTA complexes in MDA-MB-231 cancer cells.

Metal complexes play a crucial role in photo-activated chemotherapy (PACT), which has recently been used to treat specific disorders. Triple-negative breast cancer has an enormously high rate of relapse due to the existence and survival of cancer stem cells (CSCs) characterized by increased amounts of glutathione (GSH). Hence, designing a phototoxic molecule is an enticing area of research to combat triple-negative breast cancer (TNBC) via GSH depletion and DNA photocleavage. Herein, we focus on the application of PTA and non-PTA Ir(III) complexes for phototoxicity in the absence and presence of GSH against MDA-MB-231 TNBC cells. Between these two complexes, [Cp*IrIII(DD)PTA]·2Cl (DDIRP) exhibited better phototoxicity (IC50 ∼ 2.80 ± 0.52 µM) compared to the non-PTA complex [Cp*IrIII(DD)Cl]·Cl (DDIR) against TNBC cells because of the high GSH resistance power of the complex DDIRP. The significant potency of the complex DDIRP under photo irradiation in both normoxia and hypoxia conditions can be attributed to selective transportation, high cellular permeability and uptake towards the nucleus, GSH depletion by GSH-GSSG conversion, the ability of strong DNA binding including intercalation, and oxidative stress. The strong affinity to serum albumin, which serves as a carrier protein, aids in the transport of the complex to its target site while preventing glutathione (GSH) deactivation. Consequently, the complex DDIRP was developed as a suitable phototoxic complex in selective cancer therapy, ruling over the usual chemotherapeutic drug cisplatin and the PDT drug Photofrin. The ability of ROS generation under hypoxic conditions delivers this complex as a hypoxia-efficient selective metallodrug for the treatment of TNBC.

Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes for selective cancer therapy via a potential DNA damage mechanism.

Recently, achieving selective cancer therapy with trifling side effects has been a great challenge in the eradication of cancer. Thus, to amplify the cytoselective approach of complexes, herein, we developed a series of Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes and screened their potency against HeLa and MCF-7 cell lines together with the evaluation of their toxicity towards a normal kidney cell line (HEK-293). On meticulous investigation, complex [ReI(CO)3Cl(K2-N,N-(2c))] (3c) was found to be the most potent anticancer entity among other complexes. Complex 3c also showed competency to induce apoptosis in MCF-7 cells through G2/M phase cell-cycle arrest in association with the generation of ample reactive oxygen species (ROS), eventually leading to DNA intercalation and internucleosomal cleavage. The order of the cytotoxicity of these complexes depended on their lipophilic character and the electron-withdrawing halogen substitution at the para-position of the phenyl ring in the imidazophenanthroline ligand.

Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function.

Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn, which is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by α-syn-thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating α-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug development.

Indian jujube a potential fruit tree to improve the livelihood.

Indian Jujube, also known as Ber or Ziziphus Mauritiana Lam., is a fruit-bearing tree endemic to South Asia, including India, Pakistan, Bangladesh, and Sri Lanka. The tree belongs to the buckthorn family and is known for its fruit, a tiny, round, or oblong-shaped drupe roughly the size of a cherry or a small plum. Indian Jujube has been growing for thousands of years. It is a popular fruit throughout the tropical and subtropical regions of Asia, Africa, and South America. Despite the fruit's delicious flavour and health benefits, it is also known for its therapeutic value. Many studies have suggested that various components of ber trees, such as fruit, seed leaves, roots, and flowers, include bioactive substances that demonstrate the potential for antioxidant activity and have anticancer, antibacterial, and antidiabetic effects. Due to the crop's minimal management requirements, it may slow down climate change and the threat of extreme soil and weather conditions, such as drought resistance, strong winds, erosion, high salt, and floods. The main objectives of the current systematic review are to understand Ber's chemical compositions, health benefits, culinary uses, major nutraceutical features, and its function in fostering livelihoods and climatic tolerance.

Alzheimer's disease linked Aß42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.

Amyloid ß (Aß) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aß42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aß42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We show that human Aß42 peptides, but neither murine Aß42 nor human Aß17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75 and pan-cadherin. Moreover, Aß42 treatment dysregulated cellular homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aß42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aß toxicity in the context of γ-secretase-dependent homeostatic signaling.

Synthesis, characterization, photophysical and electrochemical properties, and biomolecular interaction of 2,2'-biquinoline based phototoxic Ru(II)/Ir(II) complexes.

The phototoxic nature of drugs has been seen to convey immense importance in photo activated chemotherapy (PACT) for the selective treatment of disease. Rationally, in order to eradicate the vehemence of cancer in a living body, the design of phototoxic molecules has been of growing interest in research to establish a selective strategy for cancer therapy. Therefore, the present work portrays the synthesis of a phototoxic anticancer agent by incorporating ruthenium(II) and iridium(III) metals into a biologically active 2,2'-biquinoline moiety, BQ. The complexes, RuBQ and IrBQ, have been revealed as effective anticancer agents with remarkable toxicity in the presence of light compared to the dark towards HeLa and MCF-7 cancer cell lines due to the production of a profuse amount of singlet oxygen (1O2) upon irradiation by visible light (400-700 nm). Complex IrBQ exhibited the best toxicity (IC50 = 8.75 µM in MCF-7 and 7.23 µM in HeLa) in comparison to the RuBQ complex under visible light. RuBQ and IrBQ displayed considerable quantum yields (Φf) along with a good lipophilic property, indicating the cellular imaging capability of both complexes upon significant accumulation in cancer cells. Also, the complexes have shown significant binding propensity with biomolecules, viz. deoxyribonucleic acid (DNA) as well as serum albumin (BSA, HSA).

Radical Cascade Cyclization of Unactivated Alkene-Tethered Indoles with Aryldiazonium Salt and Sodium Metabisulfite to Access Azo- and Sulfonylated-2,3-Dihyro-1H-pyrrolo[1,2-a]indoles.

A method for the construction of heterocyclic scaffold 2,3-dihyro-1H-pyrrolo[1,2-a]indoles via arylsulfonyl radical-triggered cascade cyclization of unactivated alkene-tethered indoles in the absence of any external photocatalyst has been developed. This protocol features easily accessible starting materials such as sodium metabisulfite and aryldiazonium tetrafluoroborates at room temperature and offers good functional group compatibility, enabling the introduction of various functionalized sulfonyl and azo groups into pyrrolo[1,2-a]indoles.

G2/M-Phase-Inhibitory Mitochondrial-Depolarizing Re(I)/Ru(II)/Ir(III)-2,2'-Bipyrimidine-Based Heterobimetallic Luminescent Complexes: An Assessment of In Vitro Antiproliferative Activity and Bioimaging for Targeted Therapy toward Human TNBC Cells.

Triple-negative breast cancer (TNBC) is an extremely vicious subtype of human breast cancer having the worst prognosis along with strong invasive and metastatic competency. Hence, it can easily invade into blood vessels, and presently, no targeted therapeutic approach is available to annihilate this type of cancer. Metal complexes have successfully stepped into the anticancer research and are now being applauded due to their anticancer potency after the discovery of cisplatin. Many of these metal complexes are also well recognized for their activity toward breast cancer. As the TNBC is a very dangerous subtype and has long been a challenging ailment to treat, we have intended to develop a few brand new mixed metallic Ru(II)/Ir(III)/Re(I)-2,2'-bipyrimidine complexes [L'Re2], [L'RuRe], and [L'IrRe] to abate the unbridled proliferation of TNBC cells. The potency of the complexes against TNBC cells has been justified using MDA-MB-468 TNBC cell lines where complex [L'IrRe] has displayed significant potency among all the three complexes with an IC50 value of 24.12 µM. The complex [L'IrRe] has been competent to cause apoptosis of TNBC cells through inhibition of the G2/M phase in the cell cycle in association with a profuse amount of ROS generation and mitochondrial depolarization.

Optimisation of Mix Proportion of 3D Printable Mortar Based on Rheological Properties and Material Strength Using Factorial Design of Experiment.

In the production of 3D printable mortar (3DPM), numerous efforts have been made globally to effectively utilise various cementitious materials, admixtures, and fibres. The determination of rheological and material strength properties is crucial for successful 3D concrete printing because the materials used in 3DPM must possess the unique characteristic of making mortar flowable while being strong enough to support the weight of subsequent layers in both fresh and hardened states. The complexity of the required characteristics makes it challenging to develop an optimised mix composition that satisfies both the rheological and material strength requirements, given the wide range of available admixtures, supplementary cementitious materials, and fibres. Fly ash, basalt fibre and superplasticiser when blended with cement can help to improve the overall performance of 3DPM. The objective of this research is to optimise the rheological properties and material strength of 3D printable mortars (3DPM) containing cement, fly ash, basalt fibre, and superplasticiser. This study aims to produce 3DPM with an optimised mix composition to meet the requirements of both rheological and material strength characteristics using the factorial design approach and desirability function. Different dosages of cement, fly ash, basalt fibre, and superplasticiser are chosen as the primary design parameters to develop statistical models for the responses of rheological and material strength properties at 7 and 28 days. The results expressed in terms of the measured properties are valid for mortars made with cement ranging from 550 to 650 kg/m3, fly ash from 5% to 20% (of cement), superplasticiser from 2 to 4 kg/m3, and basalt fibre from 1 to 3 kg/m3. The rheological properties are evaluated using slump flow, cone penetrometer, and cylindrical slump tests, while the mechanical strength is evaluated using a three-point bending test and compressive test. A full factorial design experiment (FoE) is used to determine the significant parameters effecting the measured properties. Prediction models are developed to express the measured properties in terms of the primary parameters. The influence of cement, fly ash, basalt fibre, and superplasticiser is analysed using polynomial regression to determine the main effects and interactions of these primary parameters on the measured properties. The results show that the regression models established by the factorial design approach are effective and can accurately predict the performance of 3DPM. Cement, fly ash, and superplasticiser dosages have significant effects on the rheological and mechanical properties of mortar, while basalt fibre is able to influence the static yield stress and flexural strength of 3DPM. The utilisation of regression models and isoresponse curves allows for the identification of significant trends and provides valuable insight into the behaviour of the material, while desirability function is useful to optimise overall performance of mix proportions to meet the desired performance objective at fresh and hardened states.

Luminescent 11-{Naphthalen-1-yl}dipyrido[3,2-a:2',3'-c]phenazine-Based Ru(II)/Ir(III)/Re(I) Complexes for HCT-116 Colorectal Cancer Stem Cell Therapy.

Due to a number of unpleasant considerations, marketed drugs have steadily lost their importance in the treatment of cancer. In order to find a viable cancer cell diagnostic agent, we therefore focused on metal complexes that displayed target adequacy, permeability to cancer cells, high standard water solubility, cytoselectivity, and luminescent behavior. In this aspect, luminescent 11-{naphthalen-1-yl} dipyrido [3,2-a:2',3'-c] phenazine based Ru(II)/Ir(III)/Re(I) complexes have been prepared for HCT-116 colorectal cancer stem cell therapy. Our study successfully established the possible cytotoxicity of IrL complex at different doses on HCT-116 colorectal cancer stem cells (CRCSCs). Additionally, an immunochemistry analysis of the complex IrL showed that the molecule was subcellularly localized in the nucleus and other regions of the cytoplasm, where it caused nuclear DNA damage and mitochondrial dysfunction. The level of BAX and Bcl-2 was further quantified by qRT-PCR. The expression of proapoptotic BAX showed increased expression in the complex IrL-treated cell compared to the control, indicating the potential of complex IrL for apoptotic induction. Upon further validation, complex IrL was developed as an inhibitor of autophagy for the eradication of cancer stem cells.

Target-specific mononuclear and binuclear rhenium(i) tricarbonyl complexes as upcoming anticancer drugs.

Metal complexes have gradually been attracting interest from researchers worldwide as potential cancer therapeutics. Driven by the many side effects of the popular platinum-based anticancer drug cisplatin, the tireless endeavours of researchers have afforded strategies for the design of appropriate metal complexes with minimal side effects compared to cisplatin and its congeners to limit the unrestricted propagation of cancer. In this regard, transition metal complexes, especially rhenium-based complexes are being identified and highlighted as promising cancer theranostics, which are endowed with the ability to detect and annihilate cancer cells in the body. This is attributed the amazing photophysical properties of rhenium complexes together with their ability to selectively attack different organelles in cancer cells. Therefore, this review presents the properties of different rhenium-based complexes to highlight their recent advances as anticancer agents based on their cytotoxicity results.

Emerging frontiers of antibiotics use and their impacts on the human gut microbiome.

Antibiotics, the primary drugs used to cure bacterial diseases, are increasingly becoming ineffective due to the emergence of multiple drug resistance (MDR) leading to recurrence of previously sensitive pathogens. Human gut microbiome (GM), known to play an important role in various physiological processes, consists of pool of diverse microbes. Indiscriminate use of antibiotics during the life span of an individual may lead to development of resistant microbes e.g. Vibrio, Acinetobacter, Escherichia, Klebsiella, Clostridia, etc. in the human GM. Transmission of antibiotic resistant genes (ARGs) between pathogenic and commensal bacteria occurs more frequently in microbiome communities wherein bacteria communicate and exchange cellular constituents both among themselves and with the host. Additionally, co-factors like 'early vs. late' exposure, type of antibiotics and duration of treatment modulate the adverse effects of antibiotics on GM maturation. Furthermore, factors like mode of birth, ethnicity, malnutrition, demography, diet, lifestyle, etc., which influence GM composition, can also indirectly alter the host response to antibiotics. Currently, advanced 'omics' and culturomics approaches are revealing novel avenues to study the interplay between antibiotics and the microbiome and to identify resistant genes in these bacterial communities. Here, we discuss the recent developments that have given insights into the effects of antibiotics on the homeostatic balance of the gut microbiome and thus on human health.

Rongalite as a Sulfone Source: Sulfonylation of para-Quinone Methides and Alkyl/allyl Halides.

A one-pot three-component reaction using p-quinone methides, rongalite and alkyl/allyl halides has been described. The corresponding unsymmetrical sulfones were obtained in good yields under mild reaction conditions in the absence of any metal, base or any other additive.

[Ru(η6-p-cymene)(N

Herein, we have introduced a class of half-sandwich [Ru(η6-p-cymene)(N^O 8-hydroxyquinoline)(PTA)] complexes for brain cancer therapy. Among all the complexes, [RuL3PTA] and [RuL4PTA] exhibited excellent cytotoxicity profiles against T98G, LN229, and U87MG cancer cells. Notably, the antiproliferative activities of the relevant complexes were also supported by neurosphere, DNA intercalation, agarose gel electrophoresis, and time-dependent ROS detection assay studies. Detailed molecular assays were obtained via real-time reverse transcription (RT)-polymerase chain reaction (PCR) experiments. Moreover, the in vivo biodistribution of the [RuL4PTA] complex in different organs and the morphological patterns of zebrafish embryos due to toxic effects have been evaluated.

Mitochondria-targeted half-sandwich iridium(iii)-Cp*-arylimidazophenanthroline complexes as antiproliferative and bioimaging agents against triple negative breast cancer cells MDA-MB-468.

To reduce the side effects of marketed cancer drugs against triple negative breast cancer cells we have reported mitochondria targeting half-sandwich iridium(iii)-Cp*-arylimidazophenanthroline complexes for MDA-MB-468 cell therapy and diagnosis. Out of five Ir(iii) complexes (IrL1-IrL5), [iridium(iii)-Cp*-2-(naphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline]PF6 (IrL1) has exhibited the best cytoselectivity against MDA-MB-468 cells compared to normal HaCaT cells along with excellent binding efficacy with DNA as well as serum albumin. The subcellular localization study of the complex revealed the localization of the compound in cytoplasm thereby pointing to a possible mitochondrial localization and consequent mitochondrial dysfunction via MMP alteration and ROS generation. Moreover, the IrL1 complex facilitated a substantial G1 phase cell-cycle arrest of MDA-MB-468 cells at the highest tested concentration of 5 µM. The study verdicts support the prospective therapeutic potential of the IrL1 complex in the treatment and eradication of triple negative breast cancer cells. These results validate that these types of scaffolds will be fairly able to exert great potential for tumor diagnosis as well as therapy in the near future.

Iridium(III)-Cp*-(imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol analogues as hypoxia active, GSH-resistant cancer cytoselective and mitochondria-targeting cancer stem cell therapeutic agents.

Herein, we have introduced a series of iridium(III)-Cp*-(imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol complexes via a convenient synthetic methodology, which act as hypoxia active and glutathione-resistant anticancer metallotherapeutics. The [IrIII(Cp*)(L5)(Cl)](PF6) (IrL5) complex exhibited the best cytoselectivity, GSH resistance and hypoxia effectivity in HeLa and Caco-2 cells among the synthesized complexes. IrL5 also exhibited highly cytotoxic effects on the HCT-116 CSC cell line. This complex was localized in the mitochondria and subsequent mitochondrial dysfunction was observed via MMP alteration and ROS generation on colorectal cancer stem cells. Cell cycle analysis also established the potential of this complex in mediating G2/M phase cell cycle arrest.

Clathrin packets move in slow axonal transport and deliver functional payloads to synapses.

In non-neuronal cells, clathrin has established roles in endocytosis, with clathrin cages enclosing plasma membrane infoldings, followed by rapid disassembly and reuse of monomers. However, in neurons, clathrin is conveyed in slow axonal transport over days to weeks, and the underlying transport/targeting mechanisms, mobile cargo structures, and even its precise presynaptic localization and physiologic role are unclear. Combining live imaging, photobleaching/conversion, mass spectrometry, electron microscopy, and super-resolution imaging, we found that unlike in dendrites, where clathrin cages rapidly assemble and disassemble, in axons, clathrin and related proteins organize into stable "transport packets" that are unrelated to endocytosis and move intermittently on microtubules, generating an overall slow anterograde flow. At synapses, multiple clathrin packets abut synaptic vesicle (SV) clusters, and clathrin packets also exchange between synaptic boutons in a microtubule-dependent "superpool." Within synaptic boundaries, clathrin is surprisingly dynamic, continuously exchanging between local clathrin assemblies, and its depletion impairs SV recycling. Our data provide a conceptual framework for understanding clathrin trafficking and presynaptic targeting that has functional implications.

Ru(ii), Ir(iii), Re(i) and Rh(iii) based complexes as next generation anticancer metallopharmaceuticals.

Several anticancer drugs such as cisplatin, and its analogues, epirubicin, and doxorubicin are well known for their anticancer activity but the therapeutic value of these drugs comes with certain side effects and they cannot distinguish between normal and cancer cells. Thus, a major challenge for researchers around the world is to develop an anticancer drug with the least toxicity and more target specificity. With the successful reporting of NAMI-A and KP1019, a new path has emerged in the anticancer field. Recently, several Ru(ii) complexes have been reported for their anticancer activity due to their enhanced cellular uptake and selectivity towards cancer cells. Apart from the Ru(ii) complexes, a large amount of research has been carried out with Ir(iii), Re(i), and Rh(iii) based complexes, which exhibited promising anticancer activity. The present review reports various Ru(ii), Ir(iii), Re(i), and Rh(iii) based complexes for their anticancer activity based on their cytotoxicity profiles, biological targets and mechanism of action.

GSH-resistant and highly cytoselective ruthenium(II)-p-cymene-(imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol complexes as potential anticancer agents.

To avoid the side effects of the current popular platinum-based anticancer drugs, researchers have made tireless attempts to design appropriate GSH-resistant Ru(ii)-arene complexes. In this regard, luminescent ruthenium(ii)-p-cymene-imidazophenanthroline complexes were developed as promising highly cytoselective cancer theraputic agents for HeLa and Caco-2 cells.