An investigation of nano- and micron-sized carriers based on calcium carbonate and polylactic acid for oral administration of siRNA.

BACKGROUND: Oral delivery of small interfering RNAs (siRNAs) draws significant attention, but the gastrointestinal tract (GIT) has many biological barriers that limit the drugs' bioavailability. The aim of this work was to investigate the potential of micro- and nano-sized CaCO3 and PLA carriers for oral delivery of siRNA and reveal a relationship between the physicochemical features of these carriers and their biodistribution. RESEARCH DESIGN AND METHODS: In vitro stability of carriers was investigated in simulated gastric and intestinal fluids. Toxicity and cellular uptake were investigated on Caco-2 cells. The biodistribution profiles of the developed CaCO3 and PLA carriers were examined using different visualization methods, including SPECT, fluorescence imaging, radiometry, and histological analysis. The delivery efficiency of siRNA loaded carriers was investigated both in vitro and in vivo. RESULTS: Micro-sized carriers were accumulated in the stomach and later localized in the colon tissues. The nanoscale particles (100-250 nm) were distributed in the colon tissues. nPLA was also detected in small intestine. The developed carriers can prevent siRNA from premature degradation in GIT media. CONCLUSION: Our results reveal how the physicochemical properties of the particles, including their size and material type can affect their biodistribution profile and oral delivery of siRNA.

Nanotopography Influences Host-Pathogen Quorum Sensing and Facilitates Selection of Bioactive Metabolites in Mesenchymal Stromal Cells and Pseudomonas aeruginosa Co-Cultures.

Orthopedic implant-related bacterial infections and resultant antibiotic-resistant biofilms hinder implant-tissue integration and failure. Biofilm quorum sensing (QS) communication determines the pathogen colonization success. However, it remains unclear how implant modifications and host cells are influenced by, or influence, QS. High aspect ratio nanotopographies have shown to reduce biofilm formation of Pseudomonas aeruginosa, a sepsis causing pathogen with well-defined QS molecules. Producing such nanotopographies in relevant orthopedic materials (i.e., titanium) allows for probing QS using mass spectrometry-based metabolomics. However, nanotopographies can reduce host cell adhesion and regeneration. Therefore, we developed a polymer (poly(ethyl acrylate), PEA) coating that organizes extracellular matrix proteins, promoting bioactivity to host cells such as human mesenchymal stromal cells (hMSCs), maintaining biofilm reduction. This allowed us to investigate how hMSCs, after winning the race for the surface against pathogenic cells, interact with the biofilm. Our approach revealed that nanotopographies reduced major virulence pathways, such as LasR. The enhanced hMSCs support provided by the coated nanotopographies was shown to suppress virulence pathways and biofilm formation. Finally, we selected bioactive metabolites and demonstrated that these could be used as adjuncts to the nanostructured surfaces to reduce biofilm formation and enhance hMSC activity. These surfaces make excellent models to study hMSC-pathogen interactions and could be envisaged for use in novel orthopedic implants.

The management of axial spondyloarthritis with cutting-edge therapies: advancements and innovations.

INTRODUCTION: Axial involvement in spondyloarthritis has significantly evolved from the original 1984 New York criteria for ankylosing spondylitis, leading to an improved understanding of axial spondyloarthritis (axSpA) as a disease continuum encompassing non- radiographic axSpA (nr-axSpA) and radiographic axSpA (r-axSpA). A clear definition for early axSpA has been established, underscoring the need for early intervention with biological and targeted synthetic drugs to mitigate pain, reduce functional impairment, and prevent radiographic progression. AREAS COVERED: This review explores therapeutic strategies in axSpA management, focusing on biological and targeted synthetic therapies and recent advancements. Biologics targeting TNFα or IL-17 and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) are primary treatment options. These therapies significantly impact clinical outcomes, radiographic progression, and patient-reported functional improvement. EXPERT OPINION: AxSpA treatment has evolved significantly, offering various therapeutic options. Biological DMARDs, particularly TNFα inhibitors, have transformed treatment, significantly enhancing patient outcomes. However, challenges persist for patients unresponsive or intolerant to existing therapies. Emerging therapeutic targets promise to address these challenges. Comprehensive management strategies and personalized approaches, considering extra-articular manifestations and individual patient factors, are crucial for achieving optimal outcomes in axSpA management.

The choroid plexus synergizes with immune cells during neuroinflammation.

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use longitudinal two-photon imaging in awake mice and single-cell transcriptomics to elucidate the mechanisms of ChP regulation of brain inflammation. We used intracerebroventricular injections of lipopolysaccharides (LPS) to model meningitis in mice and observed that neutrophils and monocytes accumulated in the ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process and revealed that ChP epithelial cells transiently specialize to nurture immune cells, coordinating their recruitment, survival, and differentiation as well as regulation of the tight junctions that control the permeability of the ChP brain barrier. Collectively, we provide a mechanistic understanding and a comprehensive roadmap of neuroinflammation at the ChP brain barrier.

[Modern topical drugs-new developments in galenics and pharmacology]. / Moderne topische Arzneimittel ­ neue Entwicklungen in Galenik und Pharmakologie.

The importance of topically applied pharmaceuticals, especially for the treatment of dermatological diseases, is still essential. Thanks to detailed knowledge of the organisation and function of the physicochemical barrier of the skin, new galenic concepts have increasingly been developed to market maturity in recent years. Colloidal drug carrier systems in particular, but also targeted physicochemical modifications of matrices are used to optimise the cutaneous bioavailability of topically applied drugs. In addition, new molecules are increasingly becoming available for the development of these preparations or drugs known from systemic therapy are being formulated into topicals. Against this background, dermatopharmacology is also developing more and more into a highly specialised science in this area, which is producing innovative concepts for the therapy of special indications. In addition to the classic small-molecule drugs, biotechnological molecules are increasingly finding their way into application, so that a modern age of dermatopharmacology has dawned, which will open up previously unimagined possibilities for topical therapy now and in the coming years.

Discovery and Profiling of New Multimodal Phenylglycinamide Derivatives as Potent Antiseizure and Antinociceptive Drug Candidates.

We developed a focused series of original phenyl-glycinamide derivatives which showed potent activity across in vivo mouse seizure models, namely, maximal electroshock (MES) and 6 Hz (using both 32 and 44 mA current intensities) seizure models. Following intraperitoneal (i.p.) administration, compound (R)-32, which was identified as a lead molecule, demonstrated potent protection against all seizure models with ED50 values of 73.9 mg/kg (MES test), 18.8 mg/kg (6 Hz, 32 mA test), and 26.5 mg/kg (6 Hz, 44 mA test). Furthermore, (R)-32 demonstrated efficacy in both the PTZ-induced kindling paradigm and the ivPTZ seizure threshold test. The expression of neurotrophic factors, such as mature brain-derived neurotrophic factor (mBDNF) and nerve growth factor (NGF), in the hippocampus and/or cortex of mice, and the levels of glutamate and GABA were normalized after PTZ-induced kindling by (R)-32. Importantly, besides antiseizure activity, (R)-32 demonstrated potent antinociceptive efficacy in formalin-induced pain, capsaicin-induced pain, as well as oxaliplatin- and streptozotocin-induced peripheral neuropathy in mice (i.p.). No influence on muscular strength and body temperature in mice was observed. Pharmacokinetic studies and in vitro ADME-Tox data (i.e., high metabolic stability in human liver microsomes, a weak influence on CYPs, no hepatotoxicity, satisfactory passive transport, etc.) proved favorable drug-like properties of (R)-32. Thermal stability of (R)-32 shown in thermogravimetry and differential scanning calorimetry gives the opportunity to develop innovative oral solid dosage forms loaded with this compound. The in vitro binding and functional assays indicated its multimodal mechanism of action. (R)-32, beyond TRPV1 antagonism, inhibited calcium and sodium currents at a concentration of 10 µM. Therefore, the data obtained in the current studies justify a more detailed preclinical development of (R)-32 for epilepsy and pain indications.

Regulation and application of quorum sensing on anaerobic digestion system.

Quorum sensing (QS) plays an important role in the social behavior of microbial communities. Anaerobic digestion (AD) is a biological process using anaerobic microorganisms to degrade organic macromolecules into small molecules for biogas and biofertilizer production. In AD, the QS signaling molecule N-acyl homoserine lactones (AHLs) induces bacterial metabolism, improving AD process efficiency. However, there are fewer systematic reports about QS regulation of microbial behavior in AD. In this report, the effects of signaling molecules on extracellular polymer secretion, biofilm formation, granulation of granular sludge and bacterial metabolism in AD were investigated in detail. At present, the regulation behavior of QS on AD is a group phenomenon, and there are few in-depth studies on the regulation pathway. Therefore, we conducted an in-depth analysis of the pure culture system, granular sludge and reactor in the AD. Then we pointed out that the future application potential of QS in the AD may be combined with quorum quenching (QQ) and omics technology, which is of great significance for the future application of AD.

Association Between Soluble Cell Adhesion Molecules (sP-Selectin, sE-Selectin, and sICAM-1) and Antibodies Against the Antigens of Proteus mirabilis in Rheumatoid Arthritis Patients.

Objective The purpose of this study was to examine the association between the serum concentration of soluble cell adhesion molecules (CAMs) and antibodies against antigens of Proteus mirabilis (P. mirabilis) in rheumatoid arthritis (RA) patients, taking into consideration the implication of P. mirabilis in the etiopathogenesis of RA. Methods The serum levels of soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule-1 (sICAM-1) were determined by sandwich enzyme-linked immunosorbent assay (ELISA) in 59 RA patients and 36 healthy controls. Using the same ELISA method, the serum levels of class-specific antibodies against hemolysin (HpmB), urease C (UreC), and urease F (UreF) enzymes of P. mirabilis were also measured.  Results In this study, increased levels of sP-selectin and sICAM-1 were observed in RA patients, while the levels of sE-selectin were increased in comparison with healthy controls but did not present a statistically significant difference. Moreover, increased levels of antibodies against HpmB, UreC, and UreF of P. mirabilis were found. Additionally, it was observed that the sE-selectin levels presented a significant correlation with IgG antibodies against the UreF antigen (there is no corresponding antigen in human tissue) in all the RA patients. A statistically significant correlation was observed between levels of soluble CAMs and antibodies against P. mirabilis in the different subgroups. Conclusion The observed correlation between soluble CAMs and antibodies against antigens of P. mirabilis, specifically in the subgroup of biologic therapy, indicates that P. mirabilis exists and provokes refractory in the treatment of RA.

Aging and physiological barriers: mechanisms of barrier integrity changes and implications for age-related diseases.

The phenomenon of compartmentalization is one of the key traits of life. Biological membranes and histohematic barriers protect the internal environment of the cell and organism from endogenous and exogenous impacts. It is known that the integrity of these barriers decreases with age due to the loss of homeostasis, including age-related gene expression profile changes and the abnormal folding/assembly, crosslinking, and cleavage of barrier-forming macromolecules in addition to morphological changes in cells and tissues. The critical molecular and cellular mechanisms involved in physiological barrier integrity maintenance and aging-associated changes in their functioning are reviewed on different levels: molecular, organelle, cellular, tissue (histohematic, epithelial, and endothelial barriers), and organ one (skin). Biogerontology, which studies physiological barriers in the aspect of age, is still in its infancy; data are being accumulated, but there is no talk of the synthesis of complex theories yet. This paper mainly presents the mechanisms that will become targets of anti-aging therapy only in the future, possibly: pharmacological, cellular, and gene therapies, including potential geroprotectors, hormetins, senomorphic drugs, and senolytics.

Bifunctional Nitrogen-Rich Heterocyclic Compounds: Synthesis, Photoluminescence and Energetic Properties.

Nitrogen-rich heterocyclic frameworks have attracted enormous interest in organic chemistry and materials science. However, their potential for developing photoluminescent materials remains underexplored due to their relatively low molecular stabilities. In this work, two tricyclic fused nitrogen-rich fluorescent heterocycles were synthesized and characterized. The photophysical properties of the synthesized 4 and 5 were investigated through theoretical and experimental studies. In addition, their physicochemical and energetic properties and the performance as an additive to the perovskite absorption layer of the perovskite solar cell were also studied.

Design, synthesis and biological evaluation of multitarget hybrid molecules containing NHC-Au(I) complexes and carbazole moieties.

N-heterocyclic carbenes (NHCs) represent suitable ligands for rapid and efficient drug design, because they offer the advantage of being easily chemically modified and can bind several substituents, including transition metals as, for instance, gold derivatives. Gold-NHC complexes possess various biological activities and were demonstrated good candidates as anticancer drugs. Besides, carbazole derivatives are characterized by various pharmacological properties, such as anticancer, antibacterial, anti-inflammatory, and anti-psychotropic. Amongst the latter, N-thioalkyl carbazoles were proved to inhibit cancer cells damaging the nuclear DNA, through the inhibition of human topoisomerases. Herein, we report the design, synthesis and biological evaluation of nine new hybrid molecules in which NHC-Au(I) complexes and N-alkylthiolated carbazoles are linked together, in order to obtain novel biological multitarget agents. We demonstrated that the lead hybrid complexes possess anticancer, anti-inflammatory and antioxidant properties, with a high potential as useful tools for treating distinct aspects of several diseases, amongst them cancer.

On the supramolecular interactions into a pH- and Metal-Actuated Molecular Shuttle: some insights from QTAIM modeling.

Supramolecular contacts responsible for chemical interaction of cucurbit[7]uril (CB[7]) macrocycle on a Tolyl-Viologen-Phenylene-Imidazole (T-VPI) molecular thread, at acid pH (T-VPI-H+) or after Ag+ cation addition (T-VPI-Ag+), are analytically addressed in a computational framework combining Quantum Theory of Atoms in Molecules (QTAIM) with Density Functional Theory (DFT). In this respect, the crystallographic structure (CCDC number 2217466) is taken as reference condition for addressing the nature of the chemical interactions driving the shuttling of the CB[7] between T and P stations recently observed in dilute water solutions. Beside the host(CB[7]) vs guest(T-VPI-H+ or T-VPI-Ag+) complexation, the coordination sphere of the Ag+ cation is also investigated by means of local electronic energy density - H(r) - descriptors. The derived non-covalent interaction patterns are found to support diagnostic 1H NMR signals used for detecting the mutual position of the CB[7] along the axle. This work highlights the potentialities of a QTAIM based approach in the characterization of supramolecular and metal-complexation effects in molecular aggregates such as not-interlocked synthetic molecular shuttles.

Comparative Efficacy of Biologics and Small Molecule Therapies in Improving Patient-Reported Outcomes in Ulcerative Colitis: Systematic Review and Network Meta-Analysis.

BACKGROUND: Ulcerative colitis (UC) is a chronic disorder with a considerable negative impact on health-related quality of life (HRQoL), which has been recently recognized as an important treatment target. The purpose of this study is to compare the efficacy of different biologics and small molecule therapies in achieving better patient-reported outcomes and HRQoL in patients with UC. METHODS: We performed a systematic review and network meta-analysis of the EMBASE, MEDLINE, and Cochrane Central databases from inception until February 1, 2024. The primary endpoint was clinical remission in the patient-reported outcome (PRO-2) score in UC patients who were treated with different biologics or small molecules during induction and maintenance phases. PRO-2 score is the sum of both stool frequency and rectal bleeding subscores. The secondary outcome was improvement of HRQoL defined as an increase in Inflammatory Bowel Disease Questionnaire score of ≥16 points from baseline or any change in total score from baseline. A random effects model was used, and outcomes were reported as odds ratio with 95% confidence interval. Interventions were ranked per the SUCRA (surface under the cumulative ranking curve) score. RESULTS: A total of 54 studies were included in the primary outcome analysis and 15 studies were included in the secondary outcome analysis. The primary analysis showed that during the induction phase all of included drugs were better than placebo in improving the PRO-2 score. Interestingly, upadacitinib was found to be superior to most medications in improving PRO-2 scores. The secondary analysis showed that guselkumab ranked first in the improvement of the Inflammatory Bowel Disease Questionnaire score, followed by upadacitinib during the induction phase. CONCLUSION: Upadacitinib ranked first in PRO-2 clinical remission during the induction and maintenance phases. Guselkumab, mirikizumab, tofacitinib, and upadacitinib were the only novel medications that were superior to placebo in improving HRQoL in UC, with guselkumab ranking the highest, followed by tofacitinib and upadacitinib. During maintenance of remission, tofacitinib ranked highest in improving HRQoL.

Patient-reported outcome (PRO-2) and disease impact on health-related quality of life (HRQoL) have been recognized as important treatment targets in ulcerative colitis. In this systematic review and network meta-analysis, we compared different biologics and small molecules in achieving these outcomes. We found that upadacitinib ranked first in PRO-2 clinical remission during induction and maintenance phases. Guselkumab, tofacitinib, and upadacitinib were the only novel medications that were superior to placebo in improving HRQoL during induction in ulcerative colitis, with guselkumab ranking the highest, followed by tofacitinib and upadacitinib. During maintenance of remission, tofacitinib ranked highest in improving HRQoL.

Hybrid Organic-Inorganic Copper and Cobalt Complexes for Antimicrobial Potential Applications.

BACKGROUND/AIMS: The naturally occurring phenolic chemical curcumin (CUR), which was derived from the Curcuma longa plant, has a variety of biological actions, including anti-inflammatory, antimicrobial, antioxidant, and anticancer activities. Curcumin is known for its restricted bioavailability due to its hydrophobicity, poor intestinal absorption, and quick metabolism. To boost the biological effects of these bioactive molecules, it is necessary to raise both their bioavailability and their solubility in water. Aim: The aim of this study is to synthesize and characterize hybrid organic-inorganic complexes of copper and cobalt, and to evaluate their antimicrobial potential against a range of pathogenic microorganisms. METHODS: The synthesis of metal curcumin complexes (Cu-CUR and Co-CUR) was achieved by mixing curcumin with copper acetate monohydrate. The solid residue was isolated, filtered, and dried in an oven. X-ray diffraction analysis was used to identify the structure and phase of the prepared samples. FTIR spectra were recorded using a Shimadzu 2200 module. The antimicrobial activity of the prepared complexes was evaluated against four bacterial strains and two Candida species. The chemical materials were dissolved in DMSO to a final concentration of 20%, and the plates were incubated at 37°C for 24 hours. The results showed that the prepared complexes had antimicrobial activity against the tested microorganisms. RESULTS: The study compared the Powder X-ray diffraction (XRD) patterns of prepared copper and cobalt complexes to pure curcumin, revealing new, isostructural complexes. The FTIR analysis showed that the Cu-CUR and Co-CUR complexes varied in their inhibitory effect against microorganisms, with Co-CUR being more effective. The results are consistent with previous studies showing the cobalt-curcumin complex was effective against various bacterial genera, with inhibition activity varying depending on the species and strains of microorganisms. CONCLUSION: Copper and cobalt curcumin complexes, synthesized at room temperature, exhibit high crystallinity and antimicrobial activity. Co-CUR, with its superior antibacterial potential, outperforms pure curcumin in inhibiting microbes. Further investigation is needed to understand their interaction mechanisms with bacteria and fungi.

Steric Engineering of Rotaxane Catalysts: Benefits and Limits of Using the Mechanical Bond in Catalyst Design.

The mechanical bond is emerging as a novel design element in catalyst development. Here, we report a series of 1,1´­binaphthyl-2,2´-diol (BINOL) based catalysts in which the number of interlocked macrocycles is varied. Unsurprisingly, the macrocycles have a profound steric influence on the catalytic performance of these molecules. However, in the enantioselective transformations examined, the macrocycles are detrimental to catalyst stereoselectivity whereas in lactide polymerization, they increase the molecular weight of the polymeric product.

Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies.

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

Central nervous system metastases in advanced non-small cell lung cancer: A review of the therapeutic landscape.

Up to 40% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases. Current treatments for this subgroup of patients with advanced NSCLC include local therapies (surgery, stereotactic radiosurgery, and, less frequently, whole-brain radiotherapy), targeted therapies for oncogene-addicted NSCLC (small molecules, such as tyrosine kinase inhibitors, and antibody-drug conjugates), and immune checkpoint inhibitors (as monotherapy or combination therapy), with multiple new drugs in development. However, confirming the intracranial activity of these treatments has proven to be challenging, given that most lung cancer clinical trials exclude patients with untreated and/or progressing CNS metastases, or do not include prespecified CNS-related endpoints. Here we review progress in the treatment of patients with CNS metastases originating from NSCLC, examining local treatment options, systemic therapies, and multimodal therapeutic strategies. We also consider challenges regarding assessment of treatment response and provide thoughts around future directions for managing CNS disease in patients with advanced NSCLC.

Reduction of biofilm and pathogenic microorganisms using curcumin-mediated photodynamic inactivation to prolong food shelf-life.

Pathogenic microbial contamination (bacteria and fungi) in food products during production poses a significant global health risk, leading to food waste, greenhouse gas emissions, and aesthetic and financial losses. Bacteria and fungi, by forming solid biofilms, enhance their resistance to antimicrobial agents, thereby increasing the potential for cross-contamination of food products. Curcumin molecule-mediated photodynamic inactivation (Cur-m-PDI) technology has shown promising results in sterilizing microbial contaminants and their biofilms, significantly contributing to food preservation without compromising quality. Photosensitizers (curcumin) absorb light, leading to a chemical reaction with oxygen and producing reactive oxygen species (ROS) that effectively reduce bacteria, fungi, and biofilms. The mechanism of microorganism inhibition is caused by exposure to ROS generated via the type 1 pathway involving electron transfer (such as O2•-, H2O2, -OH•, and other radicals), the type 2 pathway involving energy transfer (such as 1O2), secondary ROS, and weakening of antioxidant enzymes. The effectiveness of the inactivation of microorganisms is influenced by the concentration of curcumin, light (source type and energy density), oxygen availability, and duration of exposure. This article reviews the mechanism of reducing microbial food contamination and inhibiting their biofilms through Cur-m-PDI. It also highlights future directions, challenges, and considerations related to the effects of ROS in oxidizing food, the toxicity of PDI to living cells and tissues, conditions/types of food products, and the stability and degradation of curcumin.

Quantum Information Patterns Between Atoms in a Molecule.

Quantum information theory provides a powerful toolbox of descriptors that characterize many-electron systems based on quantum information patterns between open quantum systems. Despite the wealth of insights gained in the con- densed matter community, the use of these descriptors to study interactions between atoms in a molecule remains limited. In this study, we develop a quantum information framework for molecules that characterizes the quantum in- formation patterns between quantum atoms as defined in the Quantum Theory of Atoms in Molecules. We show that quantum information analyses capture key properties of quantum atoms and how they interact with their molec- ular environment. Additionally, we show that the presence of bond critical points can remain invariant despite large changes in the quantum information patterns between the quantum atoms. Our findings indicate that quantum infor- mation theory can shed a new light on molecular electronic structure.

Emerging paradigms in Alzheimer's therapy.

Alzheimer's disease is a neurodegenerative disorder that affects elderly, and its incidence is continuously increasing across the globe. Unfortunately, despite decades of research, a complete cure for Alzheimer's disease continues to elude us. The current medications are mainly symptomatic and slow the disease progression but do not result in reversal of all disease pathologies. The growing body of knowledge on the factors responsible for the onset and progression of the disease has resulted in the identification of new targets that could be targeted for treatment of Alzheimer's disease. This has opened new vistas for treatment of Alzheimer's disease that have moved away from chemotherapeutic agents modulating a single target to biologics and combinations that acted on multiple targets thereby offering better therapeutic outcomes. This review discusses the emerging directions in therapeutic interventions against Alzheimer's disease highlighting their merits that promise to change the treatment paradigm and challenges that limit their clinical translation.