Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and paranasal sinuses. Eosinophilic inflammation is described as a common endotype. The anti-interleukin-5 (IL-5) antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe CRSwNP when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, therapy monitoring and follow-up documentation are required, and therapy discontinuation has not been adequately established yet. In this paper, recommendations for monitoring the course and efficacy of therapy as well as for reviewing the duration and possible termination of therapy are provided. For this purpose, a literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching MEDLINE, PubMed, and the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including October 2022 were considered. Based on the international literature and previous experience, recommendations for follow-up, adherence to therapy intervals and possible therapy breaks, as well as termination of therapy when using mepolizumab for the indication CRSwNP in the German health care system are given by an expert panel on the basis of a documentation sheet.

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The integration of three-dimensional (3D) printing techniques into the domains of biomedical research and personalized medicine highlights the evolving paradigm shifts within contemporary healthcare. This technological advancement signifies potential breakthroughs in patient-specific therapeutic interventions and innovations. This systematic review offers a critical assessment of the existing literature, elucidating the present status, inherent challenges, and prospective avenues of 3D printing in augmenting biomedical applications and formulating tailored medical strategies. Based on an exhaustive literature analysis comprising empirical studies, case studies, and extensive reviews from the past decade, pivotal sectors including tissue engineering, prosthetic development, drug delivery systems, and customized medical apparatuses are delineated. The advent of 3D printing provides precision in the fabrication of patient-centric implants, bio-structures, and devices, thereby mitigating associated risks. Concurrently, it facilitates the ideation of individualized drug delivery paradigms to optimize therapeutic outcomes. Notwithstanding these advancements, issues concerning material biocompatibility, regulatory compliance, and the economic implications of avant-garde printing techniques persist. To fully harness the transformative potential of 3D printing in healthcare, collaborative endeavors amongst academicians, clinicians, industrial entities, and regulatory bodies are paramount. With continued research and innovation, 3D printing is poised to redefine the trajectories of biomedical science and patient-centric care. The paper aims to justify the research objective of whether to what extent the integration of 3D printing technology in biomedicine enhances patient-specific treatment and contributes to improved healthcare outcomes.

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Mitochondria are present in all mammalian cells except matured red blood cells. Mitochondria consist of several metabolic pathways for glucose, fatty acids, amino acids, and bioenergetic pathways for ATP synthesis, membrane potential, and reactive oxygen production. In the liver, hepatic mitochondria play a key role in hepatic steatosis because mitochondrial metabolism produces acetyl-CoA which is the building block for synthesis of lipids and cholesterol. Mitochondria inner membrane is impermeable of metabolites, reducing equivalents, and small molecules such as phosphate, and sulfate. Thus, mitochondrial shuttles and carriers function as the routes of influx and efflux of these metabolites and molecules across the inner membrane. The signal regulation of these shuttles and mitochondrial enzymes could play a key role in coordinating the mitochondrial metabolism to adapt the cytosolic part of metabolic pathways in liver metabolic stress. Intriguingly, the interaction of mitochondria protein SH3 domain-binding protein 5 (SAB/SH3BP5) and c-Jun N-terminal kinase (JNK) was found as a pivotal role in sustained activation of JNK and phosphorylated-JNK (P-JNK) mediated activation of lipogenic pathway in nutritional excess. Knockout or knockdown of SAB prevented or reversed the hepatic steatosis, inflammation, and fibrosis, and improved metabolic intolerance and energy expenditure. Moreover, blocking the SAB peptide prevents palmitic acid-induced P-JNK interaction with SAB and inhibition of mitochondrial bioenergetics, implying the P-JNK effect on mitochondrial metabolism. This review focuses on the flow of mitochondrial metabolites in metabolic stress conditions and the contribution of mitochondria and mitochondrial stress signals in hepatic steatosis.

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Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs.

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In spite of the immense advancement in the diagnostic and treatment modalities, cancer continues to be one of the leading causes of mortality across the globe, responsible for the death of around 10 million patients every year. The foremost challenges faced in the treatment of this disease are chemoresistance, adverse effects of the drugs, and the high cost of treatment. Though scientific studies over the past few decades have foreseen and are focusing on the cancer-preventive and therapeutic potential of natural products and their underlying mechanism of action, many more of these agents are not still explored. Piperlongumine (PL), or piplartine, is one such alkaloid isolated from Piper longum Linn., which is shown to be safe and has significant potential in the prevention and therapy of cancer. Numerous shreds of evidence have established the ability of this alkaloid and its analogs and nanoformulations in modulating various complex molecular pathways such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, nuclear factor-kappa B, Janus kinases/signal transducer and activator of transcription 3, etc. and inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases, etc. In addition, PL was also shown to inhibit radioresistance and chemoresistance and sensitize the cancer cells to the standard chemotherapeutic agents. Therefore, this compound has high potential as a drug candidate for the prevention and treatment of different cancers. The current review briefly reiterates the anti-cancer properties of PL against different types of cancer, which permits further investigation by conducting clinical studies.

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Neurological disorders constitute a major global health burden with limited effective treatments. Despite advances in molecular neuroscience, critical gaps persist in understanding intercellular communication systems underlying central nervous system homeostasis and neurodegeneration. Extracellular vesicles (EVs), nanoscale to microscale membrane-bound vesicles secreted by virtually all cell types, have emerged as pivotal mediators of intercellular communication in neurological pathologies. This review examines molecular mechanisms governing EV biogenesis, cargo selection, and pathological functions in neurological disorders, emphasizing the emerging role of ubiquitin-like protein 3 (UBL3) as a novel regulator of EV-mediated protein sorting. Neural cell populations produce specialized EV subtypes containing distinct molecular cargo reflecting their physiological states. UBL3, a membrane-anchored post-translational modifier, operates through geranylgeranylation-dependent mechanisms to promote selective protein incorporation into small EVs (sEVs), with knockout studies demonstrating approximately 60% reduction in EV protein content. Proteomic analyses reveal UBL3 interacts with over 1,200 proteins, with ~30% classified as EV cargo proteins. Critically, UBL3-mediated sorting influences disease-associated protein trafficking, including α-synuclein in Parkinson’s disease and mutant huntingtin in Huntington’s disease, suggesting involvement in prion-like spreading mechanisms. EVs’ dual nature as pathological mediators and therapeutic vehicles represents a paradigm shift in neurological medicine. EVs offer advantages as natural drug delivery systems capable of crossing the blood-brain barrier, accessible biomarkers for noninvasive disease monitoring via liquid biopsies (achieving diagnostic accuracies exceeding 0.88 ROC-AUC), and engineered therapeutic platforms for delivering CRISPR-Cas9 systems and neuroprotective factors. However, clinical translation requires addressing challenges, including standardizing isolation protocols, elucidating cell-type-specific cargo sorting mechanisms, and defining optimal administration routes. Understanding UBL3-mediated cargo sorting mechanisms presents promising therapeutic opportunities by selectively modulating pathogenic protein trafficking. EVs, positioned at the intersection of pathogenesis and therapy, represent attractive targets for precision medicine approaches in neurological conditions, with UBL3 emerging as a novel molecular handle for manipulating EV composition and function.

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Diabetic wound healing presents a unique and complex challenge due to the impaired cellular and molecular functions associated with diabetes. Chronic wounds in diabetic patients are characterized by prolonged inflammation, reduced angiogenesis, and impaired collagen deposition, which significantly hinder the healing process. This comprehensive review focuses on the innovative applications of designer cytokines in precision therapy for diabetic wound healing, emphasizing the remarkable advancements made in overcoming the limitations of natural cytokines, such as their short half-life, potential cytotoxicity, and lack of specificity. We begin by detailing the intricate biological characteristics of diabetic wounds and the essential role that cytokines play in orchestrating the healing process. The review critically examines the constraints of natural cytokines and traces the evolution of synthetic alternatives, with a particular emphasis on peptide-based and nucleic acid-based artificial cytokines. Advanced strategies for designing these artificial cytokines are discussed, including molecular modifications, functional enhancements, and specificity improvements to better target pathological conditions in diabetic wounds. Furthermore, we explore the utilization of synthetic biology techniques to engineer effective cytokine-based therapies. The promising therapeutic potential of rationally designed cytokines is highlighted, showcasing their ability to modulate the wound microenvironment, enhance tissue regeneration, and reduce chronic inflammation. This review not only provides valuable perspectives on the future research directions but also offers insights into the potential clinical applications of these innovative therapies, aiming to significantly improve the outcomes for patients suffering from diabetic wounds.

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The advent of three-dimensional (3D) printing has transformed modern dentistry by introducing innovative approaches that enhance customization, precision, and efficiency in clinical and educational settings. This review provides a comprehensive analysis of recent developments and emerging trends in 3D printing applications within dentistry. It explores key domains, including Applications in Orthodontics, Applications in Crown Production, Applications in Implants and Surgical Guides, 3D Printing Applications in Dentures, and Applications in Dental Models and Educational Tools. In orthodontics, 3D printing facilitates the production of patient-specific aligners, brackets, and retainers, improving treatment accuracy and reducing turnaround times. In crown production, the integration of computer-aided design and manufacturing (CAD/CAM) with additive manufacturing allows for the fabrication of highly precise and esthetic prosthetic crowns with rapid chairside delivery. One of the most impactful uses is seen in implants and surgical guides, where 3D printing supports the creation of customized surgical templates and implant components, thus enhancing procedural outcomes and reducing surgical risks. 3D printing has revolutionized denture fabrication by enabling the production of complete and partial dentures with improved fit, material efficiency, and reduced laboratory time. In dental education, the technology is increasingly employed to produce anatomical models, simulated teeth, and other educational tools that improve student training and diagnostic planning. The novelty of this review lies in its integrative perspective linking technical advancements with practical dental applications and highlighting material innovations such as nanocomposites and biocompatible polymers. It also discussed future prospects such as AI-driven design optimization and the role of smart materials in expanding clinical applicability. By presenting a structured overview across multiple specialties, this paper offers valuable insights into how 3D printing is reshaping the future of dental care and education.

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Protein phosphorylation is a fundamental regulatory mechanism governing a broad spectrum of cellular processes. In the nervous system, it is critical for modulating neurotransmitter release, synaptic plasticity, neuronal excitability, and cell survival. Dysregulation of protein kinase activity is closely linked to the pathogenesis of various neurological and psychiatric disorders, positioning several kinases as promising therapeutic targets. Although protein kinase inhibitors (PKIs), a major class of compounds that modulate kinase activity, have shown considerable therapeutic success in oncology, their application in neurological diseases remains in the early stages of exploration. Of the 82 PKIs approved by the Food and Drug Administration (FDA), 37 are now in various preclinical and clinical trials for neurological conditions, primarily targeting signaling pathways mediated by key protein kinases implicated in these diseases. This review examines the roles of critical protein kinases and the therapeutic effects of their inhibitors in neurodegenerative, psychiatric, and selected neurological disorders, such as autism spectrum disorders (ASD) and epilepsy. We focus on Abelson kinase I (ABL1), calmodulin-dependent kinase II (CaMKII), casein kinase 1δ (CK1δ), c-Jun N-terminal kinase (JNK), cyclin-dependent kinase 5 (CDK5), dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A), leucine-rich repeat kinase 2 (LRRK2), extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3β (GSK3β), mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase, and protein kinase C (PKC) in neurodegenerative diseases. Additionally, we discuss CaMKII, CDK5, ERK1/2, PI3K/AKT/GSK3, protein kinase A (PKA), and PKC in psychiatric disorders, focusing on schizophrenia and mood disorders, and analyze GSK3β, ERK1/2, and mTOR in ASD and epilepsy. This review underscores the therapeutic potential of PKIs in neurological disorders while highlighting ongoing challenges and the need for further research to refine kinase-targeted therapies.

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Arginase-1 (Arg1) and the inducible nitric oxide synthase 2 (NOS2) compete for the common substrate L-arginine, semi-essential amino acid, and central intestinal metabolite. Both enzymes exhibit various, sometimes opposing effects on immune responses, tissue regeneration, or microbial growth and replication. In sub-mucosal tissues of patients suffering from inflammatory bowel disease (IBD), similar as in experimental colitis, the expression and activity of both enzymes, Arg1 and NOS2 are more prominent than in respective controls. Accordingly, the metabolism of L-arginine is altered in IBD patients. Thus, L-arginine represents a promising medical target for clinical intervention in these devastating diseases. Previous studies primarily focused on the host side of L-arginine metabolism. Initial reports using Arg1 inhibitors generated conflicting results in murine colitis models. Subsequently, only the generation of conditional Arg1 knockout mice allowed reliable functional analyses of Arg1 and the L-arginine metabolism in the immune system. Utilizing cell-specific conditional Arg1 knockouts, we have recently reported that Arg1, surprisingly, hampered the resolution of experimental colitis due to the restriction of the intraluminal availability of L-arginine. Reduced levels of L-arginine restrained the compositional diversity of the intestinal microbiota and subsequently the mutual metabolism between the microbiota and the host. Thus, the intraluminal microbiota represents a potential therapeutic target for L-arginine metabolism aside from host-dependent L-arginine consumption.

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