Extracellular vesicles in cancer cachexia: deciphering pathogenic roles and exploring therapeutic horizons.

Cancer cachexia (CC) is a debilitating syndrome that affects 50-80% of cancer patients, varying in incidence by cancer type and significantly diminishing their quality of life. This multifactorial syndrome is characterized by muscle and fat loss, systemic inflammation, and metabolic imbalance. Extracellular vesicles (EVs), including exosomes and microvesicles, play a crucial role in the progression of CC. These vesicles, produced by cancer cells and others within the tumor environment, facilitate intercellular communication by transferring proteins, lipids, and nucleic acids. A comprehensive review of the literature from databases such as PubMed, Scopus, and Web of Science reveals insights into the formation, release, and uptake of EVs in CC, underscoring their potential as diagnostic and prognostic biomarkers. The review also explores therapeutic strategies targeting EVs, which include modifying their release and content, utilizing them for drug delivery, genetically altering their contents, and inhibiting key cachexia pathways. Understanding the role of EVs in CC opens new avenues for diagnostic and therapeutic approaches, potentially mitigating the syndrome's impact on patient survival and quality of life.

MicroRNAs targeted mTOR as therapeutic agents to improve radiotherapy outcome.

MicroRNAs (miRNAs) are small RNA molecules that regulate genes and are involved in various biological processes, including cancer development. Researchers have been exploring the potential of miRNAs as therapeutic agents in cancer treatment. Specifically, targeting the mammalian target of the rapamycin (mTOR) pathway with miRNAs has shown promise in improving the effectiveness of radiotherapy (RT), a common cancer treatment. This review provides an overview of the current understanding of miRNAs targeting mTOR as therapeutic agents to enhance RT outcomes in cancer patients. It emphasizes the importance of understanding the specific miRNAs that target mTOR and their impact on radiosensitivity for personalized cancer treatment approaches. The review also discusses the role of mTOR in cell homeostasis, cell proliferation, and immune response, as well as its association with oncogenesis. It highlights the different ways in which miRNAs can potentially affect the mTOR pathway and their implications in immune-related diseases. Preclinical findings suggest that combining mTOR modulators with RT can inhibit tumor growth through anti-angiogenic and anti-vascular effects, but further research and clinical trials are needed to validate the efficacy and safety of using miRNAs targeting mTOR as therapeutic agents in combination with RT. Overall, this review provides a comprehensive understanding of the potential of miRNAs targeting mTOR to enhance RT efficacy in cancer treatment and emphasizes the need for further research to translate these findings into improved clinical outcomes.

Emerging role of lipophagy in liver disorders.

Lipophagy is a selective degradation of lipids by a lysosomal-mediated pathway, and dysregulation of lipophagy is linked with the pathological hallmark of many liver diseases. Downregulation of lipophagy in liver cells results in abnormal accumulation of LDs (Lipid droplets) in hepatocytes which is a characteristic feature of several liver pathologies such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Contrarily, upregulation of lipophagy in activated hepatic stellate cells (HSCs) is associated with hepatic fibrosis and cirrhosis. Lipid metabolism reprogramming in violent cancer cells contributes to the progression of liver cancer. In this review, we have summarized the recent studies focusing on various components of the lipophagic machinery that can be modulated for their potential role as therapeutic agents against a wide range of liver diseases.

When will the immune-stimulating antibody conjugates (ISACs) be transferred from bench to bedside?

Immunostimulatory antibody conjugates (ISACs) as a promising new generation of targeted therapeutic antibody-drug conjugates (ADCs), that not only activate innate immunity but also stimulate adaptive immunity, providing a dual therapeutic effect to eliminate tumor cells. However, several ISACs are still in the early stages of clinical development or have already failed. Therefore, it is crucial to design ISACs more effectively to overcome their limitations, including high toxicity, strong immunogenicity, long development time, and poor pharmacokinetics. This review aims to summarize the composition and function of ISACs, incorporating current design considerations and ongoing clinical trials. Additionally, the review delves into the current issues with ISACs and potential solutions, such as adjusting the drug-antibody ratio (DAR) to improve the bioavailability of ISACs. By leveraging the affinity and bioavailability-enhancing properties of bispecific antibodies, the utility between antibodies and immunostimulatory agents can be balanced. Commonly used immunostimulatory agents may induce systemic immune reactions, and BTK (Bruton's tyrosine kinase) inhibitors can regulate immunogenicity. Finally, the concept of grafting ADC's therapeutic principles is simple, but the combination of payload, linker, and targeted functional molecules is not a simple permutation and combination problem. The development of conjugate drugs faces more complex pharmacological and toxicological issues. Standing on the shoulders of ADC, the development and application scenarios of ISAC are endowed with broader space.

Dysregulation of noncoding RNA in chordoma; implications in identifying potential targets for novel therapeutic approaches.

Chordoma is a rare form of bone cancer develops in the spinal cord and skull. Instead of conventional (radio/chemotherapies) and targeted therapies, the disease is associated with high rate of recurrence and poor patient survival. Thus, for better disease management, the molecular pathogenesis of chordoma should be studied in detail to identify dysregulated biomolecules that can be targeted by novel therapeutics. Recent research showed frequent dysregulation of long noncoding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) in association with aggressive tumor phenotypes like cell proliferation, migration, invasion, and metastasis in a variety of cancers, including chordoma. Apart from diagnostic and prognostic importance, noncoding RNAs may serve as promising targets for novel therapeutics in cancer. In this review, we summarized a list of miRNAs, lncRNAs, and circRNA found to be dysregulated in chordoma from available data published in relevant databases (PubMed), as such an approach seems to be rare to date. The dysregulated noncoding RNAs were also associated with adverse tumor phenotypes to assess the impact on disease pathogenesis and, associated downstream molecular pathways were focused. Synthetic compounds and natural products that were reported to target the noncoding RNAs in other malignancies were also listed from published literature and proposed as potential therapeutic agents in chordoma. This review will provide information for further research on chordoma focusing on detailed characterization of dysregulated lncRNAs, miRNAs, and circRNA to understand the disease pathogenesis and, exploration of suitable natural and synthetic products targeting dysregulated non-coding RNAs to develop effective therapeutic measures.

Ribosome biogenesis and ribosomal proteins in cancer stem cells: a new therapeutic prospect.

Ribosome has been considered as the fundamental macromolecular machine involved in protein synthesis in both prokaryotic and eukaryotic cells. This protein synthesis machinery consists of several rRNAs and numerous proteins. All of these factors are synthesized, translocated and assembled in a tightly regulated process known as ribosome biogenesis. Any impairment in this process causes development of several diseases like cancer. According to growing evidences, cancer cells display alteration of several ribosomal proteins. Besides, most of them are considered as key molecules involved in ribosome biogenesis, suggesting a correlation between those proteins and formation of ribosomes. Albeit, defective ribosome biogenesis in several cancers has gained prime importance, regulation of this process in cancer stem cells (CSCs) are still unrecognized. In this article, we aim to summarize the alteration of ribosome biogenesis and ribosomal proteins in CSCs. Moreover, we want to highlight the relation of ribosome biogenesis with hypoxia and drug resistance in CSCs based on the existing evidences. Lastly, this review wants to pay attention about the promising anti-cancer drugs which have potential to inhibit ribosome biogenesis in cancer cells as well as CSCs.

Biological and genomic characteristics of three novel bacteriophages and a phage-plasmid of Klebsiella pneumoniae.

Bacteriophages have emerged as promising candidates for the treatment of difficult-to-treat bacterial infections. The aim of this study is to isolate and characterize phages infecting carbapenem-resistant and extended-spectrum beta-lactamase producer Klebsiella pneumoniae isolates. Water samples were taken for the isolation of bacteriophages. One-step growth curve, the optimal multiplicity of infection (MOI), thermal and pH stabilities, transmission electron microscopy and whole-genome sequencing of phages were studied. Four phages were isolated and named Klebsiella phage Kpn02, Kpn17, Kpn74, and Kpn13. The optimal MOI and latent periods of phage Kpn02, Kpn17, Kpn74, and Kpn13 were 10, 1, 0.001, and 100 PFU/CFU and 20, 10, 20, and 30 min, respectively. Burst sizes ranged from 811 to 2363. No known antibiotic resistance and virulence genes were identified. No tRNAs were detected except Klebsiella phage Kpn02 which encodes 24 tRNAs. Interestingly, Klebsiella phage Kpn74 was predicted to be a lysogenic phage whose prophage is a linear plasmid molecule with covalently closed ends. Of the Klebsiella-infecting phages presented in current study, virulent phages suggest that they may represent candidate therapeutic agents against MDR K. pneumoniae, based on short latent period, high burst sizes and no known antibiotic resistance and virulence genes in their genomes.

Anti-cancer therapeutic agents and carpal tunnel syndrome: Clinical, electrodiagnostic, and ultrasound findings in seven patients.

INTRODUCTION: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and rarely develops after drug therapy. This study describes the clinical, electrodiagnostic (EDX), and ultrasound (US) findings in seven patients who experienced CTS due to anti-cancer therapeutic agents. METHODS: All patients underwent EDX testing, and four patients had an US study. RESULTS: CTS occurred in four patients with aromatase inhibitors, two with immune checkpoint inhibitors, and one with a selective estrogen receptor modulator. The mean duration between initiation of the anti-cancer therapeutic agents and symptom onset was 6 weeks (range: 2-12 weeks). Decreased digit sensation was noted in all patients; wasting and weakness of the abductor pollicis brevis (APB) was observed in three (42.8%) patients. The compound muscle action potentials (CMAP) of the APB and sensory nerve action potentials of the second or third digit could not be recorded in two (28.5%) and four (57.1%) patients, respectively. The needle EMG detected fibrillations and positive sharp waves in the APB in two patients. The motor unit potentials of the APB were decreased with large polyphasics in three (42.8%) patients. Of the four patients who underwent US testing, all had increased cross-sectional area of the median nerve at the carpal tunnel inlet, three (75%) had thenar muscle atrophy, and two (50%) had a loss of fascicular pattern. Three (42.8%) patients underwent a CTR. CONCLUSIONS: Physicians should be cognizant of the relationship between anti-cancer therapeutic agents and CTS. EDX studies and US play important roles in the diagnostic assessment of such patients.

Emerging Therapeutic Strategies in Sarcopenia: An Updated Review on Pathogenesis and Treatment Advances.

Sarcopenia is a prevalent degenerative skeletal muscle condition in the elderly population, posing a tremendous burden on diseased individuals and healthcare systems worldwide. Conventionally, sarcopenia is currently managed through nutritional interventions, physical therapy, and lifestyle modification, with no pharmaceutical agents being approved for specific use in this disease. As the pathogenesis of sarcopenia is still poorly understood and there is no treatment recognized as universally effective, recent research efforts have been directed at better comprehending this illness and diversifying treatment strategies. In this respect, this paper overviews the new advances in sarcopenia treatment in correlation with its underlying mechanisms. Specifically, this review creates an updated framework for sarcopenia, describing its etiology, pathogenesis, risk factors, and conventional treatments, further discussing emerging therapeutic approaches like new drug formulations, drug delivery systems, stem cell therapies, and tissue-engineered scaffolds in more detail.

Development of Potential Therapeutic Agents from Black Elderberries (the Fruits of Sambucus nigra L.).

Elderberry (Sambucus nigra L.) is a widespread deciduous shrub, of which the fruits (elderberries) are used in the food industry to produce different types of dietary supplement products. These berries have been found to show multiple bioactivities, including antidiabetic, anti-infective, antineoplastic, anti-obesity, and antioxidant activities. An elderberry extract product, Sambucol®, has also been used clinically for the treatment of viral respiratory infections. As the major components, phenolic compounds, such as simple phenolic acids, anthocyanins and other flavonoids, and tannins, show promising pharmacological effects that could account for the bioactivities observed for elderberries. Based on these components, salicylic acid and its acetate derivative, aspirin, have long been used for the treatment of different disorders. Dapagliflozin, an FDA-approved antidiabetic drug, has been developed based on the conclusions obtained from a structure-activity relationship study for a simple hydrolyzable tannin, ß-pentagalloylglucoside (ß-PGG). Thus, the present review focuses on the development of therapeutic agents from elderberries and their small-molecule secondary metabolites. It is hoped that this contribution will support future investigations on elderberries.

The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review.

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion.

[Recent findings and advances in treatment of chronic myeloid leukemia].

Imatinib, the first ABL-tyrosine kinase inhibitor (TKI), was approved in 2000 for the treatment of chronic myeloid leukemia (CML). Second- and third-generation TKIs, as well as asciminib, which targets a different site of BCR-ABL1 (the myristoyl pocket), were later approved in 2022. Currently, six drugs are approved for the treatment of CML. Revisions to the clinical guidelines for hematopoietic tumors in 2023 provided new guidance on the utility of new agents as well as TKI dose reduction and treatment discontinuation. This article outlines recently reported predictions regarding TKI treatment response, the role of asciminib in the treatment of CML, and development of new agents, as well as the latest findings regarding the current state of TKI treatment discontinuation.

Metal Nanoparticles as Novel Agents for Lung Cancer Diagnosis and Therapy.

Lung cancer is one of the most common malignancies worldwide and contributes to most cancer-related morbidity and mortality cases. During the past decades, the rapid development of nanotechnology has provided opportunities and challenges for lung cancer diagnosis and therapeutics. As one of the most extensively studied nanostructures, metal nanoparticles obtain higher satisfaction in biomedical applications associated with lung cancer. Metal nanoparticles have enhanced almost all major imaging strategies and proved great potential as sensor for detecting cancer-specific biomarkers. Moreover, metal nanoparticles could also improve therapeutic efficiency via better drug delivery, improved radiotherapy, enhanced gene silencing, and facilitated photo-driven treatment. Herein, the recently advanced metal nanoparticles applied in lung cancer therapy and diagnosis are summarized. Future perspective on the direction of metal-based nanomedicine is also discussed. Stimulating more research interests to promote the development of metal nanoparticles in lung cancer is devoted.

How Much is Enough? Impact of Efflux Transporters on Drug delivery Leading to Efficacy in the Treatment of Brain Tumors.

The lack of effective chemotherapeutic agents for the treatment of brain tumors is a serious unmet medical need. This can be attributed, in part, to inadequate delivery through the blood-brain barrier (BBB) and the tumor-cell barrier, both of which have active efflux transporters that can restrict the transport of many potentially effective agents for both primary and metastatic brain tumors. This review briefly summarizes the components and function of the normal BBB with respect to drug penetration into the brain and the alterations in the BBB due to brain tumor that could influence drug delivery. Depending on what is rate-limiting a compound's distribution, the limited permeability across the BBB and the subsequent delivery into the tumor cell can be greatly influenced by efflux transporters and these are discussed in some detail. Given these complexities, it is necessary to quantify the extent of brain distribution of the active (unbound) drug to compare across compounds and to inform potential for use against brain tumors. In this regard, the metric, Kp,uu, a brain-to-plasma unbound partition coefficient, is examined and its current use is discussed. However, the extent of active drug delivery is not the only determinant of effective therapy. In addition to Kp,uu, drug potency is an important parameter that should be considered alongside drug delivery in drug discovery and development processes. In other words, to answer the question - How much is enough? - one must consider how much can be delivered with how much needs to be delivered.

In vitro and Pharmacoinformatics-based phytochemical screening for anticancer impacts of pistachio hull essential oil on AGS, PLC/PRF/5, and CACO2 cell lines.

BACKGROUND: The essential oil of pistacia vera (cv. Ohadi) hull (PHEO) was checked using gas chromatography mass spectrometry (GC/MS) analysis. It was studied the genes of the wnt pathway with a certain concentration of PHEO on Human gastric cancer (AGS), human hepatocellular carcinoma (PLC/PRF/5), and human colon cancer (CACO2) cell lines. METHODS AND RESULTS: After evaluating the survival rate of cancer cells by MTT test and determining IC50, pistachio hull essential oil (PHEO) was used for 24-hours to treat the cells. After RNA extraction, the expression of wnt pathway genes was evaluated by Real-Time PCR. Considering the crucial role of ß-catenin accumulation and its effect on the progression of gastrointestinal cancers, Western blot analysis was also used to determine the effect of PHEO in protein expression of ß-catenin inhibition. Also, an in silico analysis was carried out to investigate the effect of PHEO extracted compounds on protein expression of ß-catenin and FZD7 inhibition. According to the results, wnt pathway genes were changed in samples treated using PHEO. The results showed the up-regulation of GSK-3ß and down-regulation of Wnt-1, LEF-1, TCF1, and CTNNB1 genes compared to the control. CONCLUSION: We showed inhibition of ß-catenin protein in cancer cell lines. Four compounds of PHEO were suggested to have an inhibition effect on ß-catenin and FZD7. These compounds can be useful in the treatment of gastrointestinal cancers. Altogether, the inhibitory role of ß-catenin protein can be very effective and can be considered one of the therapeutic goals in the treatment of gastrointestinal cancers.

Nanotechnology: A promising strategy for the control of parasitic infections.

Annually 3.5 billion people are affected by the parasitic infections that results around 200,000 deaths per annum. Major diseases occur due to the neglected tropical parasites. Variety of methods have been used to treat the parasitic infections but now these methods have become ineffective due to the development of resistance in the parasites and some other side effects of traditional treatment methods. Previous methods include use of chemotherapeutic agents and ethnobotanicals for the treatment of parasites. Parasites have developed resistance against the chemotherapeutic agents. A major problem related to Ethnobotanicals is the unequal availability of drug at the target site which is responsible for the low efficacy of drug. Nanotechnology technology involves the manipulation of matter on a nanoscale level and has the potential to enhance the efficacy and safety of existing drugs, develop new treatments, and improve diagnostic methods for parasitic infections. Nanoparticles can be designed to selectively target parasites while minimizing toxicity to the host, and they can also be used to improve drug delivery and increase drug stability. Some important nanotechnology-based tools for parasitic control include nanoparticle-based drug delivery, nanoparticle diagnostics, nanoparticle vaccines, nanoparticle insecticides. Nanotechnology has the potential to revolutionize the field of parasitic control by providing new methods for detection, prevention and treatment of parasitic infections. This review discusses the current state of nanotechnology-based approaches for controlling parasitic infections and highlights their potential to revolutionize the field of parasitology.

Extracellular Vesicles and Pathological Cardiac Hypertrophy.

Pathological cardiac hypertrophy is a well-recognized risk factor for cardiovascular diseases (CVDs). Although lots of efforts have been made to illustrate the underlying molecular mechanisms, many issues remain undiscovered. Recently, intercellular communication by delivering small molecules between different cell types in the progression of cardiac hypertrophy has been reported, including bioactive nucleic acids or proteins. These extracellular vesicles (EVs) may act in an autocrine or paracrine manner between cardiomyocytes and noncardiomyocytes to provoke or inhibit cardiac remodeling and hypertrophy. Besides, EVs can be used as novel diagnostic or prognostic biomarkers in cardiac hypertrophy and also may serve as potential therapeutic targets due to its biocompatible nature and low immunogenicity. In this chapter, we will first summarize the current knowledge about EVs from different cells in pathological cardiac hypertrophy. Then, we will focus on the value of EVs as therapeutic agents and biomarkers for pathological myocardial hypertrophy.

Identification of lncRNA-miRNA-mRNA Regulatory Network and Therapeutic Agents for Skin Aging by Bioinformatics Analysis.

Skin aging is the most intuitive manifestation of aging. Skin aging inevitably leads to cosmetic and psychological problems, and even diseases. The present study aims to research the pathological and molecular mechanisms underlying skin aging and identify the therapeutic agents for reversing skin aging. Two available gene expression datasets (GSE55118 and GSE72264) for skin aging were downloaded from Gene Expression Omnibus, followed by bioinformatic analyses performed on the datasets. Firstly, 169 crucial mRNAs, 27 crucial miRNAs and 50 crucial lncRNAs closely related to skin aging were identified by weighted gene co-expression network analysis. Then, function Enrichment Analysis performed by Metascape database showed that skin aging involves a variety of biological functions, such as detection of stimulus, response to steroid hormone and water channel activity, regulation of muscle contraction. Next, ten hub genes including AQP4, TRPM8, TBR1, NTSR2, MPPED1, BARHL2, PAX9, CPN1, CES3, and CHGB were screened out by the protein-protein interaction analysis. Next, the "lncRNA-miRNA-mRNA" network and the "lncRNA-miRNA-hub mRNA" network were constructed to explore the competing endogenous RNAs mechanism of skin aging. Finally, ten significant potential small molecules mitigating skin aging were screened using CMAP platform, including tretinoin, pifithrin, selamectin, entinostat, bretazenil, syringic-acid, BRD-K96475865, emedastine, abacavir, and rotenone, and their reliability was verified by molecular docking experiments. The present study provided basis for revealing the molecular mechanism of skin aging and identified the potential candidate drugs for mitigating skin aging.

Extracellular Vesicles as "Very Important Particles" (VIPs) in Aging.

In recent decades, extracellular vesicles have been recognized as "very important particles" (VIPs) associated with aging and age-related disease. During the 1980s, researchers discovered that these vesicle particles released by cells were not debris but signaling molecules carrying cargoes that play key roles in physiological processes and physiopathological modulation. Following the International Society for Extracellular Vesicles (ISEV) recommendation, different vesicle particles (e.g., exosomes, microvesicles, oncosomes) have been named globally extracellular vesicles. These vesicles are essential to maintain body homeostasis owing to their essential and evolutionarily conserved role in cellular communication and interaction with different tissues. Furthermore, recent studies have shown the role of extracellular vesicles in aging and age-associated diseases. This review summarizes the advances in the study of extracellular vesicles, mainly focusing on recently refined methods for their isolation and characterization. In addition, the role of extracellular vesicles in cell signaling and maintenance of homeostasis, as well as their usefulness as new biomarkers and therapeutic agents in aging and age-associated diseases, has also been highlighted.

Review of the Application of Dual Drug Delivery Nanotheranostic Agents in the Diagnosis and Treatment of Liver Cancer.

Liver cancer has high incidence and mortality rates and its treatment generally requires the use of a combination treatment strategy. Therefore, the early detection and diagnosis of liver cancer is crucial to achieving the best treatment effect. In addition, it is imperative to explore multimodal combination therapy for liver cancer treatment and the synergistic effect of two liver cancer treatment drugs while preventing drug resistance and drug side effects to maximize the achievable therapeutic effect. Gold nanoparticles are used widely in applications related to optical imaging, CT imaging, MRI imaging, biomarkers, targeted drug therapy, etc., and serve as an advanced platform for integrated application in the nano-diagnosis and treatment of diseases. Dual-drug-delivery nano-diagnostic and therapeutic agents have drawn great interest in current times. Therefore, the present report aims to review the effectiveness of dual-drug-delivery nano-diagnostic and therapeutic agents in the field of anti-tumor therapy from the particular perspective of liver cancer diagnosis and treatment.