
==== Front
Biomed J
Biomed J
Biomedical Journal
2319-4170
2320-2890
Chang Gung University

S2319-4170(24)00076-3
10.1016/j.bj.2024.100773
100773
Highlights
Ancient wisdom and modern innovations: Methods of administering healing
Kattner Aila Akosua aila.kattner@gmail.com

Freelance Journalist, Berlin, Germany
23 7 2024
8 2024
23 7 2024
47 4 10077322 7 2024
22 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
This issue of the Biomedical Journal highlights major advancements in drug delivery, including aptamer-functionalized liposomes and nanozymes. A new biomarker combination shows promise for improved diagnosis of idiopathic pulmonary fibrosis. Mesenchymal stem cells are suggested to mitigate inflammation in systemic lupus erythematosus, and a potential positive feedback loop driven by a prevalent mRNA modification is suggested to enhance NSCLC progression. Additional articles explore a pathological impact on autophagy leading to muscle dysfunction, the benefits of integrating an orphan drug with standard therapy for glioblastoma patients, and the influence of transcriptional super-enhancers in early-stage esophageal squamous cell carcinoma. Finally, this issue provides insights into the roles of different Blastocystis subtypes, and the use of laser light for treating infantile hemangioma.

Keywords

Nanozyme
Lupus
NSCLC
Glioblastoma
ESCC
Blastocystis
==== Body
pmc1 Spotlight on reviews

Ayurveda, meaning "science of life," is a traditional Indian medicine system over 3000 years old. The ancient knowledge known as Vedas contains numerous formulations for treating various diseases, listing around 600 drugs of plant, animal, and mineral origin. Other verses describe hundreds of types of surgical instruments and their uses. Drug administration in Ayurveda is highly developed, involving techniques such as infusion, powdering, mixing herbs, creating ash products from metals, and using carrier materials like oils [1,2].

In indigenous African tribes, traditional medicine (TM) was the primary medical system for millions before European colonization. In the TM of the region of Nigeria, for instance, 522 medicinal plant species have been identified. Additionally, the medicinal use of insects has been documented, a number of them addressing ailments untreatable by Western medicine and therapy [3].

Traditional Chinese Medicine (TCM) has a history of at least 3000 years, with classic texts detailing numerous healing and dietary herbs. TCM also encompasses acupuncture and Qi Gong [4]. Aboriginal people in present-day Canada have used medicinal plants for thousands of years, with over 500 species reported in their traditional healthcare systems [5].

In some Amazonian indigenous communities, a secretion from the frog Phyllomedusa bicolor, known as Kambo, is applied transdermally through superficial burns of the skin. The medicine is used to treat infections, as a mental invigorator, analgesic, to boost physical strength and sexual stamina, and to ward off panema, which could be translated as bad luck or a specific type of weakness or depression [[6], [7], [8]].

The complex use of substances from different origins for medical purposes targeting a broad range of physical and mental disturbances required our ancestors to build an impressive level of knowledge, observational skills, and practical expertise to ensure effectiveness of the treatments.

1.1 Tiny marvels

Modern drug delivery technology is relatively young, and modern drug delivery systems (DDSs) involve methods for carrying drugs into or throughout the body, protecting them from degradation as they travel to their target. Until the 1980s, DDS research focused on finding solutions for physicochemical challenges such as water solubility, molecular weight, and release kinetics. The second generation of DDSs tackled biological barriers. Until the 1980s, oral and transdermal formulations providing therapeutic durations up to 24 hours for small molecules dominated the market. Since 1989, efforts have extended drug delivery duration from days to months, occasionally years. The advent of PEGylation in the 1990s marked a new era, and advances in nanomedicine led to the development of lipid nanoparticle formulations for COVID-19 vaccine delivery in 2020.1 [9] Common drug delivery vehicles include micelles, liposomes, and nanoparticles.1 As life expectancy increases and unforeseen challenges like the COVID-19 pandemic arise, the future requires innovative approaches to drug delivery.

The robotic pill for instance can survive the harsh stomach environment, propel itself through intestinal mucus, and disperse its load once it reaches the target area. This method could facilitate the administration of drugs that typically require injection or intravenous delivery, such as insulin.,2,3 Vaccinations through microneedle arrays, each thinner than a strand of human hair, can deliver medications painlessly without reaching the nerves.1 As bigger is not necessarily better, Wong et al. emphasize in this issue of the Biomedical Journal, how aptamers have gained increasing interest due to their smaller size compared to antibodies. Further advantages include their ease of modification and their batch-to-batch consistency. Given that liposomes are highly effective for drug loading, aptamer-functionalized liposomes present promising opportunities for targeted drug delivery. Although the clinical application of these conjugates still remains distant due to challenges such as DNA degradation in the bloodstream, substantial progress has been made. Further pharmacokinetic studies will help address challenges related to safety, circulation, and biodistribution of aptamer-functionalized liposomes, expanding their potential applications beyond cancer therapy to include wound healing, microneedles, and more [10].

1.2 Nanozyme revolution: Catalysts of the future

The past decade has seen a boom in the development of nanomaterials, particularly nanozymes. These materials exhibit intrinsic enzyme-like properties, whilst addressing the limitations of natural enzymes related to stability, durability, cost, storage, controllable activity, and reusability. Nanozymes effectively mimic the catalytic sites of natural enzymes or contain multivalent elements for reactions. Beyond merely substituting enzymes, they provide a versatile platform that interfaces with complex biological environments. Remarkably, beyond regulation of their catalytic activity via pH, H2O2, glutathione concentrations, and oxygen levels in various microenvironments, nanozymes may also be remotely controlled using stimuli like magnetic fields, light, ultrasound, and heat [[11], [12], [13]].

In this journal issue, Han et al. review recent groundbreaking advancements, emphasizing the achievements possible for the application of nanozymes. In biosensing and diagnostics, these artificial enzymes offer a unique approach due to their catalytic capacity for signal amplification and multifunctionality. Redox nanozymes have emerged as powerful tools in therapeutics by regulating reactive oxygen species (ROS) levels. They can stimulate ROS generation as a cancer therapy strategy, catalyze ROS to produce free radicals that kill pathogens, or enable new methods of ROS clearance to combat inflammatory diseases. The precise manipulation of nanozymes facilitates personalized medicine, tailoring treatments to individual patients and optimizing therapeutic outcomes [14] [Fig. 1].Fig. 1 Multifunctional nanozymes offer a multitude of application opportunities, including innovations in targeted therapies, enhanced sensing and diagnostic capabilities, and effective treatments for ROS-related diseases.

Fig. 1

2 Also in this issue

2.1 Reviews

2.1.1 Sniffing out disease

For specific cases, early medical practitioners relied heavily on their sense of smell to identify the cause of human disease. The odor of a patient's skin or breath could indicate diseases such as diabetes, liver failure, or yellow fever.4 Today, exhaled biomarkers are recognized and used to diagnose a wide range of diseases [15].

Idiopathic pulmonary fibrosis (IPF) may present without symptoms and is diagnosed through exclusion. It is crucial to distinguish it from other interstitial lung diseases to opt for the appropriate therapeutic approach. Bartold et al. critically reviewed recent literature on molecular biomarkers potentially useful in IPF diagnosis. They profiled two groups of candidates, breath and sputum biomarkers, which showed promise in predicting and monitoring IPF in preclinical and clinical trials [16].

2.1.2 It's (not) lupus

The TV show "House," which aired for eight seasons starting in 2004, features Dr. Gregory House, a brilliant yet borderline antisocial diagnostician. Much like Sherlock Holmes, House solves medical mysteries with his elite team of young experts while grappling with his own chronic physical pain and drug addiction. Unlike many other shows in its genre, "House" emphasized accurate and consistent portrayals of complex medical conditions, with medical consultants providing detailed explanations of the conditions and procedures to the actors before each scene. In 2008, the iconic show became the most-watched TV drama worldwide, airing in 66 countries. Dr. House was notorious for two recurring statements: "Everybody lies", reflecting his belief in the inherent dishonesty of human beings, and "It's not Lupus”, perhaps hinting at the disease's high morbidity and mortality, making miraculous cures unlikely.,5,6,7,8

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a significant inflammatory response. Despite recent improvements in prognosis, the disease's complexity and the influence of various factors continue to pose major challenges. In search of less toxic and more effective treatments, Barbado reviewed how mesenchymal stem cells (MSCs) could reduce self-antigen-activated lymphocytes and induce antigen-specific immune tolerance, thereby diminishing inflammation and promoting immune balance in SLE [17].

2.2 Original articles

2.2.1 m6A in the molecular web of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) presents serious health threats due to its high incidence, recurrence, and mortality rates in humans. Early diagnosis remains arduous owing to the absence of precise biomarkers [18]. N6-methyladenosine (m6A), the most prevalent mRNA modification, is catalyzed by the methyltransferase complex with methyltransferase-like 3 (METTL3) being its only catalytic subunit. METTL3 has been demonstrated to play key roles in various cancer types [19].

Liu et al. focused their study on the m6A modification of LINC01006, that is involved in NSCLC progression. Their findings revealed that the oncogenes c-MYC, METTL3, and LINC01006 were elevated in NSCLC cells and tissues. c-MYC was found to increase METTL3 expression, which in turn stabilized LINC01006 via m6A modification, suggesting a positive feedback loop [18,20].

2.2.2 Excessive autophagy at the root of muscular dystrophy

Else Loewenheim was among the pioneering women in Germany to specialize in ophthalmology. Despite the patriarchal constraints of the educational system, she was only permitted to attend university as a guest listener, she successfully earned her medical license in 1905. As her male colleagues returned from World War I, she would soon be replaced in her position at the Ophthalmology Clinic at Leipzig University. In her graduation year, Loewenheim had married German neurologist Hans Steinert, whose name is associated with the first accurate clinical characterization of myotonic dystrophy. Steinert's early death in 1911 at age 36 left the widow to navigate the rising Nazi regime alone. Although initially her former marriage to a German offered her some protection, she was forced to go into hiding in 1937 due to her Jewish heritage. Hans Steinert's work laid the foundation for the current understanding of myotonic dystrophy type 1 (DM1), the most common inherited myopathy in adults. DM1 is a multisystem disorder that affects skeletal and smooth muscle, the eye, heart, endocrine, and central nervous systems [[21], [22], [23]].9

In a murine model, Sabater-Arcis et al. investigated their hypothesis that Musashi homolog 2 (MSI2) overexpression contributes to muscle dysfunction. Their research suggested that MSI2 influences miR-7 biogenesis, which subsequently represses muscle catabolism through excessive autophagy. The findings confirmed the pathological role of MSI2 expression levels [24].

2.2.3 An orphan drug elevating standard therapy

A few thousand rare diseases have been identified to date, typically affecting a small portion of the population. However, a disease might be rare in one region but prevalent in another, such as thalassemia, a genetic anemia. Also, some common diseases have rare variants. Orphan drugs are designed to treat rare diseases, and their development is incentivized differently depending on the region. These incentives can include exclusive marketing rights, accelerated marketing processes, tax credits, or specific government research funding.,10,11

The human fusion protein asunercept (CAN008) has orphan drug status. It consists of the extracellular domain of the CD95 receptor linked to the Fc domain of an IgG antibody. This drug has been developed for treating glioblastoma and myelodysplastic syndromes.,12,13,14

Chang et al. combined CAN008 with standard concurrent chemoradiotherapy (CCRT) in their study to evaluate the drug's efficacy in terms of overall survival (OS) in Taiwanese glioblastoma patients. Compared to standard therapy alone, treatment with CAN008 improved both OS and progression-free survival (PFS) in newly diagnosed patients [25].

2.2.4 Super trouper shining the light on ESCC

Esophageal squamous cell carcinoma (ESCC) is among the most aggressive malignancies, with its molecular mechanisms still largely elusive. The asymptomatic nature of early-stage ESCC often results in patients being diagnosed at a locally advanced stage. Despite progress in various treatment regimens over recent decades, survival rates for locally advanced ESCC remain low, with recurrence and metastasis being the primary causes of mortality [26,27].

Transcriptional super-enhancers (SEs) drive the expression of genes that define cell identity. They have been recognized as prognostic markers in several cancers [28,29]. In search of biomarkers for early ESCC detection, Chu et al. investigated secreted proteins encoded by SE-driven genes. Their integrative analysis of multiple datasets highlighted serum EFNA1 and MMP13 as effective markers for the detection of early-stage ESCC [30].

2.2.5 Misrecognized, mislabeled and misunderstood: Blastocystis

Blastocystis, a prevalent eukaryotic organism found in human fecal samples, was initially thought to be a harmless commensal yeast in the human intestine. However, it is now recognized as a protist. Originally, Blastocystis taxonomy was based on the host species, like for instance B. hominis and B. ratti. This classification changed once it was discovered that Blastocystis lacks host specificity, leading to a consensus to classify specific subtypes according to ribosomal lineages. Blastocystis is usually associated with gastrointestinal (GI) symptoms such as diarrhea and irritable bowel syndrome (IBS) and can cause pathogenic infections in immunocompromised individuals. Interestingly, Blastocystis spp subtype (ST) 4 has been suggested as an indicator of a healthy GI tract due to its role in promoting microbiota diversity, which signifies a stable gut environment [[31], [32], [33]].

A study by Huang et al. retrospectively analyzed the prevalence of Blastocystis in nearly 14,000 subjects at a Northern Taiwanese teaching hospital. The research aimed to better understand the impact of different Blastocystis STs on gut microbiota. The team identified six prevalent STs that influence microbial richness and diversity in the gut to a varying degree [34].

2.2.6 Strawberry marks

"God could have made a better berry, but [ …] God never did", claimed an English 17th-century writer, reflecting the high esteem people hold for strawberries. Initially, humans consumed strawberries sparingly. In Ancient Rome, they were considered ornamental and later valued for their medicinal properties, believed to alleviate melancholy from kidney stones. A prominent figure at Emperor Napoleon's court was known for bathing regularly in 22 pounds (10 kg) of strawberry juice. The modern strawberry, beloved by many, resulted from an accidental cross-pollination. In the 1300s, the French began cultivating wood strawberries. In the 1600s, the Virginia strawberry from North America arrived in Europe. Later on, a French spy imported Chilean strawberries, notable for their unprecedented size. Crossing these two New World species in Europe gave rise to the modern strawberry.,15,16,17

Ke et al. studied a common vascular tumor in infants, known as infantile hemangioma (IH) or "strawberry marks".18 Although usually benign, IH can cause aesthetic issues and facial scarring. Using a patient-derived xenograft model, Ke et al. found that exposing hemangioma endothelial cells to alexandrite laser pulses effectively suppressed cell proliferation and induced apoptosis [35].

Disclaimer

None.

Conflicts of interest

The author declares no conflict of interests.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the author used ChatGPT Open AI in order to improve readability and language of the work. After using this tool/service, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Acknowledgments

None.

Peer review under responsibility of Chang Gung University.

1 https://www.nibib.nih.gov/science-education/science-topics/drug-delivery-systems-getting-drugs-their-targets-controlled-manner, last access 07/10/2024.

2 https://www.newscientist.com/article/2340045-robotic-pill-that-delivers-drugs-to-gut-could-end-insulin-injections/, last access 07/10/2024.

3 https://www.sciencenews.org/article/robotic-pill-mucus-gut-deliver-medicine, last access 07/10/2024.

4 https://atlasofscience.org/finding-aroma-clues-in-the-human-breath-to-diagnose-diseases/, last access 07/11/2024.

5 https://www.hulu.com/series/house-ed64adb8-e1bf-490c-84b7-6c16c6d3cce3, last access 07/12/2024.

6 https://medium.com/@michellerichardson_11188/behind-the-scenes-of-house-md-b6b2ce67d6a6, last access 07/12/2024.

7 https://web.archive.org/web/20120401043907/https://www.google.com/hostednews/afp/article/ALeqM5gGRhjVWTeAVMws-iEDRJOY3IDH7g, last access 07/12/2024.

8 https://theconversation.com/why-its-never-lupus-television-illness-and-the-making-of-a-meme-1198, last access 12.

9 https://geschichte.charite.de/aeik/biografie.php?ID=AEIK00708, last access 07/13/2024.

10 https://www.orpha.net/en/other-information/about-rare-diseases, last access 07/11/2024.

11 https://www.orpha.net/en/other-information/about-orphan-drugs?stapage=worldwide, last access 07/11/2024.

12 https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=293009, last access 07/12/2024.

13 https://www.orpha.net/en/drug/substance/82093?name=asunercept, last access 07/11/2024.

14 https://apogenix.com/en/pipeline/clinical-candidates#APG101%E2%80%93Overview, last access 07/11/2024.

15 https://ipm.missouri.edu/meg/2012/5/Strawberry-A-Brief-History/, last access 07/13/2024.

16 https://www.uvm.edu/vtvegandberry/factsheets/strawberryhistory.html, last access 07/13/2024.

17 https://www.canr.msu.edu/news/celebrating_the_history_of_the_strawberry, last access 07/13/2024.

18 https://www.hopkinsmedicine.org/health/conditions-and-diseases/infantile-hemangioma, last access 07/13/2024.
==== Refs
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