Stem Cells and Natural Agents in the Management of Neurodegenerative Diseases: A New Approach.

Neurodegenerative diseases refer to a group of neurological disorders as a consequence of various destructive illnesses, that predominantly impact neurons in the central nervous system, resulting in impairments in certain brain functions. Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and other neurodegenerative disorders represent a major risk to human health. In order to optimize structural and functional recovery, reconstructive methods integrate many approaches now, to address the complex and multivariate pathophysiology of neurodegenerative disorders. Stem cells, with their unique property of regeneration, offer new possibilities in regenerative and reconstructive medicine. Concurrently, there is an important role for natural products in controlling many health sufferings and they can delay or even prevent the onset of various diseases. In addition, due to their therapeutic properties, they have been used as neuroprotective agents to treat neurodegenerative disorders. After decades of intensive research, scientists made advances in treating these disorders so far, but current therapies are still not capable of preventing the illnesses from progressing. Therefore, in this review, we focused on a new perspective combining stem cells and natural products as an innovative therapy option in the management of neurodegenerative diseases.

Multifunctionality of Calebin A in inflammation, chronic diseases and cancer.

Chronic diseases including cancer have high case numbers as well as mortality rates. The efficient treatment of chronic diseases is a major ongoing medical challenge worldwide, because of their complexity and many inflammatory pathways such as JNK, p38/MAPK, MEK/ERK, JAK/STAT3, PI3K and NF-κB among others being implicated in their pathogenesis. Together with the versatility of chronic disease classical mono-target therapies are often insufficient. Therefore, the anti-inflammatory as well as anti-cancer capacities of polyphenols are currently investigated to complement and improve the effect of classical anti-inflammatory drugs, chemotherapeutic agents or to overcome drug resistance of cancer cells. Currently, research on Calebin A, a polyphenolic component of turmeric (Curcuma longa), is becoming of growing interest with regard to novel treatment strategies and has already been shown health-promoting as well as anti-tumor properties, including anti-oxidative and anti-inflammatory effects, in diverse cancer cells. Within this review, we describe already known anti-inflammatory activities of Calebin A via modulation of NF-κB and its associated signaling pathways, linked with TNF-α, TNF-ß and COX-2 and further summarize Calebin A's tumor-inhibiting properties that are known up to date such as reduction of cancer cell viability, proliferation as well as metastasis. We also shed light on possible future prospects of Calebin A as an anti-cancer agent.

ß1-Integrin plays a major role in resveratrol-mediated anti-invasion effects in the CRC microenvironment.

Background: Tumor microenvironment (TME) is one of the most important factors in tumor aggressiveness, with an active exchange between tumor and other TME-associated cells that promotes metastasis. The tumor-inhibitory effect of resveratrol on colorectal cancer (CRC) cells has been frequently reported. However, whether resveratrol can specifically suppress TME-induced CRC invasion via ß1-integrin receptors has not been fully elucidated yet. Methods: Two CRC cell lines (HCT116, RKO) were cultured in multicellular, pro-inflammatory 3D-alginate TME cultures (containing fibroblasts, T-lymphocytes) to investigate the role of ß1-integrin receptors in the anti-invasive and anti-metastatic effect of resveratrol by antisense oligonucleotides (ASO). Results: Our results show that resveratrol dose-dependently suppressed the migration-promoting adhesion adapter protein paxillin and simultaneously enhanced the expression of E-cadherin associated with the phenotype change of CRC cells, and their invasion. Moreover, resveratrol blocked TME-induced phosphorylation and nuclear translocation of p65-NF-κB, which was associated with changes in the expression pattern of epithelial-mesenchymal-transition-related biomarkers (slug, vimentin, E-cadherin), metastasis-related factors (CXCR4, MMP-9, FAK), and apoptosis (caspase-3). Finally, transient transfection of ß1-integrin, in contrast to knockdown of NF-κB, abrogated most anti-invasive, anti-metastatic effects as well as downstream signaling of resveratrol, resulting in a concomitant increase in CRC cell invasion, indicating a central role of ß1-integrin receptors in the anti-invasive function of resveratrol. Conclusion: These results demonstrate for the first time that silencing ß1-integrins may suppress, at least in part the inhibitory effects of resveratrol on invasion and migration of CRC cells, underscoring the crucial homeostatic role of ß1-integrin receptors.

Naringenin: A potential flavonoid phytochemical for cancer therapy.

Naringenin is an important phytochemical which belongs to the flavanone group of polyphenols, and is found mainly in citrus fruits like grapefruits and others such as tomatoes and cherries plus medicinal plants derived food. Available evidence demonstrates that naringenin, as herbal medicine, has important pharmacological properties, including anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, and anti-cancer activities. Collected data from in vitro and in vivo studies show the inactivation of carcinogens after treatment with pure naringenin, naringenin-loaded nanoparticles, and also naringenin in combination with anti-cancer agents in various malignancies, such as colon cancer, lung neoplasms, breast cancer, leukemia and lymphoma, pancreatic cancer, prostate tumors, oral squamous cell carcinoma, liver cancer, brain tumors, skin cancer, cervical and ovarian cancer, bladder neoplasms, gastric cancer, and osteosarcoma. Naringenin inhibits cancer progression through multiple mechanisms, like apoptosis induction, cell cycle arrest, angiogenesis hindrance, and modification of various signaling pathways including Wnt/ß-catenin, PI3K/Akt, NF-ĸB, and TGF-ß pathways. In this review, we demonstrate that naringenin is a natural product with potential for the treatment of different types of cancer, whether it is used alone, in combination with other agents, or in the form of the naringenin-loaded nanocarrier, after proper technological encapsulation.

Modulation of Inflammation by Plant-Derived Nutraceuticals in Tendinitis.

Tendinitis (tendinopathy) is a pro-inflammatory and painful tendon disease commonly linked with mechanical overuse and associated injuries, drug abuse, and lifestyle factors (including poor diet and physical inactivity) that causes significant healthcare expenditures due to its high incidence. Nuclear factor kappa B (NF-κB) is one of the major pro-inflammatory transcription factors, along with other inflammation signaling pathways, triggered by a variety of stimuli, including cytokines, endotoxins, physical and chemical stressors, hypoxia, and other pro-inflammatory factors. Their activation is known to regulate the expression of a multitude of genes involved in inflammation, degradation, and cell death. The pathogenesis of tendinitis is still poorly understood, whereas efficient and sustainable treatment is missing. Targeting drug suppression of the key inflammatory regulators represents an effective strategy for tendinitis therapy, but requires a comprehensive understanding of their principles of action. Conventional monotherapies are often ineffective and associated with severe side effects in patients. Therefore, agents that modulate multiple cellular targets represent therapeutic treatment potential. Plant-derived nutraceuticals have been shown to act as multi-targeting agents against tendinitis via various anti-oxidant and anti-inflammatory mechanisms, whereat they were able to specifically modulate numerous signaling pathways, including NF-κB, p38/MAPK, JNK/STAT3, and PI3K/Akt, thus down-regulating inflammatory processes. This review discusses the utility of herbal nutraceuticals that have demonstrated safety and tolerability as anti-inflammatory agents for the prevention and treatment of tendinitis through the suppression of catabolic signaling pathways. Limitations associated with the use of nutraceuticals are also described.

Bacteria-Mediated Modulatory Strategies for Colorectal Cancer Treatment.

Colorectal cancer (CRC) is one of the most common tumors worldwide, with a higher rate of distant metastases than other malignancies and with regular occurrence of drug resistance. Therefore, scientists are forced to further develop novel and innovative therapeutic treatment strategies, whereby it has been discovered microorganisms, albeit linked to CRC pathogenesis, are able to act as highly selective CRC treatment agents. Consequently, researchers are increasingly focusing on bacteriotherapy as a novel therapeutic strategy with less or no side effects compared to standard cancer treatment methods. With multiple successful trials making use of various bacteria-associated mechanisms, bacteriotherapy in cancer treatment is on its way to become a promising tool in CRC targeting therapy. In this study, we describe the anti-cancer effects of bacterial therapy focusing on the treatment of CRC as well as diverse modulatory mechanisms and techniques that bacteriotherapy offers such as bacterial-related biotherapeutics including peptides, toxins, bacteriocins or the use of bacterial carriers and underlying molecular processes to target colorectal tumors.

Calebin A, a Compound of Turmeric, Down-Regulates Inflammation in Tenocytes by NF-κB/Scleraxis Signaling.

Calebin A (CA) is one of the active constituents of turmeric and has anti-inflammatory and antioxidant effects. Excessive inflammation and cell apoptosis are the main causes of tendinitis and tendinopathies. However, the role of CA in tendinitis is still unclear and needs to be studied in detail. Tenocytes in monolayer or 3D-alginate cultures in the multicellular tendinitis microenvironment (fibroblast cells) with T-lymphocytes (TN-ME) or with TNF-α or TNF-ß, were kept without treatment or treated with CA to study their range of actions in inflammation. We determined that CA blocked TNF-ß-, similar to TNF-α-induced adhesiveness of T-lymphocytes to tenocytes. Moreover, immunofluorescence and immunoblotting showed that CA, similar to BMS-345541 (specific IKK-inhibitor), suppressed T-lymphocytes, or the TNF-α- or TNF-ß-induced down-regulation of Collagen I, Tenomodulin, tenocyte-specific transcription factor (Scleraxis) and the up-regulation of NF-κB phosphorylation; thus, its translocation to the nucleus as well as various NF-κB-regulated proteins was implicated in inflammatory and degradative processes. Furthermore, CA significantly suppressed T-lymphocyte-induced signaling, similar to TNF-ß-induced signaling, and NF-κB activation by inhibiting the phosphorylation and degradation of IκBα (an NF-κB inhibitor) and IκB-kinase activity. Finally, inflammatory TN-ME induced the functional linkage between NF-κB and Scleraxis, proposing that a synergistic interaction between the two transcription factors is required for the initiation of tendinitis, whereas CA strongly attenuated this linkage and subsequent inflammation. For the first time, we suggest that CA modulates TN-ME-promoted inflammation in tenocytes, at least in part, via NF-κB/Scleraxis signaling. Thus, CA seems to be a potential bioactive compound for the prevention and treatment of tendinitis.

Exosome application in tumorigenesis: diagnosis and treatment of melanoma.

Melanoma is the most aggressive of skin cancer derived from genetic mutations in the melanocytes. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. However, the efficiency of these strategies may be decreased due to the development of diverse resistance mechanisms. Here, it has been proven that therapeutic monoclonal antibodies (mAbs) can improve the efficiency of melanoma therapies and also, cancer vaccines are another approach for the treatment of melanoma that has already improved clinical outcomes in these patients. The use of antibodies and gene vaccines provides a new perspective in melanoma treatment. Since the tumor microenvironment is another important factor for cancer progression and metastasis, in recent times, a mechanism has been identified to provide an opportunity for melanoma cells to communicate with remote cells. This mechanism is involved by a novel molecular structure, named extracellular vesicles (EVs). Depending on the functional status of origin cells, exosomes contain various cargos and different compositions. In this review, we presented recent progress of exosome applications in the treatment of melanoma. Different aspects of exosome therapy and ongoing efforts in this field will be discussed too.

Biomedical applications of silkworm (Bombyx Mori) proteins in regenerative medicine (a narrative review).

Silk worm (Bombyx Mori) protein, have been considered as potential materials for a variety of advanced engineering and biomedical applications for decades. Recently, silkworm silk has gained significant importance in research attention mainly because of its remarkable and exceptional mechanical properties. Silk has already been shown to have unique interactions with cells in tissues through bio-recognition units. The natural silk contains fibroin and sericin and has been used in various tissues of the human body (skin, bone, nerve, and so on). Besides, silk also still has anti-cancer, anti-tyrosinase, anti-coagulant, anti-oxidant, anti-bacterial, and anti-diabetic properties. This article is supposed to describe the diverse biomedical capabilities of B. Mori silk as the appropriate biomaterial among the assorted natural and artificial polymers that are presently accessible, and ideal for usage in regenerative medicine fields.

Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies.

Rheumatoid arthritis (RA) is considered a chronic systemic, multi-factorial, inflammatory, and progressive autoimmune disease affecting many people worldwide. While patients show very individual courses of disease, with RA focusing on the musculoskeletal system, joints are often severely affected, leading to local inflammation, cartilage destruction, and bone erosion. To prevent joint damage and physical disability as one of many symptoms of RA, early diagnosis is critical. Auto-antibodies play a pivotal clinical role in patients with systemic RA. As biomarkers, they could help to make a more efficient diagnosis, prognosis, and treatment decision. Besides auto-antibodies, several other factors are involved in the progression of RA, such as epigenetic alterations, post-translational modifications, glycosylation, autophagy, and T-cells. Understanding the interplay between these factors would contribute to a deeper insight into the causes, mechanisms, progression, and treatment of the disease. In this review, the latest RA research findings are discussed to better understand the pathogenesis, and finally, treatment strategies for RA therapy are presented, including both conventional approaches and new methods that have been developed in recent years or are currently under investigation.

Curcumin Attenuates Environment-Derived Osteoarthritis by Sox9/NF-kB Signaling Axis.

Inflammation has a fundamental impact on the pathophysiology of osteoarthritis (OA), a common form of degenerative arthritis. It has previously been established that curcumin, a component of turmeric (Curcuma longa), has anti-inflammatory properties. This research evaluates the potentials of curcumin on the pathophysiology of OA in vitro. To explore the anti-inflammatory efficacy of curcumin in an inflamed joint, an osteoarthritic environment (OA-EN) model consisting of fibroblasts, T-lymphocytes, 3D-chondrocytes is constructed and co-incubated with TNF-α, antisense oligonucleotides targeting NF-kB (ASO-NF-kB), or an IkB-kinase (IKK) inhibitor (BMS-345541). Our results show that OA-EN, similar to TNF-α, suppresses chondrocyte viability, which is accompanied by a significant decrease in cartilage-specific proteins (collagen II, CSPG, Sox9) and an increase in NF-kB-driven gene proteins participating in inflammation, apoptosis, and breakdown (NF-kB, MMP-9, Cox-2, Caspase-3). Conversely, similar to knockdown of NF-kB at the mRNA level or at the IKK level, curcumin suppresses NF-kB activation, NF-kB-promotes gene proteins derived from the OA-EN, and stimulates collagen II, CSPG, and Sox9 expression. Furthermore, co-immunoprecipitation assay shows that curcumin reduces OA-EN-mediated inflammation and chondrocyte apoptosis, with concomitant chondroprotective effects, due to modulation of Sox-9/NF-kB signaling axis. Finally, curcumin selectively hinders the interaction of p-NF-kB-p65 directly with DNA-this association is disrupted through DTT. These results suggest that curcumin suppresses inflammation in OA-EN via modulating NF-kB-Sox9 coupling and is essential for maintaining homeostasis in OA by balancing chondrocyte survival and inflammatory responses. This may contribute to the alternative treatment of OA with respect to the efficacy of curcumin.