Berberine and Coptidis Rhizoma as novel antineoplastic agents: A review of traditional use and biomedical investigations

Ethnopharmacological relevance: Coptidis Rhizoma (Huanglian) and its major component, berberine, have drawn extensive attention toward their antineoplastic effects in the recent years. The antineoplastic effects are related to the Chinese Medicine (CM) properties of Huangliang in treating diseases by removing damp-heat and purging fire and counteracting toxicity. Aim of the review: To trace the long history of the traditional use of Huanglian from folk medicines, especially from Chinese medicine, to recent pharmacological studies of Huanglian and berberine, with an emphasis on their antineoplastic effects and the promise as novel antineoplastic agents. Methods: A total of seven databases were extensively searched for literature research. The terms and keywords for searching included Huanglian, berberine, Coptis, Coptidis Rhizoma, anticancer, anti-invasion, antimatastasis and mechanism. The papers including ours with studies on anticancer and mechanism, pharmacology and toxicology of Huanglian and/or berberine were focused. Results: In view of traditional use, the anticancer effects of Huanglian can be ascribed to its CM trait by removing damp-heat, fire and toxicity. From modern biomedical studies, anticancer effects have been demonstrated in both Huanglian and berberine. The underlying molecular mechanisms involve cell-cycle arrest, apoptosis induction and anti-inflammation. Berberine is an essential anticancer compound in Huanglian. In some studies, the use of Huanglian was shown to be more effective and beneficial than the use of berberine alone. The presence of other protoberberine-type alkaloids in Huanglian might give synergistic effects for the anticancer effects. Berberine also demonstrates effects of antiangiogenesis, anti-invasion and anti-metastasis in some cancer cell lines, however, more investigations are required to unravel the underlying mechanisms involved. Conclusions: The modern evidences of treating cancer with Huanglian and berberine have a strong linkage with traditional concept and rules of using Huanglian in CM practice. As anticancer candidates with low toxicity, berberine and its altered structure, as well as Huanglian and its formulae, will attract scientists to pursue the potential anticancer effects and the mechanisms by using technologies of genomics, proteomics and other advanced approaches. On the other hand, relatively few in vivo studies have been conducted on anticancer effects of Huanglian and berberine. The clinical application of berberine or Huanglian as novel cancer therapeutic agents requires in vivo validations and further investigations of their anticancer mechanisms. © 2009 Elsevier Ireland Ltd. All rights reserved.published_or_final_versio

Chronic Stress, Inflammation, and Colon Cancer: A CRH System-Driven Molecular Crosstalk.

Chronic stress is thought to be involved in the occurrence and progression of multiple diseases, via mechanisms that still remain largely unknown. Interestingly, key regulators of the stress response, such as members of the corticotropin-releasing-hormone (CRH) family of neuropeptides and receptors, are now known to be implicated in the regulation of chronic inflammation, one of the predisposing factors for oncogenesis and disease progression. However, an interrelationship between stress, inflammation, and malignancy, at least at the molecular level, still remains unclear. Here, we attempt to summarize the current knowledge that supports the inseparable link between chronic stress, inflammation, and colorectal cancer (CRC), by modulation of a cascade of molecular signaling pathways, which are under the regulation of CRH-family members expressed in the brain and periphery. The understanding of the molecular basis of the link among these processes may provide a step forward towards personalized medicine in terms of CRC diagnosis, prognosis and therapeutic targeting

Vaccine strategies to improve anti-cancer cellular immune responses

More than many other fields in medicine, cancer vaccine development has been plagued by a wide gap between the massive amounts of highly encouraging preclinical data on one hand, and the disappointing clinical results on the other. It is clear now that traditional approaches from the infectious diseases' vaccine field cannot be borrowed as such to treat cancer. This review highlights some of the strategies developed to improve vaccine formulations for oncology, including research into more powerful or "smarter" adjuvants to elicit anti-tumoral cellular immune responses. As an illustration of the difficulties in translating smart preclinical strategies into real benefit for the cancer patient, the difficult road of vaccine development in lung cancer is given as example. Finally, an outline is provided of the combinatorial strategies that leverage the increasing knowledge on tumor-associated immune suppressive networks. Indeed, combining with drugs that target the dominant immunosuppressive pathway in a given tumor promises to unlock the true power of cancer vaccines and potentially offer long-term protection from disease relapse

SiRNA Mediated Gene Silencing: A Mini Review

Abstract - RNA interference (RNAi) technology has become a novel tool for silencing gene expression in cells or organisms. RNA interference is the process that double-stranded RNA induces the homology-dependent degradation of cognate mRNA mediated by 21-23 nucleotide short interfering RNA (siRNA). RNA interference is a powerful mechanism of gene silencing that underlies many aspects of eukaryotic biology. On the molecular level, RNAi is mediated by a family of ribonucleoprotein (RNP) complexes called RNA-Induced Silencing Complexes (RISCs), which can be programmed to target virtually any nucleic acid sequence for silencing. The ability of RISC to locate target RNAs been co-opted by evolution many times to generate a broad spectrum of gene silencing pathways. The study about the Silencing of gene expression by siRNA is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. In this study, the applications of siRNA expressing recombinant adenovirus system in plants, animals and in cancer gene therapy are given importance with its modification

Exploring immunotherapeutic targets in the tumor microenvironment

The immune system has developed along with the evolution of increasingly complex cellular organisms to sustain homeostasis and protect from threats. Cancer, a detrimental side effect of increasing organismic complexity, typically sequesters the immune system and hijacks its functions for its own prosperity. Cancer immunotherapy aims to harness the intrinsic potential of the immune system for the therapeutic benefit of cancer patients. The focus of this thesis is to identify and evaluate new immunotherapeutic targets in the tumor microenvironment, which can be modulated to restrict tumor growth and metastasis. Paper I describes a novel mechanism of interaction between marginal zone macrophages (MZMs) and marginal zone B cells (MZBs) in the spleen, which can be modulated by antibodies (Abs) to scavenger receptor MARCO on MZMs. This study demonstrates that MARCO targeting diminishes antigen (Ag) uptake by MZBs, which results in reduced Ag deposition in the splenic follicles. As anti-MARCO Abs can also be found in systemic lupus erythematosus (SLE), this interaction may affect subsequent adaptive immune responses to both self- and foreign antigen. Paper II identifies MARCO as a specific marker for a tumor-promoting macrophage subtype in the tumor microenvironment of mammary carcinoma, melanoma and colon carcinoma tumor models. Targeting MARCO on tumor-associated macrophages (TAMs) by Abs, inhibits tumor growth and metastasis and reprograms TAMs to an anti-tumor phenotype. Treatment with anti-MARCO mAbs in combination with checkpoint inhibitor, anti-CTLA-4 ab, may provide a promising approach for cancer immunotherary with clinical relevance for human breast cancer and melanoma. Paper III reveals the molecular mechanism through which tumor cells imitate immune cells, during epithelial-mesenchymal transition (EMT), prompting their targeted metastasis through the lymphatics. This study demonstrates that TGF-β, a known inducer of EMT, regulates the chemotactic axis CCR7/CCL21, directing preferential lymphatic dissemination of breast cancer cells. Paper IV evaluates dendritic cell-derived exosomes in a vaccination approach to reactivate adaptive anti-tumor responses. This study shows that dendritic cell-derived CD1d expressing exosomes loaded with α-Galactosylceramide (α-GalCer) can sensitize NKT cells and lead to subsequent activation of B cell and effector T cell responses, restricting tumor growth. In summary, the work presented in this thesis describes novel targets in the tumor microenvironment that can be used in immunotherapeutic approaches to re-activate endogenous mechanisms of innate and adaptive immunity against cancer. Additionally, it gives new insight into gene regulatory pathways controlling metastatic tumor spread, as well as utilizes custom designed biological molecules in anti-tumor vaccination strategies. Increasing our understanding of the intricate mechanisms regulating the immunosuppressive tumor microenvironment will reveal new knowledge and novel targets that can contribute to the design of prospective cancer immunotherapies

COVID-19-related Vaccines and Therapeutics:Preliminary Insights on Related Patenting activity during the Pandemic Dataset.

Since the start of the COVID-19 pandemic there have been remarkable research and innovation efforts to fight the SARS-COV-2 virus and the related disease. This patent landscape report provides early observations on the patenting activity which took place in the field of COVID-19 vaccines and therapeutics, and compares results with clinical trial data for related candidate vaccines and drugs

Adopting tomorrow’s therapies today: A perspective review of adoptive cell therapy in lung cancer

Lung cancer is the leading cause of all cancer-related deaths in the United States and remains a global health challenge. While targeted therapy has revolutionized the treatment landscape of nonsmall cell lung cancer, many patients lack actionable mutations. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), have significantly impacted outcomes in lung cancer in the last decade. Some patients, however, never respond or become refractory to ICIs. Newer therapies aimed at augmenting the immune system and enhancing antitumor effects are currently being explored. Adoptive cell therapy (ACT) employs T cells isolated from either tumors or peripheral blood and often engineers them to effect antitumor immune response. Chimeric antigen receptor T (CAR-T) cell therapy, engineered T cell receptor therapy, and tumor-infiltrating lymphocytes are examples of adoptive cellular therapies. CAR-T cell therapy has been successful in the treatment of hematological malignancies with several CAR products gaining approval in the treatment of refractory blood cancers. The success of ACTs in hematological cancers has fueled research into the role of these therapies in solid cancers including lung cancer. Many trials have had early promising results, with many clinical trials currently enrolling. There are many limitations to the efficacy of ACTs, as well as risks and benefits with the individual subtypes of ACT. With growing knowledge about tumor antigens and more advanced cell engineering, there is potential for ACT to result in durable responses in immunologically “cold” tumors. Here, we review the major subtypes of ACTs, evidence supporting their use in lung cancer, challenges, and future perspectives in ACTs. Additionally, we include T cell engagers and mRNA vaccine studies and potential combinatorial strategies in lung cancer

Review of ustekinumab, an interleukin-12 and interleukin-23 inhibitor used for the treatment of plaque psoriasis

The pathogenesis of psoriasis is unknown, although it is generally accepted that this chronic inflammatory skin disorder is a complex autoimmune condition similar to other T-cell mediated disorders. Psoriasis imposes a heavy burden on the lifestyle of those affected due to the psychological, arthritic, and cutaneous morbidities; thus significant research has focused on the genetic and immunologic features of psoriasis in anticipation of more targeted, efficacious, and safe therapies. Recently, CD4+ T helper (Th) 17 cells and interleukins (IL)-12 and -23 have been important in the pathogenesis of T-cell mediated disorders such as psoriasis and has influenced the development of medications that specifically target these key immunological players. Ustekinumab is a monoclonal antibody belonging to a newly developed class of biological, anti-cytokine medications that notably targets the p40 subunit of both IL-12 and -23, both naturally occurring proteins that are important in regulating the immune system and are understood to play a role in immune-mediated inflammatory disorders. Ustekinumab’s safety and efficacy has been evaluated for the treatment of moderate-to-severe plaque psoriasis in 3 phase III clinical trials, 2 placebo-controlled (PHOENIX 1 and 2), and 1 comparator-controlled (ACCEPT) study which proved advantageous in patients who were treatment-naive, previously failed other immunosuppressive medications including cyclosporine or methotrexate, were unresponsive to phototherapy, or were unable to use or tolerate other therapies. Ustekinumab has also been investigated for other indications such as psoriatic arthritis, Crohn’s disease, and relapsing/remitting multiple sclerosis. We present a concise review evaluating the evidence that supports the use of ustekinumab in the treatment of plaque psoriasis and other conditions

Vaccination-Based Immunotherapy against Organ Fibrosis and Tumor Desmoplasia

Fibrosis represents the end-stage pathology of nearly every form of chronic disease, marked by the accumulation of extracellular matrix (ECM) proteins due to the activity of activated fibroblasts, also known as fibroblasts. This pathological process can affect virtually any organ. Unfortunately, current antifibrotic therapies that selectively target these fibrogenic cells while sparing homeostatic fibroblasts in healthy tissues are limited. During fibrogenesis, specific genes such as the disintegrin metalloprotease ADAM12 and the transcription factor GLI1 become reactivated in fibroblasts. Our research aimed to determine whether specific immunization against endogenous proteins, which are highly expressed in fibrogenic cells but restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. Through in silico epitope prediction, we identified that the activation of genes Adam12 and GLI1 in profibrotic cells results in "self-peptides" that can be exploited for T cell vaccines targeting fibrogenic cells. We demonstrated the efficacy of this vaccination approach in inducing CD8+ T cell responses, which successfully reduced fibroblasts and fibrosis in the liver, lungs and kidneys in mice. Similarly, in pancreatic ductal adenocarcinoma (PDAC), massive intratumoral fibrosis known as desmoplasia is observed. This condition involves the expansion of cancer-associated fibroblasts (CAFs) and a significant increase in ECM. We tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth and a reduction in CAFs and tumor desmoplasia. Additionally, the ADAM12 vaccine led to vascular normalization and reduced tumor hypoxia. In summary, these findings provide proof-of-concept for developing vaccination-based immunotherapies for treating both organ fibrosis and tumor desmoplasia, highlighting the potential of targeting fibrogenic cells through immunization strategies