Current status of Complementary and Alternative Medicine Interventions in the Management of Pancreatic Cancer - An Overview.

OPINION STATEMENT: Pancreatic cancer (PC) remains the deadliest cancer worldwide. Most patients are diagnosed at the advanced or metastatic stage, leading to a poor prognosis. Awareness of the limitations of current therapy and accompanying pain, depression, malnutrition, and side effects of chemoradiotherapy may lead patients and physicians towards complementary and alternative medicine (CAM). CAM refers to a diverse set of medical and healthcare practices, products, and systems that are not part of conventional Western medicine. Despite the low-quality evidence supporting the efficacy of these methods, they remain appealing due to patients' beliefs, fear of death, and the slow development of conventional therapy. Hence, the possibility of using natural products for pancreatic cancer is increasing. CAM options such as: medical cannabis, plants, fungi, herbal formulas, and injections, which originate primarily from traditional Chinese or Japanese medicine i.e. Curcuma longa, Panax ginseng, Poria cocos, Hochuekkito, Juzentaihoto, and Rikkunshito, Shi-quan-da-bu-tang/TJ-48, Huang-qin-tang, Shuangbai San, Wen Jing Zhi Tong Fang, Xiang-Sha-Liu-jun-zi-tang, Aidi injection, Brucea javanica oil emulsion/Yadanziyouru injection, Compound Kushen injection, Huachansu injection, Kangai injection and Kanglaite injections are becoming promising candidates for the management of pancreatic cancer. The abovementioned substances/medications are the most popular or potentially effective in PC treatment and consequently CAM-based adjuvant therapy through improving patients' quality of life, might be a useful addition in the treatment of pancreatic cancer patients.

Lactoferrin: an overview of its main functions, immunomodulatory and antimicrobial role, and clinical significance.

Lactoferrin (LF), a glycoprotein found in mucosal secretions, is characterized by a wide range of functions, including immunomodulatory and anti-inflammatory activities. Moreover, several investigations confirmed that LF displays high effectiveness against multiple bacteria and viruses and may be regarded as a potential inhibitor of enveloped viruses, such as presently prevailing SARS-CoV-2. In our review, we discuss available studies about LF functions and bioavailability of different LF forms in in vitro and in vivo models. Moreover, we characterize the potential benefits and side effects of LF use; we also briefly summarize the latest clinical trials examining LF application. Finally, we point potential role of LF in inflammatory bowel disease and indicate its use as a marker for disease severity.

Characterization of the Synergistic Effect between Ligands of Opioid and Free Fatty Acid Receptors in the Mouse Model of Colitis.

BACKGROUND: Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper µ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis. METHODS: The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO-an MOR agonist), 0.3 mg/kg BW (DPDPE-a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone-a non-selective OR antagonist, GLPG 0974-a FFAR2 antagonist, GSK 137647-a FFAR4 agonist and AH 7614-a FFAR4 antagonist) for 4 days. RESULTS: Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group. CONCLUSIONS: Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.

Free Fatty Acid Receptors as new potential therapeutic target in inflammatory bowel diseases.

Family of Free Fatty Acid Receptors (FFARs), specific G protein-coupled receptors comprises of four members: FFAR1-4, where each responds to different chain length of fatty acids (FAs). Over the years, FFARs have become attractive pharmacological targets in the treatment of type 2 diabetes, metabolic syndrome, cardiovascular diseases and asthma; recent studies also point to their role in inflammation. It is now well-established that activation of FFAR1 and FFAR4 by long and medium chain FAs may lead to reduction of inflammatory state; FFAR2 and FFAR3 are activated by short chain FAs, but only FFAR2 was shown to alleviate inflammation, mostly by neutrophil inhibition. All FFARs have thus been proposed as targets in inflammatory bowel diseases (IBD). Here we discuss current knowledge and future directions in FFAR research related to IBD.

Characteristics of SARS-CoV-2 and potential pharmacological treatment / Charakterystyka wirusa SARS-CoV-2 i potencjalne farmakologiczne sposoby leczenia.

In December 2019 in Wuhan, China the first cases of previously unknown, coronaviral infection-induced pneumonia have been reported. The new virus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) was named after SARS-CoV due to their similarities and the disease caused by the pathogen is COVID-19 (Coronavirus Disease 2019). On 11 March 2020 WHO (World Health Organization) defined the rapidly increasing number of incidents of COVID-19 as a pandemic. In this review we will present recent information about the SARS-CoV-2 focusing on the origin, clinical picture, diagnostic methods, structure, replication cycle of SARS-CoV-2 and potential pharmaceutical measures against COVID-19.

Effectiveness and therapeutic value of phytochemicals in acute pancreatitis: A review.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can lead to local and systemic complications. Repeated attacks of AP can lead to chronic pancreatitis, which markedly increases the probability of developing pancreatic cancer. Although many researchers have attempted to identify the pathogenesis involved in the initiation and aggravation of AP, the disease is still not fully understood, and effective treatment is limited to supportive therapy. METHODS: We aim to summarize available literature focused on phytochemicals (berberine, chlorogenic acid, curcumin, emblica officinalis, ellagic acid, cinnamtannin B-1, resveratrol, piperine and lycopene) and discuss their effectiveness and therapeutic value for improving AP. RESULTS: This study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect databases. CONCLUSIONS: Many phytochemicals hold potential in improving AP symptoms and may be a valuable and effective addition to standard treatment of AP. It has already been proven that the crucial factor for reducing the severity of AP is stimulation of apoptosis along with/or inhibition of necrosis. Supplementation of phytochemicals, which target the balance between apoptosis and necrosis can be recommended in ongoing clinical studies.

Berberine as a potential therapeutic agent in the treatment of acute pancreatitis / Berberyna jako potencjalny terapeutyk w leczeniu ostrego zapalenia trzustki.

Berberine (BRB) is a compound belonging to the group of isoquinoline alkaloids of plant origin that has long been used in traditional chinese medicine (TMC). Due to, among others anti-inflammatory properties BRB is a potential therapeutic in the treatment of acute pancreatitis (OZT). In a study in the mouse model of L-arginine-induced acute pancreatitis, we showed that BRB administered by the intravenous route at 0.1 and 0.5 mg / kg body weight significantly reduces the level of myeloperoxidase activity (an indicator of inflammation) in the pancreas and lungs. Promising results point to the need for larger, randomized studies to assess the long-term efficacy and side effects of BRB therapy.

Current and future pharmacotherapies for the management of constipation-predominant irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder affecting 9-23% of the world's population, with a higher prevalence among women. IBS is a complex disorder influenced by psychosocial, physiological, and genetic factors, exacerbated by stress. AREAS COVERED: Research confirms that the most common subtype of IBS is IBS-C. Therefore, new therapies are being developed to speed up bowel movement and reduce constipation, with drugs such as linaclotide, plecanatide, lubiprostone, or tegaserod available to reduce IBS-C symptoms. In addition, patients' condition is improved by foods rich in fiber and low in FODMAP and the use of biotics. EXPERT OPINION: The topic is of great importance due to the growing number of patients suffering from IBS-C and its significant impact on quality of life. Current clinical trials of new therapeutic options are not too successful, and it seems that one of the plausible treatment options could be the multi-drug cocktail with some, or perhaps even all its ingredients emerging from drug re-purposing. Another important path that needs to be explored further in IBS-C patients is the adjustment of dietary habits and/or introduction of dietary or nutritional intervention.

Cholesterol Nanofiber Patches with Sustainable Oil Delivery Eliminate Inflammation in Atopic Skin.

Atopic skin is dry and itchy and lacks integrity. Impaired skin barrier results from altered lipid composition of the skin. A crucial skin lipid, cholesterol, provides flexibility and homeostasis of the cell membranes' lipid bilayer. Cholesterol-based creams and natural oils, especially blackcurrant seed oil, are beneficial for skin care as they hydrate the skin and improve its integrity. The major atopic symptom, skin dryness, can be overcome by the application of porous patches enhanced with cholesterol and natural oil. The base of the patches is constructed of polyimide (PI) nanofibers with cholesterol coatings and externally added blackcurrant seed oil. The presence of cholesterol in PI mats hinders the passage of oil through the patches to the skin, resulting in sustained and prolonged skin hydration. The theoretical and numerical investigations of oil dynamics in porous mats confirmed the experimental results, showing a prolonged skin hydration effect up to 6 h. Additionally, as demonstrated by in vivo tests on atopic mice, cholesterol patches lower serum immunoglobulin E levels and expression of proinflammatory cytokines in the skin, thereby accelerating skin healing. Our results hold great promise for the long-term application of the patches in atopic dermatitis treatment.

Interactions between neurotrophins, mood, and physical activity under the conditions of sleep deprivation.

Sleep deprivation (DS) is the forced elimination of sleep. While brain-derived neurotrophic factor (BDNF) has been extensively studied in the context of in mood changes following DS, the role of other neurotrophins remains elusive. This study explores the impact of DS on BDNF, glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4) at mRNA and protein level, considering their potential links to mood disturbances. The study involved 81 participants subjected to polysomnography (PSG) and DS. Blood samples, mood assessments, and actigraphy data were collected twice, after PSG and DS. NT mRNA expression and serum protein concentrations of BDNF, GDNF, NT3, and NT4 were measured. Participants were divided into Responders and Non-Responders based on mood improvement after DS. DS reduced BDNF mRNA expression in all participants, with no change in serum BDNF protein. GDNF protein decreased in Non-Responders, while Responders exhibited reduced GDNF mRNA. NT3 protein increased in both groups, while NT3 mRNA decreased in Respondents. NT4 protein rose universally post-DS, but NT4 mRNA remained unchanged. Physical activity (PA) negatively correlated with mRNA expression of BDNF, GDNF, and NT3 post-DS. The study's short DS duration and exclusion of immature NT forms limit comprehensive insights. GDNF, together with NT3, might play an important role in mood response to DS. PA during DS seems to impair the mRNA expression of NTs in leukocytes. Future studies on the subject of sleep deprivation might consider investigating the relationship between BDNF and NT4 in the context of their apparent redundancy.

The Relationship between Sleep Parameters Measured by Polysomnography and Selected Neurotrophic Factors.

BACKGROUND: The molecular underpinnings of insufficient sleep remain underexplored, with disruptions in the neurotrophic signaling pathway emerging as a potential explanation. Neurotrophins (NTs), including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin 4 (NT4), and glial-cell-line-derived growth factor (GDNF), play crucial roles in nerve cell growth and repair. However, their associations with sleep patterns are poorly understood. This study aimed to investigate the relationship between the chosen neurotrophins and objective sleep parameters. METHODS: The study involved 81 participants subjected to polysomnography (PSG). Blood samples were collected after PSG. The mRNA expression and serum protein concentrations of BDNF, GDNF, NT3, and NT4 were measured using real-time quantitative reverse-transcription PCR (qRT-PCR) or enzyme-linked immunosorbent assay (ELISA) methods, respectively. RESULTS: BDNF and NT3 proteins were negatively correlated with NREM events, while NT4 protein positively correlated with REM events. Electroencephalography power analysis revealed BDNF protein's negative correlation with delta waves during rapid eye movement and non-rapid eye movement sleep. CONCLUSION: The study highlights associations between neurotrophins and sleep, emphasizing BDNF's role in regulating NREM and REM sleep. The EEG power analysis implicated BDNF in delta wave modulation, shedding light on potential neurotrophic mechanisms underlying sleep effects on cognitive and mood processes.

Putative molecular targets for vitamin A in neutralizing oxidative stress in acute and chronic pancreatitis - a systematic review.

Acute pancreatitis (AP) and chronic pancreatitis (CP) are debilitating diseases of gastrointestinal tract and constitute great threat for human health in high-income countries. Recent studies emphasize the impact of oxidative stress on development of these pathologies, and numerous authors evaluate the effect of the antioxidant therapy on the course of AP and CP. Though several antioxidative agents were discovered in the past decades, vitamins remain canonical antioxidants. Despite the fact that vitamin A is known for its antioxidative effect, there is little data about the impact of vitamin A on oxidative stress in the pathogenesis of AP and CP. The scope of the review is to evaluate molecular targets for vitamin A, which may be involved in oxidative stress occurring in the course of AP and CP. Our research of available literature revealed that several mechanisms are responsible for attenuation of oxidative stress in AP and CP, including Nrf2, MAPK, AMPK, TLR3, and TLR4. Furthermore, these factors are at least partially expressed in vitamin A-dependent manner, though further investigations are required for elucidating in detail the role of vitamin A in defense against reactive oxygen species. Our review revealed that vitamin A might influence the expression of several molecular pathways involved in antioxidative defense and cytoprotection; thus, its administration during AP and CP may change the course of the disease.

An overview of 5-HT3 receptor antagonists as a treatment option for irritable bowel syndrome with diarrhea.

INTRODUCTION: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain, discomfort, and altered bowel habits, which affects the quality of life of approximately 10% of the worldwide population. IBS is classified into three types: IBS-D (diarrhea-predominant), IBS-C (constipation-predominant), and mixed or alternating IBS (IBS-M). Among the potential interventions for IBS-D, the antagonism of the serotonin 5-HT3 receptor has recently emerged as an effective treatment option. Serotonin (5-HT) is a neurotransmitter and an immunoregulatory factor, which plays a key role in physiological and pathological processes of the human body, having an impact on intestinal motility and gland secretion, which assist in maintaining intestinal homeostasis. AREAS COVERED: In this paper, the concept of 5-HT3 antagonists in the treatment of individuals with IBS-D is discussed, with particular focus on mechanism of action and pre-clinical and clinical data. This study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect databases. EXPERT OPINION: Recent clinical trial data have confirmed beyond doubt the value of 5-HT3 antagonists. As for future directions, weak partial 5-HT3 receptor agonism appears to be an appealing alternative to a silent antagonist for the treatment of IBS-D.

Variations of the popliteal artery: A review.

The popliteal artery is located in the popliteal fossa. In addition to its other branches, it divides into two terminal branches, the anterior and posterior tibial arteries, which are subject to numerous morphological variations. The purpose of this review is to compile several authors' classifications of the patterns of terminal branching of the popliteal artery among adults and to describe the division among foetuses, as described in the current literature. Pathologies of the popliteal artery such as popliteal artery aneurysm and popliteal artery entrapment syndrome and methods for treating them, like open surgery and endovascular interventions are also discussed. Awareness of the morphological variations of the popliteal artery is important for radiologists and surgeons as it allows the risk of complications during surgery to be reduced.

Ghee Butter from Bovine Colostrum Reduces Inflammation in the Mouse Model of Acute Pancreatitis with Potential Involvement of Free Fatty Acid Receptors.

Acute pancreatitis (AP) is an inflammatory disease that causes severe tissue damage. Ghee butter from bovine colostrum (GBBC) is a clarified butter produced by heating milk fat to 40 °C and separating the precipitating protein. As colostrum mainly contains fatty acids (FAs), immunoglobulins, maternal immune cells, and cytokines, we hypothesized that it may exert anti-inflammatory effects. We investigated the effects of GBBC on experimental AP in mice. Two intraperitoneal (ip) injections of L-arginine (8%) were given 1 h apart to generate the AP murine model. After 12 h from the first L-arginine injection, mice were divided into the following experimental groups: AP mice treated with GBBC (oral gavage (po) every 12 h) and non-treated AP mice (po vehicle every 12 h). Control animals received vehicle only. At 72 h, mice were euthanized. Histopathological examination along with myeloperoxidase (MPO) and amylase/lipase activity assays were performed. In a separate set of experiments, FFAR1 and FFAR4 antagonists were used to verify the involvement of respective receptors. Administration of GBBC decreased MPO activity in the pancreas and lungs along with the microscopical severity of AP in mice. Moreover, treatment with GBBC normalized pancreatic enzyme activity. FFAR1 and FFAR4 antagonists tended to reverse the anti-inflammatory effect of GBBC in mouse AP. Our results suggest that GBBC displays anti-inflammatory effects in the mouse model of AP, with the putative involvement of FFARs. This is the first study to show the anti-inflammatory potential of a nutritional supplement derived from GBBC.

Chlorogenic acid reduces inflammation in murine model of acute pancreatitis.

BACKGROUND: The pathogenesis of acute pancreatitis (AP) initiation and progression is still unknown, and effective treatment is limited to supportive care. Many phytochemicals have the potential to alleviate AP symptoms and may be a useful and effective supplement to standard AP treatment. The objective of the study was to examine the potential role of chlorogenic acid (CGA), a polyphenol known for anti-inflammatory effect, in the treatment of experimental AP in mice. METHODS: Two intraperitoneal (ip) injections of L-arginine (dosage 400 mg/100 g BW) were given 1 h apart to generate the AP murine model. Mice were separated into two experimental groups after 12 h from the first L-arginine injection: AP mice treated with CGA (oral gavage (po) every 12 h; 20 mg/kg BW) and non-treated AP mice (po vehicle, 5% dimethyl sulfoxide every 12 h). Every 12 h, control mice were given an equivalent volume of vehicle. At 72 h, mice were slaughtered. Histology, as well as myeloperoxidase (MPO) and amylase activity assays, were performed on pancreatic tissues. RESULTS: In murine mouse model of AP po administration of CGA decreased MPO vs. AP (40.40 ± 2.10 U vs. 7.39 ± 0.34; p < 0.001) as well as amylase activity vs. AP (1444 ± 56 mU/mL vs. 3340 ± 144 mU/mL, Fig. 2B; p < 0.001). When comparing CGA mice to AP mice, histological research demonstrated that the severity of AP was reduced following CGA treatment. CONCLUSIONS: The current study found that CGA might have anti-inflammatory effect on L-arginine-induced pancreatitis. Dietary intervention with CGA may be advised as a supportive treatment for AP, according to our findings.

Biomarkers for early detection of pancreatic cancer - miRNAs as a potential diagnostic and therapeutic tool?

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, with poor prognosis resulting mostly from late diagnosis. Surgery remains the most effective treatment and early detection significantly increases the overall survival. Biomarkers used for diagnosis and to monitor the response to treatment, such as carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA), are not adequate as early detection markers of PDAC, partly due to low sensitivity/specificity. Therefore, new biomarkers for PDAC are critically needed. This review aims at recent advancements in the identification and characterization of new biomarkers, microRNAs, which might prove useful in the early detection of PDAC.

Activation of Free Fatty Acid Receptor 4 Affects Intestinal Inflammation and Improves Colon Permeability in Mice.

Diet is considered an important trigger in inflammatory bowel diseases (IBD), as feeding habits can affect intestinal permeability and clearance of bacterial antigens, consequently influencing the immune system. Free fatty acid receptors (FFARs), expressed on the intestinal epithelial cells, belong to the family of luminal-facing receptors that are responsive to nutrients. The objective of this study was to characterize the anti-inflammatory activity and the effect on intestinal barrier function of synthetic FFAR agonists in mouse models of colitis. Therapeutic activity of GW9508 (FFAR1 agonist), 4-CMTB (FFAR2 agonist), AR420626 (FFAR3 agonist), and GSK137647 (FFAR4 agonist) was investigated in two models of semi-chronic colitis: induced by trinitrobenzenesulfonic acid (TNBS), mimicking Crohn's disease, as well as induced by dextran sulfate sodium (DSS), which recapitulates ulcerative colitis in humans. Moreover, we assessed the influence of FFARs agonists on epithelial ion transport and measured the ion flow stimulated by forskolin and veratridine. Administration of FFAR4 agonist GSK137647 attenuated both TNBS-induced and DSS-induced colitis in mice, as indicated by macroscopic parameters and myeloperoxidase activity. The action of FFAR4 agonist GSK137647 was significantly blocked by pretreatment with selective FFAR4 antagonist AH7614. Moreover, FFAR1 and FFAR4 agonists reversed the increase in the colon permeability caused by inflammation. FFAR4 restored the tight junction genes expression in mouse colon. This is the first evaluation of the anti-inflammatory activity of selective FFAR agonists, showing that pharmacological intervention targeting FFAR4, which is a sensor of medium and long chain fatty acids, attenuates intestinal inflammation.

Nutritional Support and Probiotics as a Potential Treatment of IBD.

The pathogenesis of inflammatory bowel disease (IBD) remains unknown. However, there is growing evidence that the increase in the overall incidence of IBD relates to the improvement of sanitary and hygienic conditions of the society leading to lower exposure to both bacterial and parasitic infections. IBD is incurable and characterized by alternating periods of exacerbation and remission of symptoms. Therefore, the main goal of treatment strategies in IBD patients is the most effective maintenance of clinical and endoscopic remission, which does allow patients to function normally for a significant part of life. Taking into account the evidence from different areas, there is a strong rationale supporting the concept that bacteria are important in gut inflammation and that probiotic bacteria may modulate the host-microbe interaction in a way that is directly beneficial to IBD patients along with nutritional support. In this review, we focus on the potential role of gastrointestinal microbiota in the pathogenesis of IBD and the possible value of probiotics, prebiotics, and symbiotics as well as nutritional support in the treatment of IBD.

Free Fatty Acid Receptors as New Potential Targets in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide. In developed countries, its mortality remains high, yet the prevalence has established owing to effective screening programs; however due to the westernization of lifestyle, the incidences in many other countries have increased. Although the treatment of CRC has improved in the last few years, the side effects of these approaches cannot be neglected. Recently, members of the family of free fatty acid receptors (FFARs) have become attractive pharmacological targets in many diseases, including asthma; studies also point to their role in carcinogenesis. Here, we discuss current knowledge and future directions in FFAR research related to CRC. Contradictory results of FFARs modulation may derive from the pleiotropic effects of FFAR ligands, receptor distribution and different signal transduction. Hence, we indicate directions of further studies to fully use the potential of FFARs in CRC.