Opioid Growth Factor Receptor Research Articles

Topical naltrexone increases aquaporin 5 production in the lacrimal gland and restores tear production in diabetic rats.

Diabetes mellitus is a prevalent disease that is often accompanied by ocular surface abnormalities including delayed epithelial wound healing and decreased corneal sensitivity. The impact of diabetes on the lacrimal functional unit (LFU) and the structures responsible for maintaining tear homeostasis, is not completely known. It has been shown that the Opioid Growth Factor Receptor (OGFr), and its ligand, Opioid Growth Factor (OGF), is dysregulated in the ocular surface of diabetic rats leading to overproduction of the inhibitory growth peptide OGF. The opioid antagonist naltrexone hydrochloride (NTX) blocks the OGF-OGFr pathway, and complete blockade following systemic or topical treatment with NTX restores the rate of re-epithelialization of corneal epithelial wounds, normalizes corneal sensitivity, and reverses dry eye in diabetic animal models. These effects occur rapidly and within days of initiating treatment. The present study was designed to understand mechanisms related to the fast reversal (<5 days) of dry eye by NTX in type 1 diabetes (T1D) by investigating dysregulation of the LFU. The approach involved examination of the morphology of the LFU before and after NTX treatment. Male and female adult Sprague-Dawley rats were rendered hyperglycemic with streptozotocin, and after 6 weeks rats were considered to be a T1D model. Rats received topical NTX twice daily to one eye for 10 days. During the period of treatment, tear production and corneal sensitivity were recorded. On day 11, animals were euthanized and orbital tissues including conjunctiva, eyelids, and lacrimal glands, were removed and processed for histologic examination including immunohistochemistry. Male and female T1D rats had significantly decreased tear production and corneal insensitivity, significantly decreased number and size of lacrimal gland acini, decreased expression of aquaporin-5 (AQP5) protein and decreased goblet cell size. Thus, 10 days of NTX treatment restored tear production and corneal sensitivity to normal values, increased AQP5 expression, and restored the surface area of goblet cells to normal. NTX had no effect on the number of lacrimal gland acini or the number of conjunctival goblet cells. In summary, blockade of the OGF-OGFr pathway with NTX reversed corneal and lacrimal gland complications and restored some components of tear homeostasis confirming the efficacy of topical NTX as a treatment for ocular defects in diabetes.

Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families.

Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in 2 independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to WT BMMs. Osteoclast formation induced by RANKL was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders.

Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy.

Naltrexone (NTX) is a non-selective antagonist of opioid receptors, primarily used in the therapy of opioid and alcohol dependence. Low-dose naltrexone (LDN) exhibits antagonistic action against the opioid growth factor receptor (OGFr), whose signaling is associated with the survival, proliferation, and invasion of cancer cells. The mechanism of action of LDN depends on the dose and duration of the OGFr blockade, leading to a compensatory increase in the synthesis of the opioid growth factor (OGF), which has an inhibitory effect on carcinogenesis. Numerous studies on in vitro and in vivo models provide evidence of LDN's positive impact on inhibiting the OGF-OGFr axis in cancers. LDN's unique mechanism of action on cancer cells, lack of direct cytotoxic effect, and immunomodulating action form the basis for its use as an adjuvant in chemotherapy and immunotherapy of cancerous lesions.

Design, Synthesis, and Antitumor Evaluation of an Opioid Growth Factor Bioconjugate Targeting Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge with high lethality and limited effective drug treatments. Its heightened metastatic potential further complicates the prognosis. Owing to the significant toxicity of current chemotherapeutics, compounds like [Met5]-enkephalin, known as opioid growth factor (OGF), have emerged in oncology clinical trials. OGF, an endogenous peptide interacting with the OGF receptor (OGFr), plays a crucial role in inhibiting cell proliferation across various cancer types. This in vitro study explores the potential anticancer efficacy of a newly synthesized OGF bioconjugate in synergy with the classic chemotherapeutic agent, gemcitabine (OGF-Gem). The study delves into assessing the impact of the OGF-Gem conjugate on cell proliferation inhibition, cell cycle regulation, the induction of cellular senescence, and apoptosis. Furthermore, the antimetastatic potential of the OGF-Gem conjugate was demonstrated through evaluations using blood platelets and AsPC-1 cells with a light aggregometer. In summary, this article demonstrates the cytotoxic impact of the innovative OGF-Gem conjugate on pancreatic cancer cells in both 2D and 3D models. We highlight the potential of both the OGF-Gem conjugate and OGF alone in effectively inhibiting the ex vivo pancreatic tumor cell-induced platelet aggregation (TCIPA) process, a phenomenon not observed with Gem alone. Furthermore, the confirmed hemocompatibility of OGF-Gem with platelets reinforces its promising potential. We anticipate that this conjugation strategy will open avenues for the development of potent anticancer agents.

Biology of the Opioid Growth Factor – Opioid Growth Factor Receptor Axis: Bench to Bedside and Back

The Opioid Growth Factor – Opioid Growth Factor Receptor axis was identified nearly 30 years ago in our laboratory when we demonstrated that an endogenous opioid pentapeptide had inhibitory growth activity following injection into normal animals. In addition to validating this action for the peptide, identification, characterization and cloning of the specific receptor related to the opioid growth factor, chemically termed [Met5]-enkephalin, revealed that the receptor was unique in its biochemical and molecular structure, but had pharmacological properties similar to other opioid receptors. Mechanisms associated with binding of the opioid growth factor to its receptor located on the outer nuclear envelop and the transport into the nucleus were identified. The selectively of the peptide for the receptor was demonstrated in normal and cancer cell lines. This uniqueness of the peptide-receptor interaction was evidenced by the duration of receptor blockade in that intermittent blockade resulted in decreased cell replication and complete blockade resulted in accelerated proliferation. Investigations on the mechanism of action, as well as the dysregulation of the Opioid Growth Factor – Opioid Growth Factor Receptor axis in human pathology, have resulted in bench to bedside and bedside to bench discoveries. Receptor blockade by naltrexone has been used clinically for treatment of fatigue and other immune deficiencies in many autoimmune disorders. The research has gone from bench to bedside and has returned to the bench for additional investigation of mechanisms driving the action of the axis and resultant function following receptor blockade.

Current pharmacotherapeutic properties of low-dose naltrexone therapy in humans and possible therapeutic and prophylactic indications in cats and dogs

Naltrexone was first developed in 1963 as an opioid antagonist for therapeutic use in opioid-dependent individuals (alcohol, narcotics, and tobacco) with a 50 mg/day dose approved by the Food and Drug Administration (FDA). In 1985, Dr. Bernard Bihari explained that when naltrexone is taken in very low doses (1-5 mg/day) before bedtime, it blocks opioid receptors for 2- 4 hours and leads to the release of endorphins in the early morning hours, serving as an opioid agonist and immunomodulatory agent. This extra endorphin secretion has been proven to enhance the immune system response in AIDS patients. Endogenous opioids that affect cell development are referred to as opioid growth factor (OGF) and met-enkephalin (ME). Low-dose-naltrexone (LDN) pharmacotherapeutically possesses immunomodulatory, anticarcinogenic, antiviral, antibacterial, antiparasitic, and antifungal properties. LDN also increases the production and sensitivity of OGF, ME, and OGF receptor (OGFr) in the bloodstream, thereby enhancing quality of life. Based on these pharmacotherapeutic properties, LDN application is believed to be effective in the treatment or prophylaxis of various infectious diseases in cats and dogs, particularly vasculitis-related diseases such as feline infectious peritonitis (FIP) and infectious canine hepatitis (ICH), hypothyroidism, gastrointestinal disorders, spondylosis, rheumatoid arthritis, autoimmune diseases, pneumonia, atopic and allergic dermatitis, pyodermas, resistant pyodermas, methicillin-resistant Staphylococcus aureus (MRSA) or various gastrointestinal disorders, alopecia, stubborn dermatomycosis, stubborn demodicosis, various geriatric and oncogenic diseases, and deep depressions or obsessive-compulsive disorders. Thus, this review aims to evaluate the pharmacotherapeutic properties of LDN therapy usage and mechanisms of action in detail and assess the potential indications in cats and dogs based on these mechanisms.

Morphine Analgesia, Cannabinoid Receptor 2, and Opioid Growth Factor Receptor Cancer Tissue Expression Improve Survival after Pancreatic Cancer Surgery.

Pancreatic cancer (PDAC) has a poor prognosis despite surgical removal and adjuvant therapy. Additionally, the effects of postoperative analgesia with morphine and piritramide on survival among PDAC patients are unknown, as are their interactions with opioid/cannabinoid receptor gene expressions in PDAC tissue. Cancer-specific survival data for 71 PDAC patients who underwent radical surgery followed by postoperative analgesia with morphine (n = 48) or piritramide (n = 23) were therefore analyzed in conjunction with opioid/cannabinoid receptor gene expressions in the patients' tumors. Receptor gene expressions were determined using the quantitative real-time polymerase chain reaction. Patients receiving morphine had significantly longer cancer-specific survival (CSS) than those receiving piritramide postoperative analgesia (median 22.4 vs. 15 months; p = 0.038). This finding was supported by multivariate modelling (p < 0.001). The morphine and piritramide groups had similar morphine equipotent doses, receptor expression, and baseline characteristics. The opioid/cannabinoid receptor gene expression was analyzed in a group of 130 pancreatic cancer patients. Of the studied receptors, high cannabinoid receptor 2 (CB2) and opioid growth factor receptor (OGFR) gene expressions have a positive influence on the length of overall survival (OS; p = 0.029, resp. p = 0.01). Conversely, high delta opioid receptor gene expression shortened OS (p = 0.043). Multivariate modelling indicated that high CB2 and OGFR expression improved OS (HR = 0.538, p = 0.011, resp. HR = 0.435, p = 0.001), while high OPRD receptor expression shortened OS (HR = 2.264, p = 0.002). Morphine analgesia, CB2, and OGFR cancer tissue gene expression thus improved CSS resp. OS after radical PDAC surgery, whereas delta opioid receptor expression shortened OS.

Elevated Opioid Growth Factor Alters the Limbus in Type 1 Diabetic Rats.

Ocular surface complications occur in more than 50% of individuals diagnosed with diabetes. The financial and health-related burden of diabetes is increasing annually. Several major ocular complications associated with diabetes involve the limbus. The vascular limbus, adjacent to the avascular cornea, is the source of circulating growth factors, elevated glucose, and cytokines for the cornea. The Opioid Growth Factor (OGF) - Opioid OGF Receptor (OGFr) axis is comprised of its effector peptide, OGF, [Met5]-enkephalin and the nuclear-associated receptor, OGFr, and has been demonstrated to be dysfunctional in diabetes with elevated serum and tissue levels of the inhibitory growth factor OGF recorded in corneal tissue. Little is known regarding the impact of OGF-OGFr axis dysregulation in diabetes on the functioning of the limbus constituents in support of corneal homeostasis. Adult male and female Sprague-Dawley rats were rendered hyperglycemic through intraperitoneal injections of streptozotocin (T1D); a subset of T1D rats received topical naltrexone (NTX) applied to the cornea and limbus daily for 8 weeks. At 4 and/or 8 weeks of hyperglycemia, different cohorts of animals were euthanized, eyes removed and processed for assessment of limbal morphology, expression of OGF, OGFr, cytokeratin 15, a marker for limbal cells, and Ki-67, a marker of proliferation. Limbal epithelial morphology (cell diameter, packing density) was altered in T1D male and female rats. OGF and OGFr were overexpressed in the limbus and CK15 expression was decreased, relative to normal control rats of the same sex. Blockade of the OGF- OGFr axis with NTX reversed limbal epithelial cell defects, and reduced OGF limbal tissue levels to those recorded in non-diabetic rats. In summary, OGF-OGFr axis dysregulation was observed in the limbus of T1D rats, contributing to the altered limbal morphology and delayed corneal surface healing observed in diabetic animals.

Acute Low Dose Naltrexone Increases β-Endorphin and Promotes Neuronal Recovery Following Hypoxia-Ischemic Stroke in Type-2 Diabetic Mice.

Diabetic patients experience significant mortality and poor recovery following ischemic stroke. Our clinical and basic science studies demonstrate an overall immune suppression in the periphery of diabetic stroke patients, as well as within the central nervous system (CNS) of type-2 diabetic mice following hypoxia-ischemia (HI). Low doses of naltrexone (LDN) improved clinical outcomes in many autoimmune diseases by acting on opioid receptors to release β-endorphin which in turn balances inflammatory cytokines and modulates the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) pathway. We hypothesized that in our model of diabetic mice, LDN treatment will induce the release of β-endorphin and improve CNS response by promoting neuronal recovery post HI. To test this hypothesis, we induced HI in 10week old male db/db and db/ + mice, collected tissue at 24 and 72h post HI, and measured OGF levels in plasma and brain tissue. The infarct size and number of OGF + neurons in the motor cortex, caudate and hippocampus (CA3) were measured. Following HI, db/db mice had significant increases in brain OGF expression, increased infarct size and neurological deficits, and loss of OGFr + neurons in several different brain regions. In the second experiment, we injected LDN (1mg/kg) intraperitoneally into db/db and db/ + mice at 4, 24, and 48h post HI, and collected brain tissue and blood at 72h. Acute LDN treatment increased β-endorphin and OGF levels in plasma and promoted neuronal recovery in db/db mice compared to phosphate buffer saline (PBS)-treated diabetic mice suggesting a protective or regenerative effect of LDN.

Opioid growth factor receptor promotes adipose tissue thermogenesis via enhancing lipid oxidation

Abstract The thermogenic brown and beige adipocytes consume fatty acids and generate heat to maintain core body temperature in the face of cold challenges. Since their validated presence in humans, the activation of thermogenic fat has been an attractive target for treating obesity and related metabolic diseases. Here, we reported that the opioid growth factor receptor (Ogfr) was highly expressed in adipocytes and promoted thermogenesis. The mice with genetic deletion of Ogfr in adipocytes displayed an impaired capacity to counter environmental cold challenges. Meanwhile, Ogfr ablation in adipocytes led to reduced fatty acid oxidation, enhanced lipid accumulation, impaired glucose tolerance, and exacerbated tissue inflammation under chronic high-fat diet (HFD)-fed conditions. At the cellular level, OGFr enhanced the production of mitochondrial trifunctional protein subunit α (MTPα) and also interacted with MTPα, thus promoting fatty acid oxidation. Together, our study demonstrated the important role of OGFr in fatty acid metabolism and adipose thermogenesis.

Methionine enkephalin suppresses lung cancer metastasis by regulating the polarization of tumor-associated macrophages and the distribution of myeloid-derived suppressor cells in the tumor microenvironment and inhibiting epithelial-mesenchymal transition

Metastasis is one of the most difficult challenges for clinical lung cancer treatment. Epithelial-mesenchymal transition (EMT) is the crucial step of tumor metastasis. Immune cells in the tumor microenvironment (TME), such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), promote cancer cell EMT. In this study, we explored the effect of methionine enkephalin (MENK) on the EMT process in vitro and in vivo, and its influence on TAMs, MDSCs, and associated cytokines in vivo. The results showed that MENK suppressed growth, migration, and invasion of lung cancer cells and inhibited the EMT process by interacting with opioid growth factor receptor. MENK reduced the number of M2 macrophages and MDSC infiltration, and downregulated the expression of interleukin-10 and transforming growth factor-β1 in both primary and metastatic tumors of nude mice. The present findings suggest that MENK is a potential target for suppressing metastasis in lung cancer treatment.

Opioid growth factor receptor: Anatomical distribution and receptor colocalization in neurons of the adult mouse brain

The opioid growth factor (OGF) is an endogenous peptide that binds to the nuclear-associated receptor (OGFr), and plays a significant role in the proliferation of developing, renewing, and healing tissues. The receptor is widely expressed in a variety of organs, however its distribution in the brain remains unknown. In this study, we investigated the distribution of OGFr in different brain regions of male heterozygous (-/+ Lepr db/J), non -diabetic mice and determined the localization of the receptor in three major brain cell types, astrocytes, microglia, and neurons. Immunofluorescence imaging revealed that the highest number of OGFr was in hippocampal CA3 subregion followed by primary motor cortex, hippocampal CA2, thalamus, caudate and hypothalamus in a descending order. Double immunostaining revealed receptor colocalization with neurons and little or no colocalization in microglia and astrocytes. The highest percentage of OGFr positive neurons was identified in the CA3. Hippocampal CA3 neurons play an important role in memory processing, learning and behavior, and motor cortex neurons are important for muscle movement. However, the significance of the OGFr receptor in these brain regions and its relevance in diseased conditions are not known. Our findings provide a basis for understanding the cellular target and interaction of the OGF- OGFr pathway in neurodegenerative diseases such as Alzheimer's, Parkinson's, and stroke where hippocampus and cortex have an important role. This foundational data may also be useful in drug discovery to modulate OGFr by opioid receptor antagonist in various CNS diseases.

Long non-coding RNA OGFRP1 regulates cell proliferation and ferroptosis by miR-299-3p/SLC38A1 axis in lung cancer.

Lung cancer is devastating cancer that ranks as the leading cause of cancer-related death. Long noncoding RNA (lncRNA) opioid growth factor receptor pseudogene 1 (OGFRP1) was recognized as an oncogene in many cancers. However, the molecular mechanism of OGFRP1 in lung cancer is still poorly understood. The expression of target RNAs and genes was detected by quantitative real-time PCR and western blot. The interaction between miR-299-3p and OGFRP1 or solute carrier family 38 member 1 (SLC38A1) was predicted by StarbaseV3.0 and verified by dual-luciferase reporter assay and Pearson's correlation coefficient. Besides, a transplantation model of human lung cancer in nude mice was established to evaluate the role of OGFRP1 in lung cancer. OGFRP1 and SLC38A1 were overexpressed, whereas miR-299-3p was lowly expressed in lung cancer tumors and cells. OGFRP1 knockdown suppressed cell proliferation and facilitated ferroptosis by promoting lipid peroxidation and iron accumulation in lung cancer. Besides, Furthermore, miR-299-3p inhibitor or SLC38A1 overexpression attenuated OGFRP1 depletion-induced suppression on cell proliferation and ferroptosis in lung cancer. Animal experiments indicated that OGFRP1 deficiency restrained tumor growth in vivo by regulating the miR-299-3p/SLC38A1 axis. OGFRP1 regulated cell proliferation and ferroptosis in lung cancer by inhibiting miR-299-3p to enhance SLC38A1 expression, providing a novel therapeutic strategy for lung cancer.

Opioid Receptor Expression in Colorectal Cancer: A Nested Matched Case-Control Study.

BackgroundThere is growing interest in the possible effect of perioperative anesthetic management on the growth and spread of cancer. The impact of perioperative use of opioids on cancer recurrence remains controversial and an assessment cannot yet be established based on current publications. This study aimed to assess the differential expression of opioid receptors between healthy and tumor tissues in patients with stage II and III colorectal cancer undergoing elective surgery by immunohistochemistry (IHC).MethodsPropensity–score matched case–control study nested in a retrospective cohort of patients with stage II or III colorectal. The primary endpoint was the difference in µ–opioid receptor (MOR) expression measured by IHC between tumor and healthy tissue in subject with or without recurrence. Secondary endpoints were to evaluate the differences in Opioid Growth Factor Receptor (OGFR), cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) in the matched sample and from a from samples of colorectal cancer stored in the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression Project (GTEx).ResultsThere was a significant difference in MOR receptor (median 3 [intequartile range IQR: 1–3] and 0 [IQR: 0–2], P<0.001) and OGFR receptor (median 6 [IQR: 5–6] and 2 [IQR: 1–2], P<0.001) in tumor and control tissue respectively. However, there were no significant differences in cAMP nor PKA expression between both types of tissues and in expression in any of the analyzed variables by recurrence status. The MOR and OGFR expression data from TCGA database were similar to our sample size data with lower expression of MOR and higher expression of OGFR in tumoural samples with a skewed distribution for MOR expression in tumor tissue both in patients with and without recurrence.ConclusionIn patients with stage II and III colorectal cancer, overall expression of MOR and OGFR was significantly increased but was not different between previously matched patients with or without recurrence. No differences were found in the analyzed metabolic pathway of cAMP–PKA: These results were confirmed by an in silico analysis of samples from the TCGA–GTEx database.

LncRNA OGFRP1 promotes cell proliferation and suppresses cell radiosensitivity in gastric cancer by targeting the miR-149-5p/MAP3K3 axis.

Gastric cancer (GC) is an aggressive malignancy with high incidence and mortality. Radiotherapy is a common treatment for patients with advanced GC. Many long noncoding RNAs (lncRNAs) have been verified to affect the radiosensitivity of multiple cancers in previous studies. Nevertheless, whether lncRNA opioid growth factor receptor pseudogene 1 (OGFRP1) affects the radiosensitivity of GC has not been determined. We hypothesized that OGFRP1 might affect cellular processes in GC development. The present study aims to explore the role of OGFRP1 in GC development. First, high expression of OGFRP1 in GC tissues and cells was determined through RT-qPCR. Subsequently, functional assays including colony formation assays, 5-Ethynyl-2'-deoxyuridine assays and flow cytometry analyses were performed to probe the biological functions of OGFRP1 in GC. Specifically, the effect of OGFRP1 on the radiosensitivity of GC cells was detected. Subsequently, with the help of the starBase tool, we found that miR-149-5p might bind to OGFRP1, which was confirmed through a luciferase reporter assay. Furthermore, we identified that MAP3K3 was targeted by miR-149-5p in GC cells. Finally, the results from rescue experiments validated that enhanced MAP3K3 expression counteracted the effect of OGFRP1 silencing on GC cell proliferation, apoptosis and radiosensitivity. Overall, OGFRP1 was determined to promote GC cell proliferation while suppressing cell apoptosis and radiosensitivity by regulating the miR-149-5p/MAP3K3 axis.

Dysregulation of the OGF-OGFr pathway and associated diabetic complications.

Diabetes is a worldwide epidemic with more than 550 million individuals expected to be diagnosed with the disease by 2030. Complications associated with diabetes affect nearly all systems, but more than 54% of diabetic individuals have ocular surface disorders including keratopathy, dry eye or altered corneal surface sensitivity, and nearly 70% experience slow healing foot ulcers which if left untreated, can lead to amputation. There is new information regarding the underlying pathophysiology associated with these complications, as well as potential treatment. This commentary assembles data on preclinical studies showing that corneal surface complications such as dry eye and sensitivity, as well as delayed epithelial wound healing in the cornea and skin in diabetic rats and mice, correlate with a dysregulation of the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) regulatory axis. The peptide in this pathway, OGF, chemically termed [Met5]-enkephalin, is elevated in the serum of humans and animals with either type 1 or type 2 diabetes. The cause for this finding is unknown. However, there are studies that demonstrate that blockade of the interactions between OGF (or elevated levels of OGF) and its receptor can reverse and, in some cases, prevent the onset of diabetic corneal complications. Clinicians and healthcare workers need to recognize this fundamental pathophysiology leading to diabetic complications. Dysfunction of the OGF-OGFr growth regulatory system plays a role in the development of ocular surface complications and delayed cutaneous wound healing complications in multiple animal models of both Type 1 and Type 2 diabetes. Modulation of this system may hold promise for reversing or even preventing these diabetic complications in humans. Moreover, monitoring serum levels of OGF should be investigated as an indicator of the development of these and other diabetic complications.

A 20-Year Research Trend Analysis of the Influence of Anesthesia on Tumor Prognosis Using Bibliometric Methods

BackgroundBibliometric analysis is used to gain a systematic understanding of developments in the field of the influence of anesthesia on tumor prognosis and changes in research hot spots over the past 20 years.MethodsRelevant publications from the Web of Science Core Collection (WoSCC) were downloaded on May 5, 2021. Acquired data were then analyzed using the Online Analysis Platform of Literature Metrology (http://biblimetric.com) and the CiteSpace software was used to analyze and predict trends and hot spots in this field.Results1,521 publications on the influence of anesthesia on tumor prognosis were identified and 1494 qualifying records were included in the final analysis. The leading country in this field was the United States of America (USA). The University of Texas MD Anderson Cancer Center (Houston, TX, USA) and Pennsylvania State University (State College, PA, USA) featured the highest number of publications among all institutions. Co-citation cluster labels revealed characteristics of ten main clusters: total intravenous anesthesia, opioid growth factor receptor, gastric cancer cell, opioid receptor, murine model, natural killer cell activity, health-related quality, glioma cell, opioid switching and mu-type opioid receptor. Keyword burst detection indicated that randomized controlled trials (RCTs), volatile anesthetics, and ropivacaine were the newly emerging research hot spots.ConclusionsThis study compiled 1494 publications covering anesthesia and tumor prognosis research and showed that the direction of these studies is likely in transition from opioids and their receptors to other anesthetics, and from retrospective studies to prospective randomized controlled trials. It provides guidance for further research and clinical applications on choosing anesthetic methods and drugs.

A novel mechanism of lung cancer inhibition by methionine enkephalin through remodeling the immune status of the tumor microenvironment

This study examined the antitumor effect of methionine enkephalin (MENK) against lung cancer in vivo and in vitro and explored the underlying mechanisms. Changes in the immune status of the tumor microenvironment (TME) in response to MENK administration were examined in mice. MENK significantly inhibited the proliferation of lung cancer cells in vivo and in vitro by regulating the Wnt/β-catenin pathway and causing cell cycle arrest at the G0/G1 phase. Knockdown of opioid growth factor receptor abolished the effect of MENK on lung cancer cells. The immune status of the TME of mice differed between the MENK and control groups. MENK increased the infiltration of M1-type macrophages, natural killer cells, CD8+ T cells, CD4+ T cells, and dendritic cells into the TME, and decreased the proportion of myeloid inhibitory cells and M2-type macrophages. Immunohistochemical analysis of the expression of cytokines in the TME showed that MENK upregulated IL-15, IL-21, IFN-γ, and granzyme B and downregulated IL-10 and TGF-β1 in mice. Taken together, these finding indicate that MENK may be a potential agent for lung cancer treatment in the future, especially for overcoming immune escape and immune resistance.

Low Doses Naltrexone: The Potential Benefit Effects for its Use in Patients with Cancer.

Naltrexone (NTX) is an opioid antagonist that inhibits cell proliferation in vivo when administered in low doses. Naltrexone in low doses can reduce tumor growth by interfering with cell signalling as well as by modifying the immune system. It acts as an Opioid Growth Factor receptor (OGFr) antagonist and the OGF-OGFr axis is an inhibitory biological pathway present in human cancer cells and tissues, being a target for the treatment with naltrexone low-dose (LDN). Clinical trials have proposed a unique mechanism(s) allowing LDN to affect tumors. LDN shows promising results for people with primary cancer of the bladder, breast, liver, lung, lymph nodes, colon and rectum. This short review provides further evidence to support the role of LDN as an anticancer agent.

Naltrexone blockade of OGFr enhances cutaneous wound closure in diabetic rats

AimsNon-healing wounds are a major complication for the 27 million individuals in the United States with diagnosed diabetes. This study investigated the efficacy of a novel formulation to treat diabetic foot ulcers by targeting an underlying pathophysiology of diabetes. Main methodsThe proprietary GMP formulations utilized increasing dosages of naltrexone (NTX) to block the inhibitory peptide Opioid Growth Factor (OGF) from binding to the OGF receptor (OGFr). Efficacy of topical application was studied using male Sprague-Dawley rats with uncontrolled (T1D) or insulin-controlled (T1D-INS) diabetes. Wound closure time, tensile strength of healed skin, and angiogenesis were endpoints. Serum drug dispersion was assessed. Key findingsResidual wound areas were significantly reduced within 2 days of surgery in T1D rats receiving either 0.5% or 1% NTX. By day 10, NTX-treated wounds were 5-fold smaller than those measured on T1D rats receiving vehicle. Tensile strength measurements and morphology studies revealed that NTX treatment of cutaneous wounds on T1D or T1D-INS rats accelerated epithelialization, accelerated angiogenesis, and increased the integrity of healed skin. Topical application of NTX resulted in no visible toxicity, and the NTX was not detected in serum. SignificanceProprietary GMP formulations up to 1% NTX were found to be effective and safe for topical treatment of full-thickness cutaneous wounds in diabetic rats. The mechanism of action involves blockade of the OGF-OGFr axis, a pathway known to become dysregulated with diabetes. These data warrant proof-of-concept human clinical trials for treatment of diabetic foot ulcers.