Psychoneuroimmunological approach to gastrointestinal related pain

BACKGROUND AND PURPOSE (AIMS): Psychoneuroimmunology is both a theoretical and practical field of medicine in which human biology and psychology are considered an interconnected unity. Through such a framework it is possible to elucidate complex syndromes in gastrointestinal related pain, particularly chronic non-malignant. The aim is to provide insight into pathophysiological mechanisms and suggest treatment modalities according to a comprehensive paradigm. The article also presents novel findings that may guide clinicians to recognize new targets or scientists to find new research topics. ----- METHODS: A literature search of 'PubMed' and 'Google Scholar' databases was performed. Search terms included: 'Visceral pain', 'Psychoneuroimmunology', 'Psychoneuroimmunology and pain', 'Pain in GI system', 'GI related pain', 'Pain and microbiota', 'Enteric nervous system', 'Enteric nervous system and inflammation', 'CNS and pain', 'Inflammation and pain in GI tract', 'Neurogastroenterology', 'Neuroendocrinology', 'Immune system in GI pain'. After searching and reading sources deemed recent and relevant, a narrative review was written with a tendency to discriminate the peripheral, intermediate, and central pathophysiological mechanisms or treatment targets. ----- RESULTS: Recent evidence point out the importance of considering the brain-gut axis as the main connector of the central and peripheral phenomena encountered in patients suffering from chronic non-malignant gastrointestinal related pain. This axis is also a prime clinical target with multiple components to be addressed in order for therapy to be more effective. Patients suffering from inflammatory bowel disease or functional gastrointestinal disorders represent groups that could benefit most from the proposed approach. ----- CONCLUSIONS (BASED ON OUR FINDINGS): Rather than proceeding with established allopathic single-target central or peripheral treatments, by non-invasively modulating the brain-gut axis components such as the psychological and neuroendocrinological status, microbiota, enteric nervous system, or immune cells (e.g. glial or mast cells), a favourable clinical outcome in various chronic gastrointestinal related pain syndromes may be achieved. Clinical tools are readily available in forms of psychotherapy, prebiotics, probiotics, nutritional advice, and off-label drugs. An example of the latter is low-dose naltrexone, a compound which opens the perspective of targeting glial cells to reduce neuroinflammation and ultimately pain. ----- IMPLICATIONS (OUR OPINION ON WHAT OUR FINDINGS MEAN): Current findings from basic science provide sound mechanistic evidence and once entering clinical practice should yield more effective outcomes for patients. In addition to well-established pharmacotherapy comprised notably of anti-inflammatories, antibiotics, and proton-pump inhibitors, valid treatment strategies may contain other options. These disease modulating add-ons include probiotics, prebiotics, food supplements with anti-inflammatory properties, various forms of psychotherapy, and low-dose naltrexone as a glial modulator that attenuates neuroinflammation. Clearly, a broader and still under exploited set of evidence-based tools is available for clinical use

Sex Hormone Binding Globulin (SHBG) as a Marker of Clinical Disorders

Sex hormone binding globulin (SHBG) is an important protein, not only for transporting sex steroids which is its primary role, but with the discovery of a specific receptor that binds SHBG, a novel approach regarding classic ‘free-hormone hypothesis’ should be implemented. Research in SHBG gene and it expression has been done, as well as cellular signaling that controls it. It provides significant knowledge of the impact of certain well –defined cellular level signaling pathways and how they affect the level of SHBG production. Moreover, new insights have proven that SHBG isn’t just a peripherally synthesized protein. Its origin has been proven to exist in the brain, namely in the hypothalamus and the pituitary, where it is spatially closely related to oxytocin-producing neurons. The main peripheral organ that produces SHBG is the liver. Since the liver is the central metabolic organ, certain metabolic diseases will result in changed SHBG serum levels. On the other hand, endocrine disorders that affect tissues involved in sex hormone regulation will also have an impact on SHBG levels. Thusly, SHBG stands as one of the mediators between various endocrine tissues and definitely contributes with its own pathophysiological role in diseases such as: obesity, metabolic syndrome, polycystic ovary syndrome, osteoporosis, breast and prostate cancer. Its value expands to the area of clinical medicine as a marker of certain pathological states. Some studies already established its reliability and the growing trend to implement it as a useful clinical marker is present. It still remains largely understudied, from physiological and clinical aspect, but recent findings give notions that SHBG plays an important role in health and disease and could be a useful assessment marker

Sex hormone binding globulin (SHBG) as a marker of clinical disorders [Globulin koji veže spolne hormone (SHGB) kao marker u kliničkim poremećajima]

Sex hormone binding globulin (SHBG) is an important protein, not only for transporting sex steroids which is its primary role, but with the discovery of a specific receptor that binds SHBG, a novel approach regarding classic ‘free-hormone hypothesis’ should be implemented. Research in SHBG gene and it expression has been done, as well as cellular signaling that controls it. It provides significant knowledge of the impact of certain well –defined cellular level signaling pathways and how they affect the level of SHBG production. Moreover, new insights have proven that SHBG isn’t just a peripherally synthesized protein. Its origin has been proven to exist in the brain, namely in the hypothalamus and the pituitary, where it is spatially closely related to oxytocin-producing neurons. The main peripheral organ that produces SHBG is the liver. Since the liver is the central metabolic organ, certain metabolic diseases will result in changed SHBG serum levels. On the other hand, endocrine disorders that affect tissues involved in sex hormone regulation will also have an impact on SHBG levels. Thusly, SHBG stands as one of the mediators between various endocrine tissues and definitely contributes with its own pathophysiological role in diseases such as: obesity, metabolic syndrome, polycystic ovary syndrome, osteoporosis, breast and prostate cancer. Its value expands to the area of clinical medicine as a marker of certain pathological states. Some studies already established its reliability and the growing trend to implement it as a useful clinical marker is present. It still remains largely understudied, from physiological and clinical aspect, but recent findings give notions that SHBG plays an important role in health and disease and could be a useful assessment marker

Equivalent: Sex hormone binding globulin (SHBG) as a marker of clinical disorders

Sex hormone binding globulin (SHBG) is an important protein, not only for transporting sex steroids which is its primary role, but with the discovery of a specific receptor that binds SHBG, a novel approach regarding classic ‘freehormone hypothesis’ should be implemented. Research in SHBG gene and it expression has been done, as well as cellular signaling that controls it. It provides significant knowledge of the impact of certain well –defined cellular level signaling pathways and how they affect the level of SHBG production. Moreover, new insights have proven that SHBG isn’t just a peripherally synthesized protein. Its origin has been proven to exist in the brain, namely in the hypothalamus and the pituitary, where it is spatially closely related to oxytocin-producing neurons. The main peripheral organ that produces SHBG is the liver. Since the liver is the central metabolic organ, certain metabolic diseases will result in changed SHBG serum levels. On the other hand, endocrine disorders that affect tissues involved in sex hormone regulation will also have an impact on SHBG levels. Thusly, SHBG stands as one of the mediators between various endocrine tissues and definitely contributes with its own pathophysiological role in diseases such as: obesity, metabolic syndrome, polycystic ovary syndrome, osteoporosis, breast and prostate cancer. Its value expands to the area of clinical medicine as a marker of certain pathological states. Some studies already established its reliability and the growing trend to implement it as a useful clinical marker is present. It still remains largely understudied, from physiological and clinical aspect, but recent findings give notions that SHBG plays an important role in health and disease and could be a useful assessment marker.Globulin koji veže spolne hormone (SHBG) je važan protein, ne samo kao primarni nosač spolnih steroida, nego se i otkrićem specifičnog receptora koji veže SHBG treba usvojiti novi pristup klasičnoj teoriji ‘slobodnih hormona’. Istražen je gen SHBG, kao i stanični mehanizmi koji utječu na njegovu ekspresiju. Značajna saznanja su dobivena i postoje dobro objašnjeni signalni putevi na staničnoj razini koji utječu na proizvodnju SHBG. Štoviše, pokazano je da SHBG nije samo periferno sintetiziran protein, već je njegovo postojanje potvrđeno i u moždanom tkivu, u području hipotalamusa i hipofize. Ovdje je prostorno razmješten u bliskosti s neuronima koji proizvode oksitocin. Glavni periferni organ koji proizvodi SHBG jesu jetra. Budući da su jetra središnji metabolički organ, određene metaboličke bolesti će rezultirati promijenjenom razinom SHBG u krvi. S druge strane, endokrinološki poremećaji tkiva uključenih u regulaciju spolnih hormona također će imati utjecaj na razinu SHBG. Stoga, SHBG stoji kao jedan od posrednika između različitih endokrinološki aktivnih tkiva i definitivno pridonosi svojom patofiziološkom ulogom u bolestima poput: debljine, metaboličkog sindroma, sindroma policističnih ovarija, osteoporoze, raka dojke i raka prostate. Njegova vrijednost prelazi i u područje kliničke medicine kao biljega određenih patoloških stanja. Neke studije su već utvrdile njegovu pouzdanost i postoji rastući trend da se uvede kao korisni biljeg u kliničkoj medicini. U pogledu patofiziologije i kliničke medicine, još uvijek nije dovoljno proučen, ali nedavni pronalasci daju naznake da SHBG ima važnu ulogu u zdravlju i bolesti i mogao bi predstavljati koristan biljeg za procjenu u kliničkoj medicini

Equivalent: Sex hormone binding globulin (SHBG) as a marker of clinical disorders

Sex hormone binding globulin (SHBG) is an important protein, not only for transporting sex steroids which is its primary role, but with the discovery of a specific receptor that binds SHBG, a novel approach regarding classic ‘freehormone hypothesis’ should be implemented. Research in SHBG gene and it expression has been done, as well as cellular signaling that controls it. It provides significant knowledge of the impact of certain well –defined cellular level signaling pathways and how they affect the level of SHBG production. Moreover, new insights have proven that SHBG isn’t just a peripherally synthesized protein. Its origin has been proven to exist in the brain, namely in the hypothalamus and the pituitary, where it is spatially closely related to oxytocin-producing neurons. The main peripheral organ that produces SHBG is the liver. Since the liver is the central metabolic organ, certain metabolic diseases will result in changed SHBG serum levels. On the other hand, endocrine disorders that affect tissues involved in sex hormone regulation will also have an impact on SHBG levels. Thusly, SHBG stands as one of the mediators between various endocrine tissues and definitely contributes with its own pathophysiological role in diseases such as: obesity, metabolic syndrome, polycystic ovary syndrome, osteoporosis, breast and prostate cancer. Its value expands to the area of clinical medicine as a marker of certain pathological states. Some studies already established its reliability and the growing trend to implement it as a useful clinical marker is present. It still remains largely understudied, from physiological and clinical aspect, but recent findings give notions that SHBG plays an important role in health and disease and could be a useful assessment marker.Globulin koji veže spolne hormone (SHBG) je važan protein, ne samo kao primarni nosač spolnih steroida, nego se i otkrićem specifičnog receptora koji veže SHBG treba usvojiti novi pristup klasičnoj teoriji ‘slobodnih hormona’. Istražen je gen SHBG, kao i stanični mehanizmi koji utječu na njegovu ekspresiju. Značajna saznanja su dobivena i postoje dobro objašnjeni signalni putevi na staničnoj razini koji utječu na proizvodnju SHBG. Štoviše, pokazano je da SHBG nije samo periferno sintetiziran protein, već je njegovo postojanje potvrđeno i u moždanom tkivu, u području hipotalamusa i hipofize. Ovdje je prostorno razmješten u bliskosti s neuronima koji proizvode oksitocin. Glavni periferni organ koji proizvodi SHBG jesu jetra. Budući da su jetra središnji metabolički organ, određene metaboličke bolesti će rezultirati promijenjenom razinom SHBG u krvi. S druge strane, endokrinološki poremećaji tkiva uključenih u regulaciju spolnih hormona također će imati utjecaj na razinu SHBG. Stoga, SHBG stoji kao jedan od posrednika između različitih endokrinološki aktivnih tkiva i definitivno pridonosi svojom patofiziološkom ulogom u bolestima poput: debljine, metaboličkog sindroma, sindroma policističnih ovarija, osteoporoze, raka dojke i raka prostate. Njegova vrijednost prelazi i u područje kliničke medicine kao biljega određenih patoloških stanja. Neke studije su već utvrdile njegovu pouzdanost i postoji rastući trend da se uvede kao korisni biljeg u kliničkoj medicini. U pogledu patofiziologije i kliničke medicine, još uvijek nije dovoljno proučen, ali nedavni pronalasci daju naznake da SHBG ima važnu ulogu u zdravlju i bolesti i mogao bi predstavljati koristan biljeg za procjenu u kliničkoj medicini

Equivalent: Sex hormone binding globulin (SHBG) as a marker of clinical disorders

Sex hormone binding globulin (SHBG) is an important protein, not only for transporting sex steroids which is its primary role, but with the discovery of a specific receptor that binds SHBG, a novel approach regarding classic ‘freehormone hypothesis’ should be implemented. Research in SHBG gene and it expression has been done, as well as cellular signaling that controls it. It provides significant knowledge of the impact of certain well –defined cellular level signaling pathways and how they affect the level of SHBG production. Moreover, new insights have proven that SHBG isn’t just a peripherally synthesized protein. Its origin has been proven to exist in the brain, namely in the hypothalamus and the pituitary, where it is spatially closely related to oxytocin-producing neurons. The main peripheral organ that produces SHBG is the liver. Since the liver is the central metabolic organ, certain metabolic diseases will result in changed SHBG serum levels. On the other hand, endocrine disorders that affect tissues involved in sex hormone regulation will also have an impact on SHBG levels. Thusly, SHBG stands as one of the mediators between various endocrine tissues and definitely contributes with its own pathophysiological role in diseases such as: obesity, metabolic syndrome, polycystic ovary syndrome, osteoporosis, breast and prostate cancer. Its value expands to the area of clinical medicine as a marker of certain pathological states. Some studies already established its reliability and the growing trend to implement it as a useful clinical marker is present. It still remains largely understudied, from physiological and clinical aspect, but recent findings give notions that SHBG plays an important role in health and disease and could be a useful assessment marker.Globulin koji veže spolne hormone (SHBG) je važan protein, ne samo kao primarni nosač spolnih steroida, nego se i otkrićem specifičnog receptora koji veže SHBG treba usvojiti novi pristup klasičnoj teoriji ‘slobodnih hormona’. Istražen je gen SHBG, kao i stanični mehanizmi koji utječu na njegovu ekspresiju. Značajna saznanja su dobivena i postoje dobro objašnjeni signalni putevi na staničnoj razini koji utječu na proizvodnju SHBG. Štoviše, pokazano je da SHBG nije samo periferno sintetiziran protein, već je njegovo postojanje potvrđeno i u moždanom tkivu, u području hipotalamusa i hipofize. Ovdje je prostorno razmješten u bliskosti s neuronima koji proizvode oksitocin. Glavni periferni organ koji proizvodi SHBG jesu jetra. Budući da su jetra središnji metabolički organ, određene metaboličke bolesti će rezultirati promijenjenom razinom SHBG u krvi. S druge strane, endokrinološki poremećaji tkiva uključenih u regulaciju spolnih hormona također će imati utjecaj na razinu SHBG. Stoga, SHBG stoji kao jedan od posrednika između različitih endokrinološki aktivnih tkiva i definitivno pridonosi svojom patofiziološkom ulogom u bolestima poput: debljine, metaboličkog sindroma, sindroma policističnih ovarija, osteoporoze, raka dojke i raka prostate. Njegova vrijednost prelazi i u područje kliničke medicine kao biljega određenih patoloških stanja. Neke studije su već utvrdile njegovu pouzdanost i postoji rastući trend da se uvede kao korisni biljeg u kliničkoj medicini. U pogledu patofiziologije i kliničke medicine, još uvijek nije dovoljno proučen, ali nedavni pronalasci daju naznake da SHBG ima važnu ulogu u zdravlju i bolesti i mogao bi predstavljati koristan biljeg za procjenu u kliničkoj medicini

Vladimir Sertić: forgotten pioneer of virology and bacteriophage therapy

Vladimir Sertić was a pioneer of bacteriophage research in the period between the two world wars. He was born and educated in Croatia, where he made his initial discoveries, and joined Félix d'Herelle's Laboratoire du Bactériophage in Paris in 1928. Original documents and a box with hundreds of sealed bacteriophages samples were kept in Sertić's Zagreb home for decades. Following Vladimir's death, his sister passed this archival material to Professor Zdravko Lacković in 1989. Some years later, these artefacts were opened and studied. Additionally, we conducted a literature search using the term ‘Vladimir Sertić’ in the databases PubMed and Google Scholar. After a detailed examination of these data, we established a chronology of his work and compiled a list of his scientific publications. A complete bibliography, with the exception of those publications already cited here, is provided as an appendix. Sertić's key contributions included the exploration of the properties of phage lysins, the devising of a uniform bacteriophage classification system and, in collaboration with his protégé, Nikolai Boulgakov, the isolation of numerous bacteriophage strains, including the famous φX174. Finally it was Sertić's pioneering work in Zagreb that offered confirmation that phages are live agents

Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization

Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn’s disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed

Circadian Rhythm and Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder with a growing epidemiological importance characterized by significant disease burden. Sleep-related pathological symptomatology often accompanies AD. The etiology and pathogenesis of disrupted circadian rhythm and AD share common factors, which also opens the perspective of viewing them as a mutually dependent process. This article focuses on the bi-directional relationship between these processes, discussing the pathophysiological links and clinical aspects. Common mechanisms linking both processes include neuroinflammation, neurodegeneration, and circadian rhythm desynchronization. Timely recognition of sleep-specific symptoms as components of AD could lead to an earlier and correct diagnosis with an opportunity of offering treatments at an earlier stage. Likewise, proper sleep hygiene and related treatments ought to be one of the priorities in the management of the patient population affected by AD. This narrative review brings a comprehensive approach to clearly demonstrate the underlying complexities linking AD and circadian rhythm disruption. Most clinical data are based on interventions including melatonin, but larger-scale research is still scarce. Following a pathophysiological reasoning backed by evidence gained from AD models, novel anti-inflammatory treatments and those targeting metabolic alterations in AD might prove useful for normalizing a disrupted circadian rhythm. By restoring it, benefits would be conferred for immunological, metabolic, and behavioral function in an affected individual. On the other hand, a balanced circadian rhythm should provide greater resilience to AD pathogenesis