The Green Walnut Husks Induces Apoptosis of Colorectal Cancer through Regulating NLRC3/PI3K Pathway.

BACKGROUND: Colorectal cancer (CRC) is the most common type of gastrointestinal tumor, but the available pharmacological treatment is insufficient. As a traditional Chinese medicine, the green walnut husks (QLY) exhibit anti-inflammatory, analgesic, anti-bacterial and anti-tumor effects. However, the effects and molecular mechanisms of QLY extracts on CRC were not yet made known. OBJECTIVE: This study aims to provide efficient and low toxicity drugs for the treatment of CRC. The purpose of this study is to explore the anti-CRC effect and mechanism of QLY, providing preliminary data support for clinical research of QLY. METHODS: Western blotting, Flow cytometry, immunofluorescence, Transwell, MTT, Cell proliferation assay, and xenograft model were used to perform the research. RESULTS: In this study, the potential of QLY to inhibit the proliferation, migration invasion and induce apoptosis of the mouse colorectal cancer cell line CT26 in vitro was identified. The xenograft tumor model of CRC noted that QLY suppressed tumor growth without sacrificing body weight in mice. In addition, QLY-induced apoptosis in tumor cells through NLRC3/PI3K/AKT signaling pathway was revealed. CONCLUSION: QLY regulates the levels of mTOR, Bcl-2 and Bax by affecting the NLRC3/PI3K/AKT pathway to promote apoptosis of tumor cells, suppressing cell proliferation, invasion and migration, and subsequently preventing the progression of colon cancer.

Regenerative medicine for the treatment of chronic low back pain: a narrative review.

Low back pain (LBP) is a common and important clinical problem. In addition to pain, patients are also affected by personal, social, and economic burdens. Intervertebral disc (IVD) degeneration is a common cause of LBP, further increasing the patient's morbidity and medical costs. The limitations of current treatment strategies for long-term pain relief mean that increasing attention has been paid to regenerative medicine. We carried out a narrative review to explore the roles of four types of regenerative medicine for treating LBP: marrow-derived stem cells, growth factors, platelet-rich plasma, and prolotherapy. Marrow-derived stem cells are regarded as an ideal cell source for IVD regeneration. Growth factors may stimulate the synthesis of extracellular matrix and attenuate or reverse the degenerative process in IVD, while platelet-rich plasma, which contains multiple growth factors, is thought to be a promising alternative therapy for IVD degeneration. Prolotherapy can initiate the body's inflammatory healing response to repair injured joints and connective tissues. This review summarizes the mechanisms, in vitro and in vivo studies, and clinical applications of these four types of regenerative medicine in patients with LBP.

Rational selection of bioactive principles for wound healing applications: Growth factors and antioxidants.

Wound healing is a complex process of communication between growth factors, reactive species of oxygen, cells, signalling pathways, and cytokines in the extracellular matrix, in which growth factors are the key regulators. In humans, the main regulators of the cellular responses in wound healing are five growth factors, namely EGF, bFGF, VEGF, and TGF-ß1. On the other hand, antioxidants such as astaxanthin, beta-carotene, epigallocatechin gallate, delphinidin, and curcumin have been demonstrated to stimulate cell proliferation, migration and angiogenesis, and control inflammation, to suggest a practical approach to design new strategies to treat non-healing cutaneous conditions. Based on the individual effects of growth factors and antioxidants, it may be envisioned that the use of both types of bioactives in wound healing formulations may have an additive or synergistic effect on the healing potential. This review addresses the effect of growth factors and antioxidants on wound healing-related processes. Furthermore, a prospective on their potential additive or synergistic effect on wound healing formulations, based on their individual effects, is presented. This may serve as a guide for the development of a new generation of wound healing formulations.

Anterior Cruciate Ligament Reconstruction: Is Biological Augmentation Beneficial?

Surgical reconstruction in anterior cruciate ligament (ACL) ruptures has proven to be a highly effective technique that usually provides satisfactory results. However, despite the majority of patients recovering their function after this procedure, ACL reconstruction (ACLR) is still imperfect. To improve these results, various biological augmentation (BA) techniques have been employed mostly in animal models. They include: (1) growth factors (bone morphogenetic protein, epidermal growth factor, granulocyte colony-stimulating factor, basic fibroblast growth factor, transforming growth factor-ß, hepatocyte growth factor, vascular endothelial growth factor, and platelet concentrates such as platelet-rich plasma, fibrin clot, and autologous conditioned serum), (2) mesenchymal stem cells, (3) autologous tissue, (4) various pharmaceuticals (matrix metalloproteinase-inhibitor alpha-2-macroglobulin bisphosphonates), (5) biophysical/environmental methods (hyperbaric oxygen, low-intensity pulsed ultrasound, extracorporeal shockwave therapy), (6) biomaterials (fixation methods, biological coatings, biosynthetic bone substitutes, osteoconductive materials), and (7) gene therapy. All of them have shown good results in experimental studies; however, the clinical studies on BA published so far are highly heterogeneous and have a low degree of evidence. The most widely used technique to date is platelet-rich plasma. My position is that orthopedic surgeons must be very cautious when considering using PRP or other BA methods in ACLR.

Biotechnology-based therapeutics for management of cerebral stroke.

Cerebral stroke, commonly caused due to hindrance in blood flow, is broadly classified into two categories-ischemic and haemorrhagic strokes. The onset of stroke triggers multiple mechanisms causing inflammation, generation of free radicals and protein damage leading to apoptosis of neuronal cells. The current therapies available for cerebral strokes involve use of complex surgical treatments and tissue plasminogen activator which increases the risk of internal bleeding, brain edema and cerebral damage, thereby restricting their use in clinical setting. The alarming need to develop safe, effective, target specific systems which, promote neuronal growth and reduce cerebral inflammation can be accomplished with use of biotechnological approaches. The article gives an insight to biotechnology-based advancements for tissue plasminogen activators, cell penetrating peptides, growth factors, ribonucleic acid systems and monoclonal antibodies for cerebral stroke. We also emphasis on challenges and future perspective of biotechnology-based therapeutics for better management of stroke.

Apelin-13 attenuates spatial memory impairment by anti-oxidative, anti-apoptosis, and anti-inflammatory mechanism against ethanol neurotoxicity in the neonatal rat hippocampus.

It has been shown that alcohol consumption by pregnant women can have detrimental effects on the developing fetus and lead to fetal alcohol spectrum disorders (FASD). Exposure to alcohol in rat pups during this period causes long-term changes in the structure of the animal's hippocampus, leading to impaired hippocampal-related brain functions such as navigation tasks and spatial memory. Apelin-13, a principal neuropeptide with inhibitory effects on neuroinflammation and brain oxidative stress production, has beneficial properties on memory impairment and neuronal injury. The protective effects of apelin-13 have been evaluated on ethanol-related neurotoxicity in the hippocampus of rat pups. Rat pups from 2 until 10 postnatal day, similar to the third trimester of pregnancy in humans, were intubated total daily dose of ethanol (5/27 g/kg/day). Immediately after intubation, 25 and 50 µg/ kg of apelin-13 was injected subcutaneously. By using Morris water maze task, the hippocampus- dependent memory and spatial learning were evaluated 36 days after birth. Then, Immunohistochemical staining was done to determine the levels of GFAP and caspase-3. ELISA assay was also performed to measure both TNF-α and antioxidant enzymes levels. The current study demonstrates that administration of apelin-13 attenuates spatial memory impairment significantly (P < 0.001). After ethanol neurotoxicity, apelin-13 could also increase the catalase level (P < 0.001), activity of total superoxide dismutase as well as glutathione concentration noticeably (P < 0.05). Other impacts of it could be mentioned as attenuating TNF-α production and also preventing lipid peroxidation (P < 0.001). In addition, the results showed that the level of GFAP as a neuroinflammation factor and the number of active caspase-3 positive cells can be decreased by apelin-13 (P < 0.01). Regarding the protective effects of apelin-13 against ethanol-induced neurotoxicity, it is a promising therapeutic choice for FASD; but more studies are needed.

Modulation of Interleukin-1 and -18 Mediated Injury in Donation after Circulatory Death Mouse Hearts.

BACKGROUND: Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS: Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS: Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS: Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.

In vivo protective effects of upper zone of growth plate and cartilage matrix associated protein against cartilage degeneration in a monosodium iodoacetate induced osteoarthritis model.

Osteoarthritis (OA) is a degenerative disease affecting the majority of over 65 year old people and characterized by cartilage degeneration, subchondral abnormal changes, and inflammation. Despite the enormous socioeconomic burden caused by OA, currently, there is no effective therapy against it. Upper zone of growth plate and cartilage matrix associated protein (UCMA) is a vitamin K dependent protein and has a critical role in pathophysiological conditions associated with bone and cartilage. However, there is no research on the protective role of intra-articular UCMA treatment in OA pathogenesis. Therefore, we aimed to investigate the potential therapeutic role of UCMA in an in vivo model of OA. We report for the first time that intra-articular UCMA injection ameliorated cartilage degeneration in a monosodium iodoacetate induced OA rat model. Furthermore, the OA-induced activation of nuclear factor kappa B and bone morphogenetic protein 2 signals was attenuated by UCMA. Our results indicated that UCMA decreased cartilage oligomeric matrix protein levels but did not affect interleukin 6, total antioxidant status, and total oxidant status levels in the serum. In conclusion, UCMA exhibited a therapeutic potential in the treatment of OA. This protective effect of UCMA is possibly achieved by reducing the aggrecanase activity and the production of inflammatory cytokines.

The Role of Hormones and Trophic Factors as Components of Preservation Solutions in Protection of Renal Function before Transplantation: A Review of the Literature.

Transplantation is currently a routine method for treating end-stage organ failure. In recent years, there has been some progress in the development of an optimal composition of organ preservation solutions, improving the vital functions of the organ and allowing to extend its storage period until implantation into the recipient. Optimizations are mostly based on commercial solutions, routinely used to store grafts intended for transplantation. The paper reviews hormones with a potential nephroprotective effect, which were used to modify the composition of renal perfusion and preservation solutions. Their effectiveness as ingredients of preservation solutions was analysed based on a literature review. Hormones and trophic factors are innovative preservation solution supplements. They have a pleiotropic effect and affect normal renal function. The expression of receptors for melatonin, prolactin, thyrotropin, corticotropin, prostaglandin E1 and trophic factors was confirmed in the kidneys, which suggests that they are a promising therapeutic target for renal IR (ischemia-reperfusion) injury. They can have anti-inflammatory, antioxidant and anti-apoptotic effects, limiting IR injury.

Anti-inflammation and anti-apoptosis effects of growth arrest-specific protein 6 in acute liver injury induced by LPS/D-GalN in mice.

PURPOSE: To investigate the effect of growth arrest-specific protein 6 (Gas6) on acute liver injury in mice and related mechanisms. METHODS: Thirty C57BL/6 (6-8 weeks old) mice were randomly divided into control, LPS/D-GalN, and LPS/D-GalN+Gas6 groups (10 mice in each group). The LPS/D-GalN group was intraperitoneally administered with LPS (0.25 mg/Kg) and D-GalN (400 mg/Kg) for 5h. The LPS/D-GalN+Gas6 group was intraperitoneally administered with rmGas6 one hour before intraperitoneal application of LPS/D-GalN. All subjects were sacrificed at 5 h for blood and tissue analysis. The expression of protein and mRNA was assessed by western blotting and RT-PCR, respectively. RESULTS: Compared with the control group, AST, ALT, IL-1ß, TNF-α, IL-6 IL-10, MPO activity were increased in the LPS/D-GalN group. However, they were significantly inhibited by Gas6. Gas6 markedly suppressed the expression of apoptosis-related protein induced by LPS/D-GalN. Moreover, Gas6 attenuated the activation of the NF-κB signaling pathway in acute liver injury induced by LPS/D-GalN. CONCLUSIONS: Gas6 alleviates acute liver injury in mice through regulating NF-κB signaling pathways. Gas6 can be a potential therapeutic agent in treating LPS/D-GalN-induced acute liver injury in the future.

Anti-inflammation and anti-apoptosis effects of growth arrest-specific protein 6 in acute liver injury induced by LPS/D-GalN in mice

Abstract Purpose To investigate the effect of growth arrest-specific protein 6 (Gas6) on acute liver injury in mice and related mechanisms. Methods Thirty C57BL/6 (6-8 weeks old) mice were randomly divided into control, LPS/D-GalN, and LPS/D-GalN+Gas6 groups (10 mice in each group). The LPS/D-GalN group was intraperitoneally administered with LPS (0.25 mg/Kg) and D-GalN (400 mg/Kg) for 5h. The LPS/D-GalN+Gas6 group was intraperitoneally administered with rmGas6 one hour before intraperitoneal application of LPS/D-GalN. All subjects were sacrificed at 5 h for blood and tissue analysis. The expression of protein and mRNA was assessed by western blotting and RT-PCR, respectively. Results Compared with the control group, AST, ALT, IL-1β, TNF-α, IL-6 IL-10, MPO activity were increased in the LPS/D-GalN group. However, they were significantly inhibited by Gas6. Gas6 markedly suppressed the expression of apoptosis-related protein induced by LPS/D-GalN. Moreover, Gas6 attenuated the activation of the NF-κB signaling pathway in acute liver injury induced by LPS/D-GalN. Conclusions Gas6 alleviates acute liver injury in mice through regulating NF-κB signaling pathways. Gas6 can be a potential therapeutic agent in treating LPS/D-GalN-induced acute liver injury in the future.

[Wnt signaling in myeloma.]

Multiple myeloma(MM)develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. A variety of cytokines are overproduced in MM to stimulate RANKL-mediated osteoclastogenesis while suppressing osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. Soluble Wnt inhibitors elaborated from MM cells and/or their surrounding cells in bone lesions play an important role. Novel therapeutic neutralizing antibodies against DKK-1 or sclerotin are expected as bone anabolic agents;however, their effects on MM tumor progression through activation of the Wnt/ß-catenin pathway remain to be carefully clarified.

Orthobiologics for Bone Healing.

Orthobiologics are a group of biological materials and substrates that promote bone, ligament, muscle, and tendon healing. These substances include bone autograft, bone allograft, demineralized bone matrix, bone graft substitutes, bone marrow aspirate concentrate, platelet-rich plasma, bone morphogenetic proteins, platelet-derived growth factor, parathyroid hormone, and vitamin D and calcium. Properties of orthobiologics in bone healing include osteoconduction, osteoinduction, and osteogenesis. This article discusses the important properties of orthobiologics in bone healing, many of the orthobiologics currently available for bone healing, the related literature, their current clinical uses in sports medicine, and systemic factors that inhibit bone healing.

PRP Therapy.

Osteochondral lesions remain as a clinical challenge despite the advances in orthopedic regenerative strategies. Biologics, in particular, platelet-rich plasma, has been applied for the reparative and regenerative effect in many tissues, and osteochondral tissue is not an exception. Platelet-rich plasma is an autologous concentrate prepared from the collected blood; thus, this safe application is free of immune response or risk of transmission of disease. It has a high potential to promote regeneration, thanks to its content, and can be applied alone or can reinforce a tissue engineering strategy. The relevant works making use of platelet-rich plasma in osteochondral lesions are overviewed herein. The practical success of platelet-rich plasma is uncertain since there are many factors involved including but not limited to its preparation and administration method. Nevertheless, today, the issues and challenges of platelet-rich plasma have been well acknowledged by researchers and clinicians. Thus, it is believed that a consensus will be built it, and then with high-quality randomized controlled trials and standardized protocols, the efficacy of platelet-rich plasma therapy can be better evaluated. HIGHLIGHTS: The need of treating the osteochondral lesions has not been yet met in the clinics. Thanks to being an autologous source of growth factors, interleukins, and other cytokines and relative ease of clinical application, i.e., during a single-step surgical procedure, the use of platelet-rich plasma is of great interest. The high theoretical potential of the role of platelet-rich plasma in the regeneration process of osteochondral lesions is known, and the efficiency needs to be confirmed by high-quality randomized controlled trials for a robust position in the treatments of osteochondral lesions in the clinics.

Small Animal Models.

Animal assays represent an important stage between in vitro studies and human clinical applications. These models are crucial for biomedical research and regenerative medicine studies, as these offer precious information for systematically assessing the efficacy and risks of recently created biomaterials, medical devices, drugs, and therapeutic modalities prior to initiation of human clinical trials. Therefore, selecting a suitable experimental model for tissue engineering purposes is essential to establish valid conclusions. However, it remains important to be conscious of the advantages and limitations of the various small and large animal models frequently used for biomedical research as well as the different challenges encountered in extrapolating data obtained from animal studies and the risks of misinterpretation. This chapter discusses the various small animal model strategies used for osteochondral defect repair. Particular emphasis will be placed on analyzing the materials and strategies used in each model.

Current Pharmacological Concepts in the Treatment of the Retinitis Pigmentosa.

Retinitis pigmentosa (RP) encompasses a heterogeneous group of inherited retinal disorders characterized by progressive photoreceptor and/or retinal pigment epithelial (RPE) degenerations with a prevalence approximately 1 in 4000 in the general population. Over 70 causative genes have been defined in RP families, and a number of animal models have been identified so far. However there have been no widely recognized treatments able to recover or reverse the degenerating retina, to prevent the disease deterioration, ultimately to restore the remaining vision. Therapeutics advancements have been achieved including gene therapy, pharmacotherapy, cell replacement, neurotrophic factors, and retinal prosthesis. In this review, we focus on the pharmaceutical drugs for RP with emphases on the context of drug discovery, development, and clinical translation.

Fractional non-ablative laser-assisted drug delivery leads to improvement in male and female pattern hair loss.

Androgenetic alopecia, also known as male and female pattern hair loss, is a very prevalent condition; however, approved therapeutic options are limited. Fractionated laser has been proposed to assist in penetration of topical medications to the cutaneous tissue. We present four cases of androgenetic alopecia that underwent treatment with a non-ablative erbium glass fractional laser followed by the application of topical finasteride 0,05% and growth factors including basic fibroblast growth factor, insulin-like growth factor, vascular endothelial growth factor, and copper peptide 1%. During all laser treatment sessions, eight passes were performed, at 7 mJ, 3-9% of coverage and density of 120 mzt/cm2. A positive response was observed in all of the four patients. Photographs taken 2 weeks after the last session showed improvement in hair regrowth and density. No significant side effects were observed.

Update on management of diabetic foot ulcers.

Diabetic foot ulcers (DFUs) are a serious complication of diabetes that results in significant morbidity and mortality. Mortality rates associated with the development of a DFU are estimated to be 5% in the first 12 months, and 5-year morality rates have been estimated at 42%. The standard practices in DFU management include surgical debridement, dressings to facilitate a moist wound environment and exudate control, wound off-loading, vascular assessment, and infection and glycemic control. These practices are best coordinated by a multidisciplinary diabetic foot wound clinic. Even with this comprehensive approach, there is still room for improvement in DFU outcomes. Several adjuvant therapies have been studied to reduce DFU healing times and amputation rates. We reviewed the rationale and guidelines for current standard of care practices and reviewed the evidence for the efficacy of adjuvant agents. The adjuvant therapies reviewed include the following categories: nonsurgical debridement agents, dressings and topical agents, oxygen therapies, negative pressure wound therapy, acellular bioproducts, human growth factors, energy-based therapies, and systemic therapies. Many of these agents have been found to be beneficial in improving wound healing rates, although a large proportion of the data are small, randomized controlled trials with high risks of bias.

Effects of Osteoglycin (OGN) on treating senile osteoporosis by regulating MSCs.

BACKGROUND: Significant amount of bone mass is lost during the process of aging due to an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption in bone marrow microenvironment, which leads to net bone loss in the aging population, resulting in the pathogenesis of osteoporosis. METHODS: Firstly, differences in proliferative capacity of adipocyte or adipogenic differentiation in mouse mesenchymal stem cells (MMSCs) and senile mouse model-derived bone marrow mesenchymal stem cells (SMMSCs), as well as mRNA expression of OGN and PPARγ2 were observed. Secondly, osteogenic abilities of MMSCs and SMMSCs treated with rosiglitazone (a PPARγ2 agonist) to induce osteogenic changes were observed, and negative correlation of PPARγ2 with OGN was evaluated. Thirdly, the role of SMMSCs in promoting osteogenesis was examined through enhancing expression of OGN; besides, the related mechanism was investigated by means of expression of related adipocyte and osteoblast specific genes. RESULTS: Forced OGN expression by OGN-infected lentivirus could increase expression of Wnt5b, RUNX2, OCN, ALP and Colla1, as well as bone formation, while decreases expression of adipogenesis marker PPARγ2. It resulted in expression inhibition of adipocyte genes such as adipocytic differentiation related genes adipocyte binding protein 2 (aP2) and osteoclast differentiation factor Rankl in bone marrow, giving rise to increased bone mass. CONCLUSION: OGN may plays a significant role in osteoporosis, which may also provide a potential target for therapeutic intervention of senile osteoporosis characterized by altered differentiation of BMSCs into osteoblasts and adipocytes.

Interventions for managing medication-related osteonecrosis of the jaw.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some individuals to certain medicines commonly used in the treatment of cancer and osteoporosis (e.g. bisphosphonates, denosumab and antiangiogenic agents) and involves the progressive destruction of bone in the mandible or maxilla. Depending on the drug, its dosage, and the duration of exposure, the occurrence of this adverse drug reaction may be rare (e.g. following the oral administration of bisphosphonate or denosumab treatments for osteoporosis, or antiangiogenic agent-targeted cancer treatment) or common (e.g. following intravenous bisphosphonate for cancer treatment). MRONJ is associated with significant morbidity, adversely affects quality of life (QoL), and is challenging to treat. OBJECTIVES: To assess the effects of interventions versus no treatment, placebo, or an active control for the prophylaxis of MRONJ in people exposed to antiresorptive or antiangiogenic drugs.To assess the effects of non-surgical or surgical interventions (either singly or in combination) versus no treatment, placebo, or an active control for the treatment of people with manifest MRONJ. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 23 November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 10), MEDLINE Ovid (1946 to 23 November 2016), and Embase Ovid (23 May 2016 to 23 November 2016). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases; however, the search of Embase was restricted to the last six months due to the Cochrane Embase Project to identify all clinical trials and add them to CENTRAL. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing one modality of intervention with another for the prevention or treatment of MRONJ. For 'prophylaxis of MRONJ', the primary outcome of interest was the incidence of MRONJ; secondary outcomes were QoL, time-to-event, and rate of complications and side effects of the intervention. For 'treatment of established MRONJ', the primary outcome of interest was healing of MRONJ; secondary outcomes were QoL, recurrence, and rate of complications and side effects of the intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, extracted the data, and assessed the risk of bias in the included studies. For dichotomous outcomes, we reported the risk ratio (RR) (or rate ratio) and 95% confidence intervals (CI). MAIN RESULTS: We included five RCTs (1218 participants) in the review. Three trials focused on the prophylaxis of MRONJ. Two trials investigated options for the treatment of established MRONJ. The RCTs included only participants treated with bisphosphonates and, thus, did not cover the entire spectrum of medications associated with MRONJ. Prophylaxis of MRONJOne trial compared standard care with regular dental examinations in three-month intervals and preventive treatments (including antibiotics before dental extractions and the use of techniques for wound closure that avoid exposure and contamination of bone) in men with metastatic prostate cancer treated with zoledronic acid. The intervention seemed to lower the risk of MRONJ: RR 0.10; 95% CI 0.02 to 0.39 (253 participants; low-quality evidence). Secondary outcomes were not evaluated.As dentoalveolar surgery is considered a common predisposing event for developing MRONJ, one trial investigated the effect of plasma rich in growth factors (PRGF) for preventing MRONJ in people with cancer undergoing dental extractions. There was insufficient evidence to support or refute a benefit of PRGF on MRONJ incidence when compared with standard treatment (RR 0.08, 95% CI 0.00 to 1.51; 176 participants; very low-quality evidence). Secondary outcomes were not reported. In another trial comparing wound closure by primary intention with wound closure by secondary intention after dental extractions in people treated with oral bisphosphonates (700 participants), no cases of intraoperative complications or postoperative MRONJ were observed. QoL was not investigated. Treatment of MRONJOne trial analysed hyperbaric oxygen (HBO) treatment used in addition to standard care (antiseptic rinses, antibiotics, and surgery) compared with standard care alone. HBO in addition to standard care did not significantly improve healing from MRONJ compared with standard care alone (at last follow-up: RR 1.56; 95% CI 0.77 to 3.18; 46 participants included in the analysis; very low-quality evidence). QoL data were presented qualitatively as intragroup comparisons; hence, an effect estimate of treatment on QoL was not possible. Other secondary outcomes were not reported.The other RCT found no significant difference between autofluorescence- and tetracycline fluorescence-guided sequestrectomy for the surgical treatment of MRONJ at any timepoint (at one-year follow-up: RR 1.05; 95% CI 0.86 to 1.30; 34 participants included in the analysis; very low-quality evidence). Secondary outcomes were not reported. AUTHORS' CONCLUSIONS: Prophylaxis of MRONJOne open-label RCT provided some evidence that dental examinations in three-month intervals and preventive treatments may be more effective than standard care for reducing the incidence of MRONJ in individuals taking intravenous bisphosphonates for advanced cancer. We assessed the certainty of the evidence to be low.There is insufficient evidence to either claim or refute a benefit of either of the interventions tested for prophylaxis of MRONJ (i.e. PRGF inserted into the postextraction alveolus during dental extractions, and wound closure by primary or secondary intention after dental extractions). Treatment of MRONJAvailable evidence is insufficient to either claim or refute a benefit for hyperbaric oxygen therapy as an adjunct to conventional therapy. There is also insufficient evidence to draw conclusions about autofluorescence-guided versus tetracycline fluorescence-guided bone surgery.