Antioxidative and Anti-inflammatory Effects of Plant-derived Hypoglycemic Medicines: An In vivo/In vitro Systematic Review.

BACKGROUND: The activation of oxidative stress and inflammatory conditions has been associated with acceleration in diabetes (DM) onset and complications. Despite various anti-DM medications, there is a growing trend to discover inexpensive and effective treatments with low adverse effects from plants as one of the promising sources for drug development. OBJECTIVE: This study aimed to systematically investigate the simultaneous anti-inflammatory and antioxidant effects of plant-derived hypoglycemic medicines in diabetic experimental models. METHODS: The search terms consisted of "diabetes", "herbal medicine", "antioxidant", "Inflammatory biomarker", and their equivalents among PubMed, Scopus, Web of Science, and Cochrane Library databases up to 17 August 2021. RESULTS: Throughout the search of databases, 201 eligible experimental studies were recorded. The results showed that the most commonly assessed inflammatory and oxidative stress biomarkers were tumor necrosis factor (TNF)-α, interleukin (IL) 6, IL-1ß, IL-10, malondialdehyde (MDA), and nitric oxide (NO). The activity of antioxidant enzymes, including superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) were assessed in the present review. Among herbal treatments, Trigonella foenum-graecum L., Centella asiatica (L.) Urb., Vitis vinifera L., and Moringa oleifera Lam. were most commonly used for diabetic complications. Due to the dispersion of the treatments, meta-analysis was not applicable. CONCLUSION: Our findings showed that the application of different plant-derived hypoglycemic treatments in animal models improved diabetes and its complications, as well as modulated concomitant inflammatory and oxidative stress biomarkers. These findings suggest that plant-based antidiabetic medicines and food supplements have the potential to manage diabetes and its complications.

[Natural 5α-reductase inhibitors in treatment of benign prostatic hyperplasia].

Benign prostatic hyperplasia(BPH) is a common disease of the male urinary system, and its incidence rate in China is increasing. However, the mechanism underlying the pathogenesis of BPH remains unclear. Some studies demonstrated that the incidence of BPH was related to the change in the levels of steroid hormones. Too high content of dihydrotestosterone(DHT) in the body may cause BPH and other related diseases. Testosterone(T) is converted to DHT by 5α-reductase(SRD5A). By inhibiting the activity of this enzyme, the production of DHT can be reduced, and then the incidence of BPH can be lowered. Therefore, it has drawn great attention to screen and discover safer and more effective 5α-reductase inhibitors from natural medicines to treat prostatic hyperplasia without affecting the physiological function of men. This review summarizes the characteristics and tissue distribution of 5α-reductase, the discovery of 5α-reductase inhibitors in traditional Chinese medicine and natural medicines, 5α-reductase inhibitors commonly used in clinical practice and their side effects, as well as the animal models of prostatic hyperplasia and common detection indicators, aiming to provide a reference for more in-depth understanding and research about BPH and development of drugs.

Type-1 diabetes: Lessons from a decade of preclinical studies on phytotherapy.

BACKGROUND: In recent decades, numerous herbal products have been shown to have antihyperglycemic and beta cell-regenerative effects in animal studies. However, there is no clinical evidence that those products completely cure patients with type-1 diabetes (T1D). Therefore, it seems that most of the phytochemicals do not have a significant impact on human beta cells, and the results of experimental studies conducted on them may not be generalizable to the clinic. PURPOSE: The present work aims to review extensively the methods and results of preclinical studies on phytotherapy of T1D published in the last 10 years. METHODS: This paper critically analyzes the designs of studies, treatment protocols, methods of diabetes induction, characteristics of the studied animals, clinical relevance, reproducibility of research, and other aspects related to conducting preclinical studies on T1D. We discussed limitations that make many of the results of these studies not generalizable to the clinic. Finally, some recommendations were given to improve studies on the phytotherapy of T1D to avoid misleading interpretations about the antidiabetic effect of herbal compounds. CONCLUSION: This paper can be considered a practical guide for researchers interested in the field of phytotherapy of T1D to increase the reliability, reproducibility, and validity of their preclinical studies.

Efficacy and immune-inflammatory mechanism of acupuncture-related therapy in animal models of knee osteoarthritis: a preclinical systematic review and network meta-analysis.

BACKGROUND: Many KOA patients have not reached indications for surgery, thus we need to find effective non-surgical treatments. Acupuncture is thought to have the potential to modulate inflammation and cytokines in KOA through the immune system. However, the mechanisms have not been elucidated, and there is no network Meta-analysis of acupuncture on KOA animals. So we evaluate the effect and mechanism of acupuncture-related therapy in KOA animals. METHODS: A comprehensive search was conducted in multiple databases including PubMed, Web of Science, Embase, CBM, CNKI, WanFang, and VIP Database to identify relevant animal studies focusing on acupuncture therapy for KOA. The included studies were assessed for risk of bias using SYRCLE's Risk of Bias tool. Subsequently, pair-wise meta-analysis and network meta-analysis were performed using Stata 15.0 software, evaluating outcomes such as Lequesne index scale, Mankin score, IL-1ß, TNF-α, MMP3, and MMP13. RESULTS: 56 RCTs with 2394 animals were included. Meta-analysis showed that among the 6 outcomes, there were significant differences between acupuncture and model group; the overall results of network meta-analysis showed that the normal group or sham operation group performed the best, followed by the acupotomy, acupuncture, and medicine group, and the model group had the worst effect, and there were significant differences between 6 interventions. CONCLUSIONS: Acupuncture-related therapy can be a possible treatment for KOA. The mechanism involves many immune-inflammatory pathways, which may be mediated by DAMPs/TLR/NF-κB/MAPK,PI3K/Akt/NF-κB pathway, or IFN-γ/JAK-STAT pathway. It needs to be further confirmed by more high-quality animal experiments or meta-analysis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO identifier: CRD42023377228.

Efficacy and mechanism of acupuncture in animal models of depressive-like behaviors: a systematic review and meta-analysis.

Background: Many studies have investigated the efficacy of acupuncture in treating depression, but the mechanism of acupuncture for depression is still controversial and there is a lack of meta-analysis of mechanisms. Consequently, we investigated acupuncture's efficacy and mechanism of depression. Methods: We searched the Cochrane Library, PubMed, EMBASE, Web of Science. The SYRCLE Risk of Bias Tool was used to assess bias risk. Meta-analysis was performed using Stata 15.0 for indicators of depression mechanisms, body weight and behavioral tests. Results: A total of 22 studies with 497 animals with depressive-like behaviors were included. Meta-analysis showed that acupuncture significantly increased BDNF [SMD = 2.40, 95% CI (1.33, 3.46); I2 = 86.6%], 5-HT [SMD = 2.28, 95% CI (1.08, 3.47); I2 = 87.7%] compared to the control group (p < 0.05), and significantly reduced IL-1ß [SMD = -2.33, 95% CI (-3.43, -1.23); I2 = 69.6%], CORT [SMD = -2.81, 95% CI (-4.74, -0.87); I2 = 86.8%] (p < 0.05). Acupuncture improved body weight [SMD = 1.35, 95% CI (0.58, 2.11); I2 = 84.5%], forced swimming test [SMD = -1.89, 95% CI (-2.55, -1.24); I2 = 76.3%], open field test (crossing number [SMD = 3.08, 95% CI (1.98, 4.17); I2 = 86.7%], rearing number [SMD = 2.53, 95% CI (1.49, 3.57); I2 = 87.0%]) (p < 0.05) compared to the control group. Conclusion: Acupuncture may treat animals of depressive-like behaviors by regulating neurotrophic factors, neurotransmitters, inflammatory cytokines, neuroendocrine system. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023403318, identifier (CRD42023403318).

Knee osteoarthritis: A review of animal models and intervention of traditional Chinese medicine.

BACKGROUND: Knee osteoarthritis (KOA) characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults. The pathophysiology of KOA remains poorly understood, as it involves complex mechanisms that result in the same outcome. Consequently, researchers are interested in studying KOA and require appropriate animal models for basic research. Chinese herbal compounds, which consist of multiple herbs with diverse pharmacological properties, possess characteristics such as multicomponent, multipathway, and multitarget effects. The potential benefits in the treatment of KOA continue to attract attention. PURPOSE: This study aims to provide a comprehensive overview of the advantages, limitations, and specific considerations in selecting different species and methods for KOA animal models. This will help researchers make informed decisions when choosing an animal model. METHODS: Online academic databases (e.g., PubMed, Google Scholar, Web of Science, and CNKI) were searched using the search terms "knee osteoarthritis," "animal models," "traditional Chinese medicine," and their combinations, primarily including KOA studies published from 2010 to 2023. RESULTS: Based on literature retrieval, this review provides a comprehensive overview of the methods of establishing KOA animal models; introduces the current status of advantages and disadvantages of various animal models, including mice, rats, rabbits, dogs, and sheep/goats; and presents the current status of methods used to establish KOA animal models. CONCLUSION: This study provides a review of the animal models used in recent KOA research, discusses the common modeling methods, and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

Nanoparticles for Thrombus Diagnosis and Therapy: Emerging Trends in Thrombus-theranostics.

Cardiovascular disease is one of the chief factors that cause ischemic stroke, myocardial infarction, and venous thromboembolism. The elements that speed up thrombosis include nutritional consumption, physical activity, and oxidative stress. Even though the precise etiology and pathophysiology remain difficult topics that primarily rely on traditional medicine. The diagnosis and management of thrombosis are being developed using discrete non-invasive and non-surgical approaches. One of the emerging promising approach is ultrasound and photoacoustic imaging. The advancement of nanomedicines offers concentrated therapy and diagnosis, imparting efficacy and fewer side effects which is more significant than conventional medicine. This study addresses the potential of nanomedicines as theranostic agents for the treatment of thrombosis. In this article, we describe the factors that lead to thrombosis and its consequences, as well as summarize the findings of studies on thrombus formation in preclinical and clinical models and also provide insights on nanoparticles for thrombus imaging and therapy.

Therapeutic potential of curcumin on the cognitive decline in animal models of Alzheimer's disease: a systematic review and meta-analysis.

Curcumin, a polyphenol derived from the herb turmeric, has emerged as a prospective potential therapy in the treatment of Alzheimer's disease (AD). However, the efficacy of curcumin treatment in improving cognitive decline caused controversy recently. We aimed to systematically review the effect of curcumin on cognitive impairment in an animal model of AD. We conducted an exhaustive database search of related studies. Two investigators identified studies and independently extracted data. Stratified meta-analyses and meta-regression analyses were carried out to explore the sources of heterogeneity. Publication bias was assessed using funnel plots and Egger's test. Our systematic review included 33 articles. A meta-analysis of 29 publications showed that curcumin exerts significant positive effects on cognitive performance. For acquisition, the global estimated effect of curcumin was - 2.027 (95% CI - 2.435 to - 1.619, p < 0.001); for retention, the global estimated effect of curcumin was 1.606 (95% CI 1.101 to 2.111, p < 0.001). The stratified meta-analysis demonstrated that an increased effect size depended on diverse study characteristics. Additionally, publication bias was detected. We conclude that curcumin may reduce cognitive deficits in experimental AD. Furthermore, we emphasize that additional well-designed and well-reported animal studies are needed to inform further clinical studies.

The Zebrafish Model as a New Discovery Path for Medicinal Plants in the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is one of the most frequent degenerative central nervous system disorders affecting older adults. Dopaminergic neuron failure in the substantia nigra is a pathological sign connected with the motor shortfall of PD. Due to their low teratogenic and adverse effect potential, medicinal herbs have emerged as a promising therapy option for preventing and curing PD and other neurodegenerative disorders. However, the mechanism through which natural compounds provide neuroprotection against PD remains unknown. While testing compounds in vertebrates such as mice is prohibitively expensive and time-consuming, zebrafish (Danio rerio) may offer an appealing alternative because they are vertebrates and share many of the same characteristics as humans. Zebrafish are commonly used as animal models for studying many human diseases, and their molecular history and bioimaging properties are appropriate for the study of PD. However, a literature review indicated that only six plants, including Alpinia oxyhylla, Bacopa monnieri, Canavalia gladiate, Centella asiatica, Paeonia suffruticosa, and Stachytarpheta indica had been investigated as potential PD treatments using the zebrafish model. Only C. asiatica and B. monnieri were found to have potential anti-PD activity. In addition to reviewing the current state of research in this field, these plants' putative mechanisms of action against PD are explored, and accessible assays for investigation are made.

Psilocybin as a lead candidate molecule in preclinical therapeutic studies of psychiatric disorders: A systematic review.

Psilocybin is the main psychoactive compound found in hallucinogenic/magic mushrooms and can bind to both serotonergic and tropomyosin receptor kinase b (TrkB) receptors. Psilocybin has begun to show efficacy for a range of neuropsychiatric conditions, including treatment-resistant depression and anxiety disorders; however, neurobiological mechanisms are still being elucidated. Clinical research has found that psilocybin can alter functional connectivity patterns in human brains, which is often associated with therapeutic outcomes. However, preclinical research affords the opportunity to assess the potential cellular mechanisms by which psilocybin may exert its therapeutic effects. Preclinical rodent models can also facilitate a more tightly controlled experimental context and minimise placebo effects. Furthermore, where there is a rationale, preclinical researchers can investigate psilocybin administration in neuropsychiatric conditions that have not yet been researched clinically. As a result, we have systematically reviewed the knowledge base, identifying 82 preclinical studies which were screened based on specific criteria. This resulted in the exclusion of 44 articles, with 34 articles being included in the main review and another 2 articles included as Supporting Information materials. We found that psilocybin shows promise as a lead candidate molecule for treating a variety of neuropsychiatric conditions, albeit showing the most efficacy for depression. We discuss the experimental findings, and identify possible mechanisms whereby psilocybin could invoke therapeutic changes. Furthermore, we critically evaluate the between-study heterogeneity and possible future research avenues. Our review suggests that preclinical rodent models can provide valid and translatable tools for researching novel psilocybin-induced molecular and cellular mechanisms, and therapeutic outcomes.

Differences in bone microarchitecture between genetic and secondary iron-overload mouse models suggest a role for hepcidin deficiency in iron-related osteoporosis.

Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood. AIM: The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis. MATERIAL AND METHODS: We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe-/- and Bmp6-/- ) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin. RESULTS: Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe-/- and from 6 months for Bmp6-/- . Alterations in bone microarchitecture in the Bmp6-/- model were positively correlated with hepcidin levels (BV/TV (ρ = +.481, p < .05) and Tb.Th (ρ = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe-/- and Bmp6-/- mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 µM, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease. CONCLUSION: Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.

Mechanical osteoarthritis of the hip in a one medicine concept: a narrative review.

Human and veterinary medicine have historically presented many medical areas of potential synergy and convergence. Mechanical osteoarthritis (MOA) is characterized by a gradual complex imbalance between cartilage production, loss, and derangement. Any joint instability that results in an abnormal overload of the joint surface can trigger MOA. As MOA has a prevailing mechanical aetiology, treatment effectiveness can only be accomplished if altered joint mechanics and mechanosensitive pathways are normalized and restored. Otherwise, the inflammatory cascade of osteoarthritis will be initiated, and the changes may become irreversible. The management of the disease using non-steroidal anti-inflammatory drugs, analgesics, physical therapy, diet changes, or nutraceuticals is conservative and less effective. MOA is a determinant factor for the development of hip dysplasia in both humans and dogs. Hip dysplasia is a hereditary disease with a high incidence and, therefore, of great clinical importance due to the associated discomfort and significant functional limitations. Furthermore, on account of analogous human and canine hip dysplasia disease and under the One Medicine concept, unifying veterinary and human research could improve the well-being and health of both species, increasing the acknowledgement of shared diseases. Great success has been accomplished in humans regarding preventive conservative management of hip dysplasia and following One Medicine concept, similar measures would benefit dogs. Moreover, animal models have long been used to better understand the different diseases' mechanisms. Current research in animal models was addressed and the role of rabbit models in pathophysiologic studies and of the dog as a spontaneous animal model were highlighted, denoting the inexistence of rabbit functional models to investigate therapeutic approaches in hip MOA.

Effects of Dendropanax morbiferus Leaf Extract on Sleep Parameters in Invertebrate and Vertebrate Models.

Dendropanax morbiferus is highly valued in traditional medicine and has been used to alleviate the symptoms of numerous diseases owing to its excellent antioxidant activity. This study aimed to evaluate the sleep promotion and related signaling pathways of D. morbiferus extract (DE) via behavioral analysis, molecular biological techniques, and electrophysiological measurements in invertebrate and vertebrate models. In Drosophila, the group treated with 4% DE experienced decreased subjective nighttime movement and sleep bout and increased total sleeping time. Moreover, substantial changes in locomotor activity, including distance moved, velocity, and movement, were confirmed in the 4% DE-treated group. Compared to Drosophila in which insomnia and oxidative stress were induced by exposure to 0.1% caffeine, the DE-treated group improved sleep-related parameters to the level of the normal group. In the Drosophila model, exposure to 4% DE upregulated the expression of gamma-aminobutyric acid (GABA)-related receptors and serotonin receptor (5-HT1A), along with the expression of antioxidant-related factors, glutathione, and catalase. In the pentobarbital-induced sleep test using ICR mice, the duration of sleep was markedly increased by high concentration of DE. In addition, through the electroencephalography analysis of SD-rats, a significant increase in non-rapid-eye-movement sleep and delta waves was confirmed with high concentrations of DE administration. The increase in sleep time and improvement in sleep quality were confirmed to be related to the expression of altered GABA receptors and the enhancement of the contents of the neurotransmitters GABA and serotonin (5-HT) because of high DE administration. High-dose administration of DE also increased the expression of antioxidant-related factors in the brain and significantly decreased malondialdehyde content. Taken together, DE induced improvements in sleep quantity and quality by regulating neurotransmitter content and related receptor expression, along with high antioxidant activity, and may have a therapeutic effect on sleep disorders.

Effects of potentilla discolor bunge extracts on oxidative stress and glycolipid metabolism in animal models of diabetes: a systematic review and meta-analysis.

Background/aim: Potentilla discolor Bunge (PDB) is an ancient herb of traditional Chinese medicine. Studies have suggested that extracts of PDB may ameliorate diabetes mellitus (DM). This study aimed to systematically assess the efficacy of PDB extracts on glycolipid metabolism and oxidative stress in animal models of diabetes and to provide evidence-based references for the use of PDB extracts. Methods: This study followed the PRISMA 2020 guidelines. Studies were searched from eight databases until January 2023. Statistical analysis was performed using StataSE 15.0 and RevMan 5.3. The standard mean difference (SMD) and 95% confidence intervals (CI) were computed using the random-effects model. SYRCLE's risk of bias tool was used to assess the risk of bias. Results: In total, 32 studies with 574 animals were included. The findings demonstrated that PDB extracts considerably lowered fasting blood glucose (SMD: -3.56, 95%CI: -4.40 to -2.72, p < 0.00001); insulin resistance (SMD: -3.19, 95% CI: -5.46 to -0.92, p = 0.006), total cholesterol (SMD: -2.18, 95%CI: -2.89 to -1.46, p < 0.00001), triglyceride (SMD: -1.48, 95% CI: -2.01 to -0.96, p < 0.00001), low-density lipoprotein cholesterol (SMD: -1.80, 95% CI: -2.58 to -1.02], p < 0.00001), malondialdehyde (SMD: -3.46, 95% CI: -4.64 to -2.29, p < 0.00001) and free fatty acid levels (SMD: -3.25, 95%CI: -5.33 to -1.16, p = 0.002), meanwhile, increased insulin sensitivity index (SMD: 2.51 95% CI: 1.10 to 3.92, p = 0.0005), body weight (SMD:1.20, 95% CI: 0.38 to 2.01, p = 0.004), and the levels of high-density lipoprotein cholesterol (SMD: 1.04, 95% CI: 0.40 to 1.69, p = 0.001), superoxide dismutase (SMD:2.63, 95% CI: 1.53 to 3.73, p < 0.00001), glutathione peroxidase (SMD:1.13, 95%CI: 0.42 to1.83, p = 0.002), and catalase (SMD:0.75, 95% CI: 0.11 to 1.40], p = 0.02). Conclusion: These findings suggest that PDB extracts can ameliorate DM by improving glycolipid metabolism and oxidative stress. PDB may be a promising medication for DM; however, due to significant heterogeneity between studies, these findings should be interpreted with caution. In addition, future well-designed trials should determine which components of the PDB play a major role in ameliorating DM and whether these benefits persist in humans. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, CRD42023379391.

Modeling Sarcoglycanopathy in Danio rerio.

Sarcoglycanopathies, also known as limb girdle muscular dystrophy 3-6, are rare muscular dystrophies characterized, although heterogeneous, by high disability, with patients often wheelchair-bound by late adolescence and frequently developing respiratory and cardiac problems. These diseases are currently incurable, emphasizing the importance of effective treatment strategies and the necessity of animal models for drug screening and therapeutic verification. Using the CRISPR/Cas9 genome editing technique, we generated and characterized δ-sarcoglycan and ß-sarcoglycan knockout zebrafish lines, which presented a progressive disease phenotype that worsened from a mild larval stage to distinct myopathic features in adulthood. By subjecting the knockout larvae to a viscous swimming medium, we were able to anticipate disease onset. The δ-SG knockout line was further exploited to demonstrate that a δ-SG missense mutant is a substrate for endoplasmic reticulum-associated degradation (ERAD), indicating premature degradation due to protein folding defects. In conclusion, our study underscores the utility of zebrafish in modeling sarcoglycanopathies through either gene knockout or future knock-in techniques. These novel zebrafish lines will not only enhance our understanding of the disease's pathogenic mechanisms, but will also serve as powerful tools for phenotype-based drug screening, ultimately contributing to the development of a cure for sarcoglycanopathies.

Understanding the Roles of Very-Long-Chain Polyunsaturated Fatty Acids (VLC-PUFAs) in Eye Health.

Lipids serve many roles in the neural system, from synaptic stabilization and signaling to DNA regulation and neuroprotection. They also regulate inflammatory responses, maintain cellular membrane structure, and regulate the homeostatic balance of ions and signaling molecules. An imbalance of lipid subgroups is implicated in the progression of many retinal diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy, and diet can play a key role in influencing these diseases' onset, progression, and severity. A special class of lipids termed very-long-chain polyunsaturated fatty acids (VLC-PUFAs) is found exclusively in mammalian vertebrate retinas and a few other tissues. They comprise <2% of fatty acids in the retina and are depleted in the retinas of patients with diseases like diabetic retinopathy and AMD. However, the implications of the reduction in VLC-PUFA levels are poorly understood. Dietary supplementation studies and ELOVL4 transgene studies have had positive outcomes. However, much remains to be understood about their role in retinal health and the potential for targeted therapies against retinal disease.

Feline precision medicine using whole-exome sequencing identifies a novel frameshift mutation for vitamin D-dependent rickets type 2.

OBJECTIVES: A 14-week-old female domestic longhair kitten presented with shifting lameness and disproportionately smaller size compared with a co-housed littermate. METHODS: Hematology and serum biochemical testing were conducted to investigate causes for delayed growth, and radiographs of the appendicular skeleton were obtained. RESULTS: The afflicted kitten had marked hypocalcemia, mild hypophosphatemia and substantial elevations in alkaline phosphatase activity, as well as pathognomonic radiographic findings consistent with rickets. Skeletal changes and hypocalcemia prompted testing of concentrations of parathyroid hormone (PTH) and vitamin D metabolites. Endocrine testing demonstrated significant increases in serum concentrations of PTH and 1,25-dihydroxycholecalciferol (calcitriol), supporting a diagnosis of vitamin D-dependent rickets type 2. Provision of analgesia, supraphysiologic doses of calcitriol and calcium carbonate supplementation achieved normalization of the serum calcium concentration and restoration of normal growth, although some skeletal abnormalities persisted. Once skeletally mature, ongoing calcitriol supplementation was not required. Whole-exome sequencing (WES) was conducted to identify the underlying DNA variant. A cytosine deletion at cat chromosome position B4:76777621 in VDR (ENSFCAT00000029466:c.106delC) was identified and predicted to cause a stop codon in exon 2 (p.Arg36Glufs*18), disrupting >90% of the receptor. The variant was unique and homozygous in this patient and absent in the sibling and approximately 400 other cats for which whole-genome and whole-exome data were available. CONCLUSIONS AND RELEVANCE: A unique, heritable form of rickets was diagnosed in a domestic longhair cat. WES identified a novel frameshift mutation affecting the gene coding for the vitamin D3 receptor, determining the likely causal genetic variant. Precision medicine techniques, including whole-exome and whole-genome sequencing, can be a standard of care in cats to identify disease etiologies, and to target therapeutics and personalize treatment.

Efgartigimod restores muscle function in a humanized mouse model of immune-mediated necrotizing myopathy.

OBJECTIVE: Immune-mediated necrotizing myopathies (IMNMs) are severe forms of myositis often associated with pathogenic anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies (aAbs). Efgartigimod is an engineered human IgG1 Fc fragment that antagonizes the neonatal Fc receptor (FcRn), thereby preventing recycling and promoting lysosomal degradation of IgG, including aAbs. We evaluated the therapeutic effects of IgG reduction by efgartigimod in a humanized murine model of IMNM. METHODS: Disease was induced in C5-deficient (C5def) or Rag2-deficient (Rag2-/-) mice receiving co-injections of anti-HMGCR+ IgG from an IMNM patient and human complement. C5def mice were treated in a preventive setting with s.c. injections of efgartigimod and Rag2-/- mice in a curative setting after disease was induced by anti-HMGCR+ IgG injections. Anti-HMGCR aAbs levels were monitored in mouse serum and muscle tissue. Histological analysis was performed on muscle sections. Muscle force was assessed by grip test or measurement of gastrocnemius strength upon electrostimulation. RESULTS: Administration of efgartigimod rapidly reduced total IgG levels, including the level of pathogenic anti-HMGCR aAbs, in both serum (P < 0.0001) and muscle (P < 0.001). In the preventive setting, efgartigimod prevented myofibre necrosis (P < 0.05), thus precluding loss of muscle strength (P < 0.05). In the therapeutic setting, efgartigimod prevented further necrosis and allowed muscle fibre regeneration (P < 0.05). Hence, muscle strength returned to normal (P < 0.01). CONCLUSION: Efgartigimod reduces circulating IgG levels, including pathogenic anti-HMGCR+ IgG aAbs, in a humanized mouse model of IMNM, preventing further necrosis and allowing muscle fibre regeneration. These results support investigating the therapeutic efficacy of efgartigimod through a clinical trial in IMNM patients.

Understanding the Neuroplastic Effects of Auricular Vagus Nerve Stimulation in Animal Models of Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Transauricular vagus nerve stimulation (taVNS) is being studied as a feasible intervention for stroke, but the mechanisms by which this non-invasive technique acts in the cortex are still broadly unknown. OBJECTIVES: This study aimed to systematically review the current pre-clinical evidence in the auricular vagus nerve stimulation (aVNS) neuroplastic effects in stroke. METHODS: We searched, in December of 2022, in Medline, Cochrane, Embase, and Lilacs databases. The authors executed the extraction of the data on Excel. The risk of bias was evaluated by adapted Cochrane Collaboration's tool for animal studies (SYRCLES's RoB tool). RESULTS: A total of 8 studies published between 2015 and 2022 were included in this review, including 391 animal models. In general, aVNS demonstrated a reduction in neurological deficits (SMD = -1.97, 95% CI -2.57 to -1.36, I2 = 44%), in time to perform the adhesive removal test (SMD = -2.26, 95% CI -4.45 to -0.08, I2 = 81%), and infarct size (SMD = -1.51, 95% CI -2.42 to -0.60, I2 = 58%). Regarding the neuroplasticity markers, aVNS showed to increase microcapillary density, CD31 proliferation, and BDNF protein levels and RNA expression. CONCLUSIONS: The studies analyzed show a trend of results that demonstrate a significant effect of the auricular vagal nerve stimulation in stroke animal models. Although the aggregated results show high heterogeneity and high risk of bias. More studies are needed to create solid conclusions.

Therapeutic potential of flavonoids in the management of obesity-induced Alzheimer's disease: an overview of preclinical and clinical studies.

Obesity is a global epidemic that affects people of all ages, genders, and backgrounds. It can lead to a plethora of disorders, including diabetes mellitus, renal dysfunction, musculoskeletal problems, metabolic syndrome, cardiovascular, and neurodegenerative abnormalities. Obesity has also been linked to neurological diseases such as cognitive decline, dementia, and Alzheimer's disease (AD), caused by oxidative stress, pro-inflammatory cytokines, and the production of reactive oxygen free radicals (ROS). Secretion of insulin hormone is impaired in obese people, leading to hyperglycaemia and increased accumulation of amyloid-ß in the brain. Acetylcholine, a key neurotransmitter necessary for forming new neuronal connections in the brain, decreases in AD patients. To alleviate acetylcholine deficiency, researchers have proposed dietary interventions and adjuvant therapies that enhance the production of acetylcholine and assist in the management of AD patients. Such measures include dietary intervention with antioxidant and anti-inflammatory flavonoid-rich diets, which have been found to bind to tau receptors, reduce gliosis, and reduce neuroinflammatory markers in animal models. Furthermore, flavonoids like curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, and oleocanthal have shown to cause significant reductions in interleukin-1ß, increase BDNF levels, stimulate hippocampal neurogenesis and synapse formation, and ultimately prevent the loss of neurons in the brain. Thus, flavonoid-rich nutraceuticals can be a potential cost-effective therapeutic option for treating obesity-induced AD, but further well-designed, randomized, and placebo-controlled clinical studies are needed to assess their optimal dosages, efficacy, and long-term safety of flavonoids in humans. The main objectives of this review are to underscore the therapeutic potential of different nutraceuticals containing flavonoids that can be added in the daily diet of AD patients to enhance acetylcholine and reduce neuronal inflammation in the brain.