In Vivo Contribution of Cyp24a1 Promoter Vitamin D Response Elements.

CYP24A1 is a multifunctional, P450 mitochondrial enzyme that catabolizes the vitamin D hormone (calcitriol, 1,25(OH)2D3), its precursor (calcifediol, 25(OH)D3), and numerous vitamin D metabolites. In the kidney, Cyp24a1 is induced by 1,25(OH)2D3 and fibroblast growth factor 23 (FGF23) and potently suppressed by PTH to control the circulating levels of 1,25(OH)2D3. Cyp24a1 is controlled by a pair of promoter proximal (PRO) vitamin D response elements (VDREs) that are aided by distal, downstream (DS) enhancers. The downstream 1 region of Cyp24a1 (DS1) enhancer is kidney-specific and responsible for PTH and FGF23 actions, and the downstream 2 region of Cyp24a1 enhancer responds to 1,25(OH)2D3 in all tissues. Despite this knowledge, in vivo contributions of the PRO VDREs to basal expression, FGF23 activation, and PTH suppression of Cyp24a1 remain unknown. In this study, we selectively mutated the PRO VDREs in the mouse to address these questions. We found mutation of the VDREs leads to a dramatic loss of VDR occupancy, a reduction of 1,25(OH)D3-induced kidney Cyp24a1 expression, and near elimination of intestinal Cyp24a1 induction. FGF23 induction of Cyp24a1 was reduced but not eliminated and still showed a synergistic increase with 1,25(OH)2D3. PTH suppression of Cyp24a1 was unchanged, despite minor reductions in total for phosphorylated cAMP-response element binding protein occupancy. Finally, VDR recruitment was dramatically reduced across the DS enhancers in the Cyp24a1 locus. Taken together, our data suggest a cooperative relationship between the DS and PRO enhancers in the regulation of Cyp24a1 by 1,25(OH)2D3 and FGF23 and points to the DS1 region as a crucial basal switch for Cyp24a1 activity that further defines the interconnected genomic control in vitamin D catabolism.

Secretion of the human parathyroid hormone through a microcin type I secretion system in Escherichia coli.

BACKGROUND: Gram negative bacteria possess different secretion systems to export proteins to the extracellular medium. The simplest one, type I secretion system (T1SS), forms a channel across the cell envelope to export proteins in a single step. Peptides secreted by the T1SSs comprise a group of antibiotics, called class II microcins, which carry an amino terminal secretion domain that is processed concomitantly with export. Mature microcins range in size from 60 to 90 amino acids and differ in their sequences. Microcin T1SSs show a high versatility in relation to the peptides they are able to secrete, being mainly limited by the length of the substrates. Different bioactive peptides unrelated to bacteriocins could be secreted by microcin V (MccV) T1SS, while retaining their biological activity. RESULTS: In this work heterologous secretion of two variants of human parathyroid hormone (PTH) by MccV T1SS was evaluated. PTH is a bioactive peptide of 84 amino acids (PTH84), which is involved in the maintenance of bone homeostasis. Currently, a drug corresponding to the active fraction of the hormone, which resides in its first 34 amino acids (PTH34), is commercially produced as a recombinant peptide in Escherichia coli. However, research continues to improve this recombinant production. Here, gene fusions encoding hybrid peptides composed of the MccV secretion domain attached to each hormone variant were constructed and expressed in the presence of microcin T1SS in E. coli cells. Both PTH peptides (PTH34 and PTH84) were recovered from the culture supernatants and could be confirmed to lack the MccV secretion domain, i.e. microcin T1SS efficiently recognised, processed and secreted both PTH variants. Furthermore, the secreted peptides were stable in the extracellular medium unlike their unprocessed counterparts present in the intracellular space. CONCLUSION: The successful secretion of PTH variants using MccV T1SS could be considered as a new alternative for their production, since they would be recovered directly from the extracellular space without additional sequences. Furthermore, it would be a new example revealing the potential of microcin type I secretion systems to be conceived as a novel strategy for the production of recombinant peptides in E. coli.

New insight into primary hyperparathyroidism using untargeted metabolomics.

Primary Hyperparathyroidism (PHPT) is characterized by excessive parathormone (PTH) secretion and disrupted calcium homeostasis. Untargeted metabolomics offers a valuable approach to understanding the complex metabolic alterations associated with different diseases, including PHPT. Plasma untargeted metabolomics was applied to investigate the metabolic profiles of PHPT patients compared to a control group. Two complementary liquid-phase separation techniques were employed to comprehensively explore the metabolic landscape in this retrospective, single-center study. The study comprised 28 female patients diagnosed following the current guidelines of PHPT diagnosis and a group of 30 healthy females as a control group. To evaluate their association with PHPT, we identified changes in plasma metabolic profiles in patients with PHPT compared to the control group. The primary outcome measure included detecting plasma metabolites and discriminating PHPT patients from controls. The study unveiled specific metabolic imbalances that may link L-amino acids with peptic ulcer disease, gamma-glutamyls with oxidative stress, and asymmetric dimethylarginine (ADMA) with cardiovascular complications. Several metabolites, such as gamma-glutamyls, caffeine, sex hormones, carnitine, sphingosine-1-phosphate (S-1-P), and steroids, were connected with reduced bone mineral density (BMD). Metabolic profiling identified distinct metabolic patterns between patients with PHPT and healthy controls. These findings provided valuable insights into the pathophysiology of PHPT.

Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.

Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism-treating drugs can induce hypocalcemia and arrhythmias. Seeking improved modulators, we docked libraries of 2.7 million and 1.2 billion molecules against the CaSR structure. The billion-molecule docking found PAMs with a 2.7-fold higher hit rate than the million-molecule library, with hits up to 37-fold more potent. Structure-based optimization led to nanomolar leads. In ex vivo organ assays, one of these PAMs was 100-fold more potent than the standard of care, cinacalcet, and reduced serum PTH levels in mice without the hypocalcemia typical of CaSR drugs. As determined from cryo-electron microscopy structures, the PAMs identified here promote CaSR conformations that more closely resemble the activated state than those induced by the established drugs.

Prevalence of hearing loss in pseudohypoparathyroidism.

BACKGROUND: The main clinical features of pseudohypoparathyroidism (PHP)/inactivating parathyroid hormone/parathyroid hormone-related protein signaling disorders (iPPSD), including parathyroid hormone (PTH) resistance, brachydactyly and short stature, develop during middle and late childhood. Very few studies have addressed hearing loss in PHP/iPPSD patients, and these studies have yielded widely divergent conclusions. The aim of our study was to assess hearing and determine the predictive factors of hearing loss in patients with PHP/iPPSD. METHODS: Our retrospective cohort study was conducted between March 2019 and May 2020 in the Otolaryngology Department and the calcium phosphate reference center for rare diseases in Bicêtre Paris-Saclay Hospital, France. We retrospectively collected data from patients with PHP/iPPSDs (age, sex, genetic mutations, height, body mass index (BMI), PTH resistance, presence or absence of ectopic ossifications and brachydactyly). All patients underwent auditory investigations, including tonal and vocal audiometry. The primary outcome was the pure tone average (PTA). The PTA was compared with the norm according to the International Organization for Standardization. Hearing loss was defined as a PTA ≥ 20 db. RESULTS: The median age of the patients was 15.6 years [9.5, 28.5]. Thirty-six patients were diagnosed with iPPSD2, and eight were diagnosed with iPPSD3. Twenty-six of them (59%) were female. Hearing impairment was confirmed in 17 patients (39%). The mean PTA and the mean SRT of the deaf ears were 40 ± 26 db and 31 ± 14 db. The mean difference in the PTA between the patients and the normal controls was 11.4 db (p = 0.00002). Short stature and the presence of ectopic ossifications were two significant predictive factors of hearing loss (p = 0.009 and p = 0.03, respectively). Sex, BMI, PTH resistance, mutation category and brachydactyly were not associated with an increased risk of hearing loss (p = 0.19, p = 0.41, p = 0.13, p = 0.50, p = 0.19, respectively). CONCLUSION: Our study confirmed the frequency of hearing loss in patients with PHP/iPPSD disease (prevalence = 39%). A diagnosis of PHP/iPPSD should trigger auditory investigations and follow-up, especially when short stature and/or ectopic ossifications are present.

High-Throughput Preosteoblastic Spheroids Elevate Fibroblast Growth Factor 23 via Parathyroid Hormone Signaling Pathway.

Fibroblast growth factor 23 (FGF23) plays a crucial role in managing renal phosphate and the synthesis of 1,25(OH)2-vitamin D3, which is essential for bone homeostasis. Developing robust in vitro systems to study FGF23-regulating mechanisms is crucial for advancing our knowledge and identifying potential therapeutic targets. The traditional in vitro 2D culture system results in relatively low expression of FGF23, complicating further exploration of its regulatory mechanisms and potential therapeutic targets. Herein, we reported a high-throughput approach to generate preosteoblastic cell spheroids with enhanced FGF23 production. For this purpose, murine preosteoblast cell line (MC3T3-E1) was cultured in our previously reported nonadherent microwells (200 µm in diameter, 148 µm in depth, and 100 µm space in between) and self-assembled into spheroids with a diameter of 92.3 ± 15.0 µm after 24 h. Compared with monolayer culture, the MC3T3-E1 spheroids showed a significant upregulation of FGF23 in both gene and protein levels after 24 h of serum-free induction. RNA sequencing and western blotting analysis further suggested that the enhanced FGF23 production in MC3T3-E1 spheroids was attributed to the activation of the parathyroid hormone (PTH)/PTH1R signaling pathway. Impressively, inhibition of PTH signaling through small molecular inhibitors or short hairpin RNA targeting PTH1R effectively reduced FGF23 production. In summary, the current study revealed the efficacy of the high-throughput formation of preosteoblast cell spheroid in stimulating FGF23 expression for mechanistic studies. Importantly, our findings highlight the potential of the current 3D spheroid system for target identification and drug discovery.

Corticosteroid rhythms in hypoparathyroid patients.

OBJECTIVE: Previous studies indicate a possible bidirectional stimulatory relationship between parathyroid hormone (PTH) and adrenocortical hormones, but the pattern of adrenocortical secretion in hypoparathyroidism is unknown. We aimed to characterize the adrenocortical secretion in patients with postsurgical hypoparathyroidism, and whether continuous subcutaneous PTH (1-34) infusion alters secretion patterns. DESIGN: Crossover interventional study. METHODS: We recruited 10 patients with postsurgical hypoparathyroidism with very low PTH levels on stable treatment with active vitamin D and calcium. Cortisol, cortisone, and aldosterone levels were measured in microdialysate from subcutaneous tissue over 24 h, before and during continuous subcutaneous PTH (1-34) infusion. Cortisol was also assayed in serum, saliva, and urine, and aldosterone and ACTH in serum and plasma, respectively. Ten patients with primary hyperparathyroidism and 10 healthy volunteers matched for sex and age served as controls. RESULTS: Hypoparathyroid patients displayed both ultradian and circadian rhythmicity for tissue cortisol, cortisone, and aldosterone. Tissue aldosterone and cortisone levels were significantly lower in hypoparathyroid patients than in healthy controls, with no difference in tissue cortisol, but a higher cortisol to cortisone ratio. Treatment with PTH (1-34) increased tissue levels of aldosterone, cortisol, and cortisone and reduced the ratio of cortisol to cortisone. CONCLUSION: Adrenocortical hormone levels are reduced in postsurgical hypoparathyroidism, and partly restored by short-term continuous subcutaneous PTH (1-34) therapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02986607.

Advances in the management of parathyroid carcinoma.

Parathyroid carcinoma (PCA) is a rare malignancy accounting for approximately 1% of all patients with primary hyperparathyroidism. It is characterised by excessive parathyroid hormone (PTH) production. This manuscript reviews recent advances in the management of parathyroid carcinoma, focusing on molecular insights, diagnostic modalities, surgical innovations, adjuvant therapies, and emerging targeted treatments. Recently published manuscripts (between 2022 and 2023) were obtained from Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica (Embase), Cochrane Central Register of Controlled Trials (CENTRAL), and European Union Drug Regulating Authorities Clinical Trials (EudraCT). These were assessed for their relevance in terms of the diagnosis and management of patients with PCA. This manuscript explores the role of genetic profiling and presents case studies illustrating successful management strategies. The manuscript also discusses the ongoing challenges in the management of parathyroid carcinoma, suggesting future research directions and potential therapeutic avenues.

PTH receptor signalling, osteocytes and bone disease induced by diabetes mellitus.

Basic, translational and clinical research over the past few decades has provided new understanding on the mechanisms by which activation of the receptor of parathyroid hormone (parathyroid hormone 1 receptor (PTH1R)) regulates bone physiology and pathophysiology. A fundamental change in the field emerged upon the recognition that osteocytes, which are permanent residents of bone and the most abundant cells in bone, are targets of the actions of natural and synthetic ligands of PTH1R (parathyroid hormone and abaloparatide, respectively), and that these cells drive essential actions related to bone remodelling. Among the numerous genes regulated by PTH1R in osteocytes, SOST (which encodes sclerostin, the WNT signalling antagonist and inhibitor of bone formation) has a critical role in bone homeostasis and changes in its expression are associated with several bone pathologies. The bone fragility syndrome induced by diabetes mellitus is accompanied by increased osteocyte apoptosis and changes in the expression of osteocytic genes, including SOST. This Review will discuss advances in our knowledge of the role of osteocytes in PTH1R signalling and the new opportunities to restore bone health in diabetes mellitus by targeting the osteocytic PTH1R-sclerostin axis.

Vitamin D3 suppresses Npt2c abundance and differentially modulates phosphate and calcium homeostasis in Npt2a knockout mice.

Vitamin D3 is clinically used for the treatment of vitamin D3 deficiency or osteoporosis, partially because of its role in regulating phosphate (Pi) and calcium (Ca2+) homeostasis. The renal sodium-phosphate cotransporter 2a (Npt2a) plays an important role in Pi homeostasis; however, the role of vitamin D3 in hypophosphatemia has never been investigated. We administered vehicle or vitamin D3 to wild-type (WT) mice or hypophosphatemic Npt2a-/- mice. In contrast to WT mice, vitamin D3 treatment increased plasma Pi levels in Npt2a-/- mice, despite similar levels of reduced parathyroid hormone and increased fibroblast growth factor 23. Plasma Ca2+ was increased ~ twofold in both genotypes. Whereas WT mice were able to increase urinary Pi and Ca2+/creatinine ratios, in Npt2a-/- mice, Pi/creatinine was unchanged and Ca2+/creatinine drastically decreased, coinciding with the highest kidney Ca2+ content, highest plasma creatinine, and greatest amount of nephrocalcinosis. In Npt2a-/- mice, vitamin D3 treatment completely diminished Npt2c abundance, so that mice resembled Npt2a/c double knockout mice. Abundance of intestinal Npt2b and claudin-3 (tight junctions protein) were reduced in Npt2a-/- only, the latter might facilitate the increase in plasma Pi in Npt2a-/- mice. Npt2a might function as regulator between renal Ca2+ excretion and reabsorption in response to vitamin D3.

Induced pluripotent stem cells derived renal tubular cells from a patient with pseudohypoparathyroidism and its response to parathyroid hormone stimulation.

INTRODUCTION: Creating induced pluripotent stem cells (iPSCs) from somatic cells of patients with genetic diseases offers a pathway to generate disease-specific iPSCs carrying genetic markers. Differentiating these iPSCs into renal tubular cells can aid in understanding the pathophysiology of rare inherited renal tubular diseases through cellular experiments. MATERIALS AND METHODS: Two Japanese patients with Pseudohypoparathyroidism (PHP), a 49-year-old woman and a 71-year-old man, were studied. iPSC-derived tubular cells were established from their peripheral blood mononuclear cells (PBMCs). We examined changes in intracellular and extracellular cyclic adenosine monophosphate (cAMP) levels in these cells in response to parathyroid hormone (PTH) stimulation. RESULTS: Renal tubular cells, differentiated from iPSCs of a healthy control (648A1), showed a PTH-dependent increase in both intracellular and extracellular cAMP levels. However, the renal tubular cells derived from the PHP patients' iPSCs showed inconsistent changes in cAMP levels upon PTH exposure. CONCLUSION: We successfully created disease-specific iPSCs from PHP patients' PBMCs, differentiated them into tubular cells, and replicated the distinctive response of the disease to PTH in vitro. This approach could enhance our understanding of the pathophysiology of inherited renal tubular diseases and contribute to developing effective treatments.

[The role of immunohistochemical examination in the differential diagnosis of atypical tumors and carcinomas of parathyroid glands]. / Rol' immunogistokhimicheskogo analiza v differentsial'noi diagnostike atipicheskikh opukholei i kartsinom okoloshchitovidnykh zhelez.

Differential diagnosis of atypical parathyroid tumors (APT) and parathyroid carcinomas (PC) is important in determining further management and prognosis. Morphologic diagnosis is sometimes difficult, in which case it is supplemented by immunohistochemical (IHC) examination. OBJECTIVE: Studying the role of IHC analysis in the differential diagnosis of APT and PC. MATERIAL AND METHODS: The study included 44 patients with morphologic diagnosis of the APT established after surgical treatment for primary hyperparathyroidism on the basis of Endocrinology Research Centre during 2018-2023. All cases underwent IHC examination with evaluation of CD31/CD34 and parathormone (PTH) expression for identification of vascular invasion, Ki-67, parafibromin. RESULTS: According to the results of IHC analysis in 8/44 patients (18.2%) the diagnosis of APT was revised in favor of the PC: in 7 of them vascular invasion was detected; in 1 patient the additional series of slices in the surrounding fatty tissue revealed foci of tumor growth, confirmed by positive reaction with antibodies to PTH. According to IHC results, the material was divided into 2 groups: APT and PC. There were no differences in clinical and morphological characteristics, Ki-67% level and parafibromin expression between the groups. CONCLUSION: Assessment of clinical and laboratory-instrumental data at the preoperative stage does not allow differentiating APT from PC. In case of APT diagnosis and detection of suspicious morphological features, it is necessary to perform IHC examination to exclude PC.

Single-cell analysis reveals transcriptional dynamics in healthy primary parathyroid tissue.

Studies on human parathyroids are generally limited to hyperfunctioning glands owing to the difficulty in obtaining normal human tissue. We therefore obtained non-human primate (NHP) parathyroids to provide a suitable alternative for sequencing that would bear a close semblance to human organs. Single-cell RNA expression analysis of parathyroids from four healthy adult M. mulatta reveals a continuous trajectory of epithelial cell states. Pseudotime analysis based on transcriptomic signatures suggests a progression from GCM2 hi progenitors to mature parathyroid hormone (PTH)-expressing epithelial cells with increasing core mitochondrial transcript abundance along pseudotime. We sequenced, as a comparator, four histologically characterized hyperfunctioning human parathyroids with varying oxyphil and chief cell abundance and leveraged advanced computational techniques to highlight similarities and differences from non-human primate parathyroid expression dynamics. Predicted cell-cell communication analysis reveals abundant endothelial cell interactions in the parathyroid cell microenvironment in both human and NHP parathyroid glands. We show abundant RARRES2 transcripts in both human adenoma and normal primate parathyroid cells and use coimmunostaining to reveal high levels of RARRES2 protein (also known as chemerin) in PTH-expressing cells, which could indicate that RARRES2 plays an unrecognized role in parathyroid endocrine function. The data obtained are the first single-cell RNA transcriptome to characterize nondiseased parathyroid cell signatures and to show a transcriptomic progression of cell states within normal parathyroid glands, which can be used to better understand parathyroid cell biology.

Leveraging quantitative systems pharmacology and artificial intelligence to advance treatment of chronic kidney disease mineral bone disorder.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a complex clinical syndrome responsible for the accelerated cardiovascular mortality seen in individuals afflicted with CKD. Current approaches to therapy have failed to improve clinical outcomes adequately, likely due to targeting surrogate biochemical parameters as articulated by the guideline developer, Kidney Disease: Improving Global Outcomes (KDIGO). We hypothesized that using a Systems Biology Approach combining machine learning with mathematical modeling, we could test a novel approach to therapy targeting the abnormal movement of mineral out of bone and into soft tissue that is characteristic of CKD-MBD. The mathematical model describes the movement of calcium and phosphate between body compartments in response to standard therapeutic agents. The machine-learning technique we applied is reinforcement learning (RL). We compared calcium, phosphate, parathyroid hormone (PTH), and mineral movement out of bone and into soft tissue under four scenarios: standard approach (KDIGO), achievement of KDIGO guidelines using RL (RLKDIGO), targeting abnormal mineral flux (RLFLUX), and combining achievement of KDIGO guidelines with minimization of abnormal mineral flux (RLKDIGOFLUX). We demonstrate through simulations that explicitly targeting abnormal mineral flux significantly decreases abnormal mineral movement compared with standard approach while achieving acceptable biochemical outcomes. These investigations highlight the limitations of current therapeutic targets, primarily secondary hyperparathyroidism, and emphasize the central role of deranged phosphate homeostasis in the genesis of the CKD-MBD syndrome.NEW & NOTEWORTHY Artificial intelligence is a powerful tool for exploration of complex processes but application to clinical syndromes is challenging. Using a mathematical model describing the movement of calcium and phosphate between body compartments combined with machine learning, we show the feasibility of testing alternative goals of therapy for Chronic Kidney Disease Mineral Bone Disorder while maintaining acceptable biochemical outcomes. These simulations demonstrate the potential for using this platform to generate and test hypotheses in silico rapidly, inexpensively, and safely.

Crosstalk between kidney and bone: insights from CKD-MBD.

The kidneys play an important role in the regulation of phosphate and calcium balance and serum concentrations, coordinated by fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25D). In patients with chronic kidney disease (CKD), this regulation is impaired, leading to CKD-mineral and bone disorder (CKD-MBD), characterized by decreased 1,25D, elevated FGF23, secondary hyperparathyroidism, hyperphosphatemia, bone abnormalities, and vascular and soft-tissue calcification. While bone abnormalities associated with CKD-MBD, known as renal osteodystrophy, have been recognized as the most typical interaction between the kidney and bone, a number of other kidney-bone interactions have been identified, for which our knowledge of the pathogenesis of CKD-MBD has played an important role. This article summarizes recent findings on CKD-MBD and explores the crosstalk between the kidney and bone from the perspective of CKD-MBD.

Parathyroid-on-a-chip simulating parathyroid hormone secretion in response to calcium concentration.

The parathyroid gland is an endocrine organ that plays a crucial role in regulating calcium levels in blood serum through the secretion of parathyroid hormone (PTH). Hypoparathyroidism is a chronic disease that can occur due to parathyroid defects, but due to the difficulty of creating animal models of this disease or obtaining human normal parathyroid cells, the evaluation of parathyroid functionality for drug development is limited. Although parathyroid-like cells that secrete PTH have recently been reported, their functionality may be overestimated using traditional culture methods that lack in vivo similarities, particularly vascularization. To overcome these limitations, we obtained parathyroid organoids from tonsil-derived mesenchymal stem cells (TMSCs) and fabricated a parathyroid-on-a-chip, capable of simulating PTH secretion based on calcium concentration. This chip exhibited differences in PTH secretion according to calcium concentration and secreted PTH within the range of normal serum levels. In addition, branches of organoids, which are difficult to observe in animal models, were observed in this chip. This could serve as a guideline for successful engraftment in implantation therapies in the future.

Mechanistic Insights into Tanshinone IIA in the Amelioration of Post-Thyroidectomy Hypoparathyroidism.

BACKGROUND: Thyroidectomy causes impaired blood supply to the parathyroid glands, which leads to hypoparathyroidism. Tanshinone IIA (Tan IIA) is helpful in blood activation and cardiovascular protection. Therefore, the efficacy of Tan IIA in improving hypoparathyroidism was explored in this study. METHODS: New Zealand white rabbits were utilized to establish a unilateral parathyroid gland ischemia injury model. The model was created by selectively ligating the main blood supply vessel of one parathyroid gland, and the rabbits were then divided into three groups receiving 1, 5, and 10 mg/kg of Tan IIA. Serum calcium and parathyroid hormone (PTH) levels were measured using specialized assay kits. Immunohistochemistry was used to assess the microvessel density (MVD) in parathyroid glands. Western blotting (WB) was used to analyze protein expression related to the PI3K/AKT signaling pathway and the pathway-associated HIF-1α and VEGF. Moreover, MMP-2 and MMP-9 involved in angiogenesis were detected by WB. RESULTS: Tan IIA treatment effectively restored serum calcium and PTH levels in a dose-dependent manner. Notably, MVD in the parathyroid glands increased significantly, especially at higher doses. The Tan IIA treatment also elevated the p-PI3K/PI3K and p-AKT/AKT ratios, indicating that the PI3K/AKT pathway was reactivated. Moreover, Tan IIA significantly restored the decreased expression levels of VEGF and HIF-1α caused by parathyroid surgery. Additionally, Tan IIA increased MMP-2 and MMP-9 levels. CONCLUSION: Tan IIA activates the PI3K/AKT pathway, promotes angiogenesis by modulating VEGF, HIF-1α, MMP-2, and MMP-9, thereby further enhancing MVD within the parathyroid glands. This study demonstrates that Tan IIA improved post-thyroidectomy hypoparathyroidism.

The role of magnesium in the pathogenesis of osteoporosis.

Magnesium (Mg), a nutritional element which is essential for bone development and mineralization, has a role in the progression of osteoporosis. Osteoporosis is a multifactorial disease characterized by significant deterioration of bone microstructure and bone loss. Mg deficiency can affect bone structure in an indirect way through the two main regulators of calcium homeostasis (parathyroid hormone and vitamin D). In human osteoblasts (OBs), parathyroid hormone regulates the expression of receptor activator of nuclear factor-κ B ligand (RANKL) and osteoprotegerin (OPG) to affect osteoclast (OC) formation. In addition, Mg may also affect the vitamin D3 -mediated bone remodeling activity. vitamin D3 usually coordinates the activation of the OB and OC. The unbalanced activation OC leads to bone resorption. The RANK/RANKL/OPG axis is considered to be a key factor in the molecular mechanism of osteoporosis. Mg participates in the pathogenesis of osteoporosis by affecting the regulation of parathyroid hormone and vitamin D levels to affect the RANK/RANKL/OPG axis. Different factors affecting the axis and enhancing OC function led to bone loss and bone tissue microstructure damage, which leads to the occurrence of osteoporosis. Clinical research has shown that Mg supplementation can alleviate the symptoms of osteoporosis to some extent.

Surgical Management of Secondary and Tertiary Hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) often arises from kidney disease and is characterized by elevated parathyroid hormone (PTH) levels. The reported optimal PTH level to balance the compensatory physiologic response in SHPT with the pathologic morbidity and mortality has changed over time with our evolving understanding. Parathyroidectomy for kidney-related hyperparathyroidism requires consideration of the patient's dialysis status, potential for kidney transplantation, and medical history. Extent of parathyroidectomy and intraoperative decision-making requires consideration to maximize cure with the risk of permanent hypoparathyroidism. Parathyroidectomy for kidney-related hyperparathyroidism can provide a reduction in morbidity, mortality, and improved kidney allograft function and survival.

Primary Hyperparathyroidism: Part One: Evaluation.

Primary hyperparathyroidism (PHPT) is a disorder characterized by the autonomous overproduction of parathyroid hormone (PTH) that leads to hypercalcemia, multiple clinical sequelae, and heterogenous presentation. Whether PHPT is caused by a single benign adenoma (85%), multiglandular disease (15%), or parathyroid carcinoma (1%), surgery is the definitive treatment.