Alendronate-functionalized porous nano-crystalsomes mitigate osteolysis and consequent inhibition of tumor growth in a tibia-induced metastasis model.

Bone is one of the most prevalent sites of metastases in various epithelial malignancies, including breast cancer and this metastasis to bone often leads to severe skeletal complications in women due to its osteolytic nature. To address this, we devised a novel drug delivery approach using an Alendronate (ALN) functionalized self-assembled porous crystalsomes for concurrent targeting of Oleanolic acid (OA) and ALN (ALN + OA@NCs) to bone metastasis. Initially, the conjugation of both PEG-OA and OA-PEG-ALN with ALN and OA was achieved, and this conjugation was then self-assembled into porous crystalsomes (ALN + OA@NCs) by nanoemulsion crystallization. The reconstruction of a 3D single particle using transmission electron microscopy ensured the crystalline porous structure of ALN + OA@NCs, was well aligned with characteristic nanoparticle attributes including size distribution, polydispersity, and zeta potential. Further, ALN + OA@NCs showed enhanced efficacy in comparison to OA@NCs suggesting the cytotoxic roles of ALN towards cancer cells, followed by augmentation ROS generation (40.81%), mitochondrial membrane depolarization (57.20%), and induction of apoptosis (41.1%). We found that ALN + OA@NCs facilitated inhibiting osteoclastogenesis and bone resorption followed by inhibited osteolysis. In vivo activity of ALN + OA@NCs in the 4 T1 cell-induced tibia model rendered a reduced bone loss in the treated mice followed by restoring bone morphometric markers which were further corroborated bone-targeting effects of ALN + OA@NCs to reduce RANKL-stimulated osteoclastogenesis. Further, In vivo intravenous pharmacokinetics showed the improved therapeutic profile of the ALN + OA@NCs in comparison to the free drug, prolonging the levels of the drug in the systemic compartment by reducing the clearance culminating the higher accumulation at the tumor site. Our finding proposed that ALN + OA@NCs can effectively target and treat breast cancer metastasis to bone and its associated complications.

Linoleic acid blunts early osteoblast differentiation and impairs oxidative phosphorylation in vitro.

BACKGROUND: Linoleic acid (LNA), an essential polyunsaturated fatty acid (PUFA), plays a crucial role in cellular functions. However, excessive intake of LNA, characteristic of Western diets, can have detrimental effects on cells and organs. Human observational studies have shown an inverse relationship between plasma LNA concentrations and bone mineral density. The mechanism by which LNA impairs the skeleton is unclear, and there is a paucity of research on the effects of LNA on bone-forming osteoblasts. METHODS: The effect of LNA on osteoblast differentiation, cellular bioenergetics, and production of oxidized PUFA metabolites in vitro, was studied using primary mouse bone marrow stromal cells (BMSC) and MC3T3-E1 osteoblast precursors. RESULTS: LNA treatment decreased alkaline phosphatase activity, an early marker of osteoblast differentiation, but had no effect on committed osteoblasts or on mineralization by differentiated osteoblasts. LNA suppressed osteoblast commitment by blunting the expression of Runx2 and Osterix, key transcription factors involved in osteoblast differentiation, and other key osteoblast-related factors involved in bone formation. LNA treatment was associated with increased production of oxidized LNA- and arachidonic acid-derived metabolites and blunted oxidative phosphorylation, resulting in decreased ATP production. CONCLUSION: Our results show that LNA inhibited early differentiation of osteoblasts and this inhibitory effect was associated with increased production of oxidized PUFA metabolites that likely impaired energy production via oxidative phosphorylation.

A hybrid CNN with transfer learning for skin cancer disease detection.

The leading cause of cancer-related deaths worldwide is skin cancer. Effective therapy depends on the early diagnosis of skin cancer through the precise classification of skin lesions. However, dermatologists may find it difficult and time-consuming to accurately classify skin lesions. The use of transfer learning to boost skin cancer classification model precision is a promising strategy. In this work, we proposed a hybrid CNN with a transfer learning model and a random forest classifier for skin cancer disease detection. To evaluate the efficacy of the proposed model, it was verified over two datasets of benign skin moles and malignant skin moles. The proposed model is able to classify images with an accuracy of up to 90.11%. The empirical results and analysis assure the feasibility and effectiveness of the proposed model for skin cancer classification.

Intravenous Iron Therapy in Heart Failure Patients With Iron Deficiency: Benefits, Safety, and Guidelines.

Iron deficiency is a common comorbidity in heart failure (HF) patients, with up to 50% of ambulatory patients with HF affected. Intravenous (IV) iron therapy has emerged as a promising treatment approach for HF patients with concomitant iron deficiency. This review summarizes the current literature on the use of IV iron therapy in HF patients, focusing on its benefits in improving quality of life, and exercise capacity, and reducing HF hospitalizations. However, concerns about the long-term cardiotoxic effects of IV iron, including the risk of iron overload, are also addressed. The review highlights the importance of a balanced approach to iron replacement and provides an overview of the 2022 American College of Cardiology/American Heart Association guidelines, which recommend IV iron therapy for eligible patients. Additionally, the review underscores the need for further research, particularly in HF patients with preserved ejection fraction and acute HF. While IV iron therapy shows promise, questions about its safety and specific formulations remain to be fully addressed.

A Case of µ Heavy and λ Light Chain Amyloidosis in a Patient With Bi-Clonal (IgM κ and λ) Gammopathy Treated With Daratumumab.

Our case report is of an elderly male with a history of IgM κ lymphoplasmacytic lymphoma (LPL) presenting with generalized neuropathy and weakness. Due to his LPL history and worsening renal function, he underwent a renal biopsy revealing the presence of µ heavy and λ light chains, revealing a diagnosis of amyloidosis with unbound heavy & light chains (AHL), a rare type of amyloidosis. His bone marrow biopsy demonstrated κ light chain restriction by flow cytometry and amyloid deposition. The patient's serum had elevated free κ and λ light chains with a free light chain (FLC) ratio of 3.17. Serum immunofixation was positive for IgM κ and λ light chain clones. He completed six cycles of cyclophosphamide, bortezomib, dexamethasone, and rituximab (CyBorD+R), normalizing the FLC ratio. Still, he continued to present with persistently elevated M protein, IgM κ, and λ light chains on immunofixation. Thereafter, daratumumab, a human monoclonal antibody directed against CD38 expressed on myeloma cells was initiated, which led to a negative immunofixation study after two cycles accompanied by a reduction in protein excretion in the urine. The patient achieved a complete hematological response with daratumumab. To date, our case is the only reported µ heavy and λ light chain amyloidosis patient with bi-clonal (IgM κ and λ) gammopathy to be successfully treated with daratumumab.

Foundry-based waveguide-enhanced Raman spectroscopy in the visible.

Waveguide-enhanced Raman spectroscopy (WERS) is an analytical technique frequently employed for chemical and biological sensing. Operation at visible wavelengths to harness the inverse fourth power with excitation wavelength signal scaling of Raman scattering intensity is desirable, to combat the inherent inefficiency of Raman spectroscopy. Until now, WERS demonstrations in the visible have required custom materials and fabrication, resulting in high losses and low yields. In this work, we demonstrate a silicon nitride (SIN) visible WERS platform fabricated in a 300 mm complementary metal-oxide semiconductor (CMOS) foundry. We measure the propagation loss, coupling loss, WERS signal, and background for WERS spirals designed for 532 nm and 633 nm pump wavelengths. We compare these results to the state-of-the-art near-infrared WERS platform at 785 nm. Further, we theoretically validate the relative performance of each of these WERS configurations, and we discuss the optimal WERS configuration at visible wavelengths. We conclude that a configuration optimized for 785 nm pumping provides the greatest signal-to-background ratio in the fingerprint region of the spectrum, and pumping at 633 nm maximizes Stokes signal out to 3000 cm-1.

Initiation of Cancer: The Journey From Mutations in Somatic Cells to Epigenetic Changes in Tissue-resident VSELs.

Multiple theories exist to explain cancer initiation, although a consensus on this is crucial for developing effective therapies. 'Somatic mutation theory' suggests that mutations in somatic cells during DNA repair initiates cancer but this concept has several attached paradoxes. Research efforts to identify quiescent cancer stem cells (CSCs) that survive therapy and result in metastasis and recurrence have remained futile. In solid cancers, CSCs are suggested to appear during epithelial-mesenchymal transition by the dedifferentiation and reprogramming of epithelial cells. Pluripotent and quiescent very small embryonic-like stem cells (VSELs) exist in multiple tissues but remain elusive owing to their small size and scarce nature. VSELs are developmentally connected to primordial germ cells, undergo rare, asymmetrical cell divisions and are responsible for the regular turnover of cells to maintain tissue homeostasis throughout life. VSELs are directly vulnerable to extrinsic endocrine insults because they express gonadal and gonadotropin hormone receptors. VSELs undergo epigenetic changes due to endocrine insults and transform into CSCs. CSCs exhibit genomic instability and develop mutations due to errors during DNA replication while undergoing excessive proliferation and clonal expansion to form spheroids. Thus tissue-resident VSELs offer a connection between extrinsic insults and variations in cancer incidence reported in various body tissues. To conclude, cancer is indeed a stem cell disease with mutations occurring as a consequence. In addition to immunotherapy, targeting mutations, and Lgr5 + organoids for developing new therapeutics, targeting CSCs (epigenetically altered VSELs) by improving their niche and epigenetic status could serve as a promising strategy to treat cancer.

Exploring the Intricate Interplay Between Obesity and Atrial Fibrillation: Mechanisms, Management, and Clinical Implications.

Atrial fibrillation (AF) stands as a prevalent and escalating cardiac arrhythmia in the United States, with obesity emerging as a prominent modifiable risk factor. This article explores the intricate relationship between obesity and AF, delving into the multifaceted pathophysiological mechanisms linking the 2 conditions. Various factors, such as autonomic dysfunction, left atrial stretch, inflammation, and hormonal imbalances, contribute to the initiation and perpetuation of AF in obese individuals. The Atrial Fibrillation Better Care pathway, emphasizing lifestyle modifications and weight loss strategies, emerges as a practical guideline for managing AF in obesity. This comprehensive review underscores the critical role of obesity as a significant modifiable risk factor for AF, urging a proactive approach to its management. Implementing the Atrial Fibrillation Better Care approach, focusing on encouraging physical activity, promoting healthy dietary habits, and raising awareness about the risks associated with obesity prove essential in preventing and mitigating the burden of AF in the obese population.

Burden of Anxiety, Depression and Perceived Stress in Patients with Inflammatory Bowel Disease: A Cohort Study from North India.

BACKGROUND: Patients with Inflammatory bowel disease (IBD) are susceptible to psychiatric co-morbidities. We aimed to ascertain the burden of anxiety, depression, and perceived stress in patients with IBD from north India. METHODS: Consenting adult patients with an established diagnosis of IBD were enrolled. The enrolled patients filled the Hospital Anxiety and Depression Scale (HADS) and Perceived Stress Scale (PSS) questionnaires. The patient and disease characteristics were analyzed to determine the correlations and predictors of psychiatric comorbidities. RESULTS: A total of 318 patients (255 UC, 63 CD; mean age 40.13 ± 12.06 years, 168 [52.8%] males; mean partial Mayo score 2.10 ± 2.35; and mean HBI 2.77 ± 2.13) were enrolled. The prevalence of anxiety, depression and moderate to high perceived stress was 14%, 12%, and 41%, respectively. Females had higher mean perceived stress, anxiety and depression scores compared to males. The partial Mayo score (PMS) correlated poorly with anxiety (ρ = 0.083, p = 0.187), depression (ρ = 0.123, p = 0.49) and perceived stress (ρ = 0.169; p = 0.007). The Harvey Bradshaw index (HBI) correlated fairly with anxiety (ρ = 0.336, p = 0.007) and poorly with depression (ρ = 0.287, p = 0.022) and perceived stress (ρ = 0.20; p = 0.117). Younger age (OR 0.93, 95% CI 0.90-0.97; p = 0.001) and hand-grip strength (OR 4.63, 95% CI 1.88-11.42; p = 0.001) predicted anxiety in patients with UC while rural area of residence (OR 4.75, 95% CI 1.03-21.98; p = 0.046) and HBI (OR 1.60, 95% CI 1.12-2.29; p = 0.009) were significant predictors of anxiety in patients with CD. CONCLUSION: Psychiatric comorbidities are common in patients with IBD, with higher prevalence in females. Young adults with UC and sarcopenia; and individuals with active CD living in rural areas are at an increased risk of anxiety.

The Role of 5-Fluorouracil in Preventing Recurrence After Enucleation of Odontogenic Keratocyst: A Case Report.

The odontogenic keratocyst (OKC) is known for its high recurrence rate and disputed treatment modalities. In this report, we review the literature elucidating the efficacy of 5-fluorouracil (5-FU) topical application for recurrent OKC, and discuss the management of an OKC with 5-FU after enucleation and a 12-month follow-up. A 38-year-old female patient with an aggressive OKC in the right mandible underwent surgical curettage followed by topical application of 5-FU. Regular follow-up examinations for 12 months (radiological evaluation at three, six, and 12-month intervals) showed no signs of recurrence, with complete resolution of the cystic lesion and gradual bone regeneration. New bone formation was identified in the radiographic follow-up.  This case demonstrates the potential efficacy of topical 5-FU as a promising treatment modality for OKC, warranting further research and validation. A novel and successful therapy for OKC is the topical application of 5-FU. After enucleation, topical application of 5-FU efficiently treats OKC, leading to normal bone healing and regeneration without any adverse local or systemic effects.

Comparison of 2-Octyl Cyanoacrylate with Prolene (4-0) Sutures in Extra Oral Wound Closure.

Aim: To compare the healing following various maxillofacial incisions using 2-octyl cyanoacrylate (2-OCA) and prolene (4-0) sutures. Objective: To evaluate the complications and aesthetic outcome of the incision wounds after closure using 2-OCA and prolene (4-0) sutures. Materials and Methods: The patient undergoing an extraoral incision was evaluated for pain, inflammation, infection, dehiscence, scar, and surface texture. In Group I, 15 patient incisions were closed with 2-OCA and in Group II, 15 patient incisions were closed with prolene (4-0) suture. Result: A few patients experienced pain with Group I and then Group II, but infection, inflammation, and dehiscence were more in Group I than in Group II. Conclusion: A cosmetic outcome was higher in the cyanoacrylate group, and the surface texture was satisfying in the same group.

Platelet-Rich Fibrin-Enhanced Bone Healing Co-grafted With Either Hydroxyapatite and Beta Tricalcium Phosphate or Demineralized Freeze-Dried Bone in Small Maxillofacial Osseous Defects: A Clinical Comparison.

INTRODUCTION: This study was conducted to clinically compare a commercially available combination of 70:30 nanocrystalline hydroxyapatite (HA) and beta tricalcium phosphate (ßTCP) along with platelet-rich fibrin (PRF) with demineralized freeze-dried bone (DFDB) grafts along with PRF in small maxillofacial osseous defects. MATERIALS AND METHODS: Thirty patients with one osseous defect were randomly distributed into two groups of 15 each: Group A and Group B. Group A patients received HA+ßTCP+PRF while Group B received DFDB + PRF. Postoperative pain, swelling, wound dehiscence, and the presence or absence of infection were evaluated at various intervals up to seven postop days and compared between the two groups and within either group. A technetium 99m methylene diphosphonate (MDP 99mTc) scan was also done for a representative patient of either group at the end of three months to evaluate the fate of the graft. RESULTS: We found no significant difference between the two groups for any of our parameters. Significant improvements were noted for pain and swelling within either group at various intervals. The MDP 99mTc scan showed increased tracer uptake for the representing patient of either group. CONCLUSIONS: HA+ßTCP is more inexpensive than DFDB and more readily available and has no host incompatibility or infection potential, resulting in similar clinical postoperative states as DFDB when either is used with PRF.

Clinical and magnetic resonance imaging spectrum of complex perianal fistulizing Crohn's disease: A cohort study from northern India.

BACKGROUND: Fistulizing perianal Crohn's disease (CD) is a debilitating condition associated with significant morbidity and reduction in the quality of life. Magnetic resonance imaging (MRI) of the pelvis is the preferred imaging modality for the comprehensive assessment of the perianal fistula. There is a paucity of data from India on the MRI spectrum of complex perianal fistula in CD. METHODS: A single-centre cross-sectional analysis of patients with fistulizing perianal CD, who underwent pelvic MRI between January 2020 and December 2021, was performed. The clinical (age, sex, disease duration, disease location and behavior, disease activity [Perianal Disease Activity Index, PDAI] and treatment received) and radiological (number and location of fistulae, extensions, number and location of internal and external openings, fistula activity, presence or absence of perianal abscess and associated proctitis) characteristics of complex perianal fistula (defined according to the American Gastroenterological Association classification) were recorded. RESULTS: Of total 175 patients with CD who attended the gastroenterology clinic during the study period, 27 (15.42%) (mean age 42±15.5 years, 62.96% females and median disease duration four years) had complex perianal fistula and were included in the analysis. The mean PDAI was 5.48±2.53. The median Van Assche Index was 17 (interquartile range [IQR] 13-19). A majority (96.29%) of the fistulae were trans-sphincteric and four (14.81%) fistulae extended into the supralevator space. All fistulae were active on MRI. Concomitant perianal abscess and proctitis were seen in 59.26% (n=16) and 62.96% (n=17) of patients, respectively. Combination therapy with biologics and antibiotics/immune-suppressants were the most commonly prescribed medical therapy. Six (22.22%) patients underwent combined medical and surgical (non-cutting seton, fistulectomy, fecal diversion) treatment. CONCLUSION: The cumulative risk of the development of fistulizing perianal CD in a northern Indian cohort was similar to the western populations. Complex perianal fistulae were predominantly trans-sphincteric and commoner in females. MRI evaluation is pivotal for the delineation of fistula anatomy, assessment of disease extent and activity and the evaluation of concomitant perianal abscess and other complications.

Multislice forward modeling of coherent surface scattering imaging on surface and interfacial structures.

To study nanostructures on substrates, surface-sensitive reflection-geometry scattering techniques such as grazing incident small angle X-ray scattering are commonly used to yield an averaged statistical structural information of the surface sample. Grazing incidence geometry can probe the absolute three-dimensional structural morphology of the sample if a highly coherent beam is used. Coherent surface scattering imaging (CSSI) is a powerful yet non-invasive technique similar to coherent X-ray diffractive imaging (CDI) but performed at small angles and grazing-incidence reflection geometry. A challenge with CSSI is that conventional CDI reconstruction techniques cannot be directly applied to CSSI because the Fourier-transform-based forward models cannot reproduce the dynamical scattering phenomenon near the critical angle of total external reflection of the substrate-supported samples. To overcome this challenge, we have developed a multislice forward model which can successfully simulate the dynamical or multi-beam scattering generated from surface structures and the underlying substrate. The forward model is also demonstrated to be able to reconstruct an elongated 3D pattern from a single shot scattering image in the CSSI geometry through fast-performing CUDA-assisted PyTorch optimization with automatic differentiation.

Very Small Embryonic-Like Stem Cells Transform Into Cancer Stem Cells and Are Novel Candidates for Detecting/Monitoring Cancer by a Simple Blood Test.

Cancer continues to remain a "Black Box," as there is no consensus on how it initiates, progresses, metastasizes, or recurs. Many imponderables exist about whether somatic mutations initiate cancer, do cancer stem cells (CSCs) exist, and if yes, are they a result of de-differentiation or originate from tissue-resident stem cells; why do cancer cells express embryonic markers, and what leads to metastasis and recurrence. Currently, the detection of multiple solid cancers through liquid biopsy is based on circulating tumor cells (CTCs) or clusters, or circulating tumor DNA (ctDNA). However, quantity of starting material is usually adequate only when the tumor has grown beyond a certain size. We posit that pluripotent, endogenous, tissue-resident, very small embryonic-like stem cells (VSELs) that exist in small numbers in all adult tissues, exit from their quiescent state due to epigenetic changes in response to various insults and transform into CSCs to initiate cancer. VSELs and CSCs share properties like quiescence, pluripotency, self-renewal, immortality, plasticity, enrichment in side-population, mobilization, and resistance to oncotherapy. HrC test, developed by Epigeneres, offers the potential for early detection of cancer using a common set of VSEL/CSC specific bio-markers in peripheral blood. In addition, NGS studies on VSELs/CSCs/tissue-specific progenitors using the All Organ Biopsy (AOB) test provide exomic and transcriptomic information regarding impacted organ(s), cancer type/subtype, germline/somatic mutations, altered gene expressions, and dysregulated pathways. To conclude, HrC and AOB tests can confirm the absence of cancer and categorize the rest of subjects into low/moderate/high risk of cancer, and also monitor response to therapy, remission, and recurrence.

A Novel Blockchain and Internet of Things-Based Food Traceability System for Smart Cities.

Rapid urbanization has recently caused serious problems for cities all around the world. Smart cities have drawn much interest from researchers in the present research paradigm to manage the expanding urban population. Frameworks for smart cities are planned and implemented using platforms based on blockchain and the Internet of Things (BIOT). Smart cities may use the BIoT platform to provide improved transportation, food traceability, and healthcare services. Food safety is one of the sectors where less research has been done than the others. The importance of food safety is now more widely recognized, making it essential to improve the traceability and transparency of the food supply chain. In this paper, a novel BIOT-based layered framework using EOSIO has been proposed for effective food traceability. The proposed system first identifies the suitable traceability units to provide better transparency and traceability and then defines and implements a layered architecture using Ethereum and EOSIO blockchain platforms. The performance of the proposed EOSIO-based model is evaluated using the practicality of the consensus algorithm, block production rate, throughput, and block confirmation time. The proposed traceability system attains a block production rate of 0.5 s and a block confirmation time of 1 s, which is much lower than the Ethereum-based traceability system. Hence, from the experimental evidence, the superiority of the proposed EOSIO-based food traceability can be observed.

Low prevalence of primary sclerosing cholangitis in patients with inflammatory bowel disease in India.

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) represents the most common hepatobiliary extraintestinal manifestation of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). Limited data exist on PSC in patients with IBD from India. We aimed to assess the prevalence and disease spectrum of PSC in Indian patients with IBD. METHODS: Database of IBD patients at 5 tertiary care IBD centers in India were analyzed retrospectively. Data were extracted and the prevalence of PSC-IBD was calculated. RESULTS: Forty-eight patients out of 12,216 patients with IBD (9,231 UC, 2,939 CD, and 46 IBD unclassified) were identified to have PSC, resulting in a prevalence of 0.39%. The UC to CD ratio was 7:1. Male sex and pancolitis (UC) or colonic CD were more commonly associated with PSC-IBD. The diagnosis of IBD preceded the diagnosis of PSC in most of the patients. Majority of the patients were symptomatic for liver disease at diagnosis. Eight patients (16.66%) developed cirrhosis, 5 patients (10.41%), all UC, developed malignancies (3 colorectal cancer [6.25%] and 2 cholangiocarcinoma [4.16%]), and 3 patients died (2 decompensated liver disease [4.16%] and 1 cholangiocarcinoma [2.08%]) on follow-up. None of the patients mandated surgical therapy for IBD. CONCLUSIONS: Concomitant PSC in patients with IBD is uncommon in India and is associated with lower rates of development of malignancies.

Extremely Active Nano-formulation of Resveratrol (XAR™) attenuates and reverses chemotherapy-induced damage in mice ovaries and testes.

BACKGROUND: Fertility preservation and restoration in cancer patients/survivors is the need of present times when increased numbers of patients get cured of cancer but face infertility as a serious side effect. Resveratrol has beneficial effects on chemoablated ovaries and testes in mice but has failed to enter the clinics because of extremely poor bioavailability. The present study was undertaken to evaluate the protective and curative effects of Extremely active Resveratrol (XAR™)- a nano-formulation of resveratrol with significantly improved bioavailability- on mouse ovary and testis after chemotherapy. Effects of XAR™ and FSH were compared on stimulation of follicle growth in adult mice ovaries. XAR™ (25 mg/kg) was administered for two days prior to chemotherapy to study the protective effects on the mouse gonads. XAR™ was also administered for 14 days post chemoablation to study the regenerative effects. Besides effect on numbers of primordial and growing follicles and spermatogenesis, the effect of XAR™ was also evaluated on the transcripts specific for ovarian/testicular stem/progenitor/germ cells, their proliferation, differentiation, meiosis, and the antioxidant indices. RESULTS: Similar to FSH, XAR™ increased the numbers of primordial follicles (PF) as well as growing follicles. It protected the gonads from the adverse effects of chemotherapy and showed the ability to regenerate non-functional, chemoablated gonads. Besides stimulating follicle growth in adult ovaries similar to FSH, XAR™ also protected the testes from the adverse effects of chemotherapy and improved spermatogenesis. This was accompanied by improved anti-oxidant indices. CONCLUSIONS: The results of the present study potentiate the use of XAR™ in pilot clinical studies to protect gonadal function during oncotherapy and also regenerate non-functional gonads in cancer survivors by improving antioxidant indices and stem cell-based tissue regeneration.

Nanoparticles of naturally occurring PPAR-γ inhibitor betulinic acid ameliorates bone marrow adiposity and pathological bone loss in ovariectomized rats via Wnt/ß-catenin pathway.

AIMS: Postmenopausal osteoporosis is one of the world's biggest yet unnoticed health issues. After ovariectomy, declined estrogen level significantly contributes to the elevation of bone marrow adiposity and bone loss leading to osteoporosis. Therapeutics to prevent osteoporosis addressing various aspects are now in short supply. In this study we made an approach to synthesize nanoparticles of naturally occurring PPAR-γ inhibitor, betulinic acid (BA/NPs) and tested the same in altered bone metabolisms developed after ovariectomy. MAIN METHODS: The osteogenic efficacy of BA/NPs was established in human and rat primary osteoblast cells using qRT-PCR and immunoblot analysis. Furthermore, lineage allocations of multipotent bone marrow stromal cells were evaluated. Various aspects of altered bone metabolism after ovariectomy such as bone marrow adiposity and pathological bone loss were evaluated using µCT and histological assessments. KEY FINDINGS: BA/NPs exert potential osteogenic efficacy by modulating key osteogenic markers such as RUNX2 and BMP2. Mechanistically BA/NPs regulate osteoblastogenesis through Wnt/ß-catenin signaling. Further, BA/NPs showed the potential to inhibit the differentiation of multipotent BMSCs towards adipogenesis while favouring the osteogenic lineage via Wnt/ß-catenin pathway. In the in vivo study, increased bone marrow adiposity was reduced in ovariectomized rats after BA/NPs treatment as assessed by histology and µCT analysis. Loss of bone mineral density as a hallmark of pathological bone loss was also abrogated by BA/NPs. Furthermore, increased obesity after OVX was also prevented in BA/NPs treated animals. SIGNIFICANCE: Our findings imply that BA/NPs could be used further as a viable drug lead to counteract various pathophysiological challenges after menopause.