Atypical Manifestation of Acute Myocardial Infarction (AMI) in a Vicenarian Woman With Polycystic Ovary Syndrome (PCOS) Undergoing Assisted Reproductive Technology (ART) Treatment: A Case Report.

Polycystic ovary syndrome (PCOS) is a prevalent endocrinological disorder affecting women of reproductive age, characterized by hormonal imbalances leading to metabolic and reproductive dysregulations. Acute myocardial infarction (AMI) represents a critical cardiovascular event, traditionally observed in older populations but increasingly identified in younger individuals with diverse medical backgrounds. The pursuit of assisted reproductive technology (ART) by women with PCOS to address infertility may further complicate cardiovascular risks due to the exogenous hormonal manipulations involved. This case report delineates a rare presentation of AMI in a 27-year-old vicenarian woman with PCOS undergoing ART treatment. Despite the absence of conventional cardiovascular risk factors, the patient exhibited typical symptoms and diagnostic features of AMI. Prompt recognition and intervention facilitated successful management and favorable outcomes. This case underscores the importance of considering atypical cardiovascular presentations in young women with complex medical histories, necessitating heightened awareness among healthcare providers. Multidisciplinary collaboration is imperative for comprehensive risk assessment, prevention, and tailored management strategies in this population. Further research is warranted to elucidate the intricate interplay between PCOS, ART, and cardiovascular outcomes, thereby optimizing clinical care and enhancing reproductive outcomes in this vulnerable cohort. An enhanced understanding of these relationships is essential for guiding evidence-based interventions aimed at mitigating cardiovascular risks and improving overall health outcomes in women with PCOS undergoing fertility treatments.

Application of Intracytoplasmic Morphologically Selected Sperm Injection (IMSI) on a Teratozoospermic Patient and Its Effect on the In-Vitro Fertilization (IVF) Outcome.

Infertility, defined as the inability to conceive after 12 months of unprotected sexual activity, affects millions globally. Approximately 80% of cases have identifiable causes, including endometriosis, tubal obstruction, ovulatory dysfunction, and male sperm abnormalities. Lifestyle factors, such as smoking and obesity, also impact fertility. Sperm morphology, a key factor in male infertility, often presents as teratozoospermia, with defects in the head, midpiece, or tail. Poor ovarian reserve, indicated by low anti-mullerine hormone (AMH) and antra-follicular count (AFC) values, contributes to female infertility, often exacerbated by age-related factors. Elevated follicle-stimulating hormone (FSH) levels further diminish oocyte quantity and quality. Intracytoplasmic Sperm Injection (ICSI), a micromanipulation technique aiding infertile couples, may face challenges in detecting subtle sperm morphology defects. Advanced methods like Motile Sperm Organelle Morphological Examination (MSOME) and Intracytoplasmic Morphologically Selected Sperm Injection (IMSI) under high magnification enhance sperm selection accuracy. We present the case of a 36-year-old woman and her 42-year-old husband who sought assistance after seven years of infertility. Previous Intrauterine injection (IUI) and ICSI attempts failed due to the wife's low ovarian reserve and elevated FSH, compounded by the husband's teratozoospermia. Their earlier In-Vitro Fertilization (IVF) experience yielded a single poor-quality oocyte, hindering blastocyst formation. Investigations revealed the wife's poor AFC, AMH of 0.033ng/ml, and FSH at 24IU/L. Her medical history included hypertension and gallbladder removal. The husband exhibited 98% defective sperm, devoid of a substance abuse history. The wife's family had a polycystic ovarian syndrome (PCOS) history, and her low AMH and AFC yielded only three poor-quality oocytes during the current assessment. Oocytes were retrieved, and sperm were selected with the help of IMSI. After ICSI, the patient successfully conceived.

Characteristics of Polycystic Ovary Syndrome: A Case Report Investigating the Role of Kapha and Pitta Doshas.

Polycystic ovary syndrome (PCOS) presents complex challenges in diagnosis and treatment due to its multifactorial nature. This case study focuses on a 31-year-old woman exhibiting symptoms of weight gain, irregular menstruation cycles, and hirsutism, leading to a diagnosis of PCOS. Conventional diagnostic criteria and ultrasound confirmation of multiple ovarian cysts supported the diagnosis. By integrating Ayurvedic principles alongside Western medical techniques, this study sought to address imbalances in the Kapha and Pitta doshas, fundamental energies according to Ayurveda, believed to contribute to PCOS symptoms. Clinical findings emphasized the role of Pitta dosha imbalance in inflammation, hormonal irregularities, and excessive body heat, while Kapha dosha imbalance manifested in fluid retention, weight gain, and increased mucus production. A holistic treatment approach was devised, aiming to restore doshic balance while addressing hormonal and metabolic dysregulation. The treatment protocol comprised lifestyle modifications, advocating for a regular exercise regimen focusing on activities enhancing insulin sensitivity and promoting weight loss. Swimming, yoga, and brisk walking were recommended to achieve these goals. Dietary interventions tailored to balance Kapha and Pitta doshas were prescribed, emphasizing nourishing, warming foods low in carbohydrates to prevent weight gain and boost metabolism. Anti-inflammatory foods, such as turmeric and ginger, were incorporated to mitigate inflammation. The integration of Ayurvedic principles alongside Western medicine offered a comprehensive approach to PCOS management, addressing both the root causes and symptoms of the condition. This personalized treatment strategy aimed not only to alleviate immediate symptoms but also to promote long-term health and well-being by restoring doshic equilibrium and optimizing hormonal and metabolic functions. In conclusion, this case study highlights the potential efficacy of combining Ayurvedic and Western medical approaches in the management of PCOS, offering a tailored and holistic treatment paradigm for patients seeking comprehensive care.

Voltage-Gated Sodium Channel NaV1.5 Controls NHE-1-Dependent Invasive Properties in Colon Cancer Cells.

Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (NaV) are abnormally overexpressed in several carcinomas including CRC and are strongly associated with the metastatic behavior of cancer cells. Acidification of the extracellular space by Na+/H+ exchangers (NHE) contributes to extracellular matrix degradation and cell invasiveness. In this study, we assessed the expression levels of pore-forming α-subunits of NaV channels and NHE exchangers in tumor and adjacent non-malignant tissues from colorectal cancer patients, CRC cell lines and primary tumor cells. In all cases, SCN5A (gene encoding for NaV1.5) was overexpressed and positively correlated with cancer stage and poor survival prognosis for patients. In addition, we identified an anatomical differential expression of SCN5A and SLC9A1 (gene encoding for NHE-1) being particularly relevant for tumors that originated on the sigmoid colon epithelium. The functional activity of NaV1.5 channels was characterized in CRC cell lines and the primary cells of colon tumors obtained using tumor explant methodologies. Furthermore, we assessed the performance of two new small-molecule NaV1.5 inhibitors on the reduction of sodium currents, as well as showed that silencing SCN5A and SLC9A1 substantially reduced the 2D invasive capabilities of cancer cells. Thus, our findings show that both NaV1.5 and NHE-1 represent two promising targetable membrane proteins against the metastatic progression of CRC.

Structure-activity relationship (SAR) studies of N-(3-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (SRI-22819) as NF-Ò¡B activators for the treatment of ALS.

ALS is a rare type of progressive neurological disease with unknown etiology. It results in the gradual degeneration and death of motor neurons responsible for controlling the voluntary muscles. Identification of mutations in the superoxide dismutase (SOD) 1 gene has been the most significant finding in ALS research. SOD1 abnormalities have been associated with both familial as well as sporadic ALS cases. SOD2 is a highly inducible SOD that performs in concurrence with SOD1 to detoxify ROS. Induction of SOD2 can be obtained through activation of NF-Ò¡Bs. We previously reported that SRI-22819 increases NF-Ò¡B expression and activation in vitro, but it has poor ADME properties in general and has no oral bioavailability. Our initial studies were focused on direct modifications of SRI-22819. There were active compounds identified but no improvement in microsomal stability was observed. In this context, we focused on making more significant structural changes in the core of the molecule. Ataluren, an oxadiazole compound that promotes read-through and expression of dystrophin in patients with Duchenne muscular dystrophy, bears some structural similarity to SRI-22819. Thus, we synthesized a series of SRI-22819 and Ataluren (PTC124) hybrid compounds. Several compounds from this series exhibited improved activity, microsomal stability and lower calculated polar surface area (PSA). This manuscript describes the synthesis and biological evaluation of SRI-22819 analogs and its hybrid combination with Ataluren.

Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer.

PURPOSE: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. EXPERIMENTAL DESIGN: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on in vitro and in vivo phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. RESULTS: L2HGDH suppresses both in vitro cell migration and in vivo tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in an L-2-HG-dependent manner. Moreover, in vivo growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC. CONCLUSIONS: Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG-driven kidney cancers.

Discovery and evaluation of nNav1.5 sodium channel blockers with potent cell invasion inhibitory activity in breast cancer cells.

Voltage-gated sodium channels (VGSC) are a well-established drug target for anti-epileptic, anti-arrhythmic and pain medications due to their presence and the important roles that they play in excitable cells. Recently, their presence has been recognized in non-excitable cells such as cancer cells and their overexpression has been shown to be associated with metastatic behavior in a variety of human cancers. The neonatal isoform of the VGSC subtype, Nav1.5 (nNav1.5) is overexpressed in the highly aggressive human breast cancer cell line, MDA-MB-231. The activity of nNav1.5 is known to promote the breast cancer cell invasion in vitro and metastasis in vivo, and its expression in primary mammary tumors has been associated with metastasis and patient death. Metastasis development is responsible for the high mortality of breast cancer and currently there is no treatment available to specifically prevent or inhibit breast cancer metastasis. In the present study, a 3D-QSAR model is used to assist the development of low micromolar small molecule VGSC blockers. Using this model, we have designed, synthesized and evaluated five small molecule compounds as blockers of nNav1.5-dependent inward currents in whole-cell patch-clamp experiments in MDA-MB-231 cells. The most active compound identified from these studies blocked sodium currents by 34.9 ±â€¯6.6% at 1 µM. This compound also inhibited the invasion of MDA-MB-231 cells by 30.3 ±â€¯4.5% at 1 µM concentration without affecting the cell viability. The potent small molecule compounds presented here have the potential to be developed as drugs for breast cancer metastasis treatment.

Cyanobacterial Metabolite Calothrixins: Recent Advances in Synthesis and Biological Evaluation.

The marine environment is host to unparalleled biological and chemical diversity, making it an attractive resource for the discovery of new therapeutics for a plethora of diseases. Compounds that are extracted from cyanobacteria are of special interest due to their unique structural scaffolds and capacity to produce potent pharmaceutical and biotechnological traits. Calothrixins A and B are two cyanobacterial metabolites with a structural assembly of quinoline, quinone, and indole pharmacophores. This review surveys recent advances in the synthesis and evaluation of the biological activities of calothrixins. Due to the low isolation yields from the marine source and the promise this scaffold holds for anticancer and antimicrobial drugs, organic and medicinal chemists around the world have embarked on developing efficient synthetic routes to produce calothrixins. Since the first review appeared in 2009, 11 novel syntheses of calothrixins have been published in the efforts to develop methods that contain fewer steps and higher-yielding reactions. Calothrixins have shown their potential as topoisomerase I poisons for their cytotoxicity in cancer. They have also been observed to target various aspects of RNA synthesis in bacteria. Further investigation into the exact mechanism for their bioactivity is still required for many of its analogs.

Recent advances in isolation, synthesis, and evaluation of bioactivities of bispyrroloquinone alkaloids of marine origin.

The ocean continues to provide a plethora of unique scaffolds capable of remarkable biological applications. A large number of pyrroloiminoquinone alkaloids, including discorhabdins, epinardins, batzellines, makaluvamines, and veiutamine, have been isolated from various marine organisms. A class of pyrroloiminoquinone-related alkaloids, known as bispyrroloquinones, is the focus of this review article. This family of marine alkaloids, which contain an aryl substituted bispyrroloquinone ring system, includes three subclasses of alkaloids namely, wakayin, tsitsikammamines A-B, and zyzzyanones A-D. Both wakayin and the tsitsikammamines contain a tetracyclic fused bispyrroloiminoquinone ring system, while zyzzyanones contain a fused tricyclic bispyrroloquinone ring system. The unique chemical structures of these marine natural products and their diverse biological properties, including antifungal and antimicrobial activity, as well as the potent, albeit generally nonspecific and universal cytotoxicities, have attracted great interest of synthetic chemists over the past three decades. Tsitsikammamines, wakayin, and several of their analogs show inhibition of topoisomerases. One additional possible mechanism of anticancer activity of tsitsikammamines analogs that has been discovered recently is through the inhibition of indoleamine 2, 3-dioxygenase, an enzyme involved in tumoral immune resistance. This review discusses the isolation, synthesis, and evaluation of bioactivities of bispyrroloquinone alkaloids and their analogs.

L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.

UNLABELLED: Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)-dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of-function mutations of isocitrate dehydrogenase (IDH1, IDH2) found in several different tumors. In contrast, kidney tumors demonstrate elevations of the l enantiomer of 2HG (l-2HG). High-2HG tumors demonstrate reduced DNA levels of 5-hydroxymethylcytosine (5hmC), consistent with 2HG-mediated inhibition of ten-eleven translocation (TET) enzymes, which convert 5-methylcytosine (5mC) to 5hmC. l-2HG elevation is mediated in part by reduced expression of l-2HG dehydrogenase (L2HGDH). L2HGDH reconstitution in RCC cells lowers l-2HG and promotes 5hmC accumulation. In addition, L2HGDH expression in RCC cells reduces histone methylation and suppresses in vitro tumor phenotypes. Our report identifies l-2HG as an epigenetic modifier and putative oncometabolite in kidney cancer. SIGNIFICANCE: Here, we report elevations of the putative oncometabolite l-2HG in the most common subtype of kidney cancer and describe a novel mechanism for the regulation of DNA 5hmC levels. Our findings provide new insight into the metabolic basis for the epigenetic landscape of renal cancer.

Synthesis of Pyrroloquinones via a CAN Mediated Oxidative Free Radical Reaction of 1,3-Dicarbonyl Compounds with Aminoquinones.

Pyrroloquinone ring systems are important structural units present in many biologically active molecules including a number of marine alkaloids. For example, they are found in a series of marine metabolites, such as tsitsikammamines, zyzzyanones, wakayin, and terreusinone. Several of these alkaloids have exhibited antimicrobial, antimalarial, antifungal, antitumor, and photoprotecting activities. Synthesis of pyrroloquinone unit is the key step in the synthesis of many of these important organic molecules. Here, we present a ceric (IV) ammonium nitrate (CAN) mediated oxidative free radical cyclization reaction of 1,3-dicarbonyl compounds with aminoquinones as a facile methodology for making various substituted pyrroloquinones. 1,3-dicarbonyl compounds used in this study are ethyl acetoacetate, acetylacetone, benzoyl acetone, and N,N-dimethyl acetoacetamide. The aminoquinones used in this study are 2-(benzylamino)naphthalene-1,4-dione and 6-(benzylamino)-1-tosyl-1H-indole-4,7-dione. The yields of the synthesized pyrroloquinones ranged from 23-91%.

Mini-review: bmx kinase inhibitors for cancer therapy.

Kinase inhibitors are among the fastest growing class of anti-cancer therapies. One family of kinases that has recently gained attention as a target for treating malignant disorders is the Tec kinase family. Evidence has been published that one member of this family; the Bmx kinase, may play a role in the pathogenesis of glioblastoma, prostate, breast and lung cancer. Bmx has also shown potential as an anti-vascular therapy in combination with radiation or as a sensitizer to chemotherapeutic agents. Therefore, several companies such as Pharmacyclics, Avila Therapeutics, Merck and Co., Metaproteomics, IRM, and Moerae Matrix have developed compounds or peptides that function as Bmx kinase inhibitors. These companies have subsequently been issued patents for these inhibitors. Additionally, it has been shown that current clinical stage EGFR inhibitors can irreversibly inhibit Bmx, suggesting these compounds might be rapidly moved to clinical trials for other malignancies. This review will discuss current patents issued since 2009 that contain data specifically on inhibition of the Bmx kinase, and will also discuss the scientific literature that suggests their potential application as therapeutics in the treatment of the aforementioned malignancies.