Cell cycle machinery in oncology: A comprehensive review of therapeutic targets.

The cell cycle is tightly regulated to ensure controlled cell proliferation. Dysregulation of the cell cycle machinery is a hallmark of cancer that leads to unchecked growth. This review comprehensively analyzes key molecular regulators of the cell cycle and how they contribute to carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, and mitotic regulators as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib for breast cancer treatment. Other possible targets include the anaphase-promoting complex/cyclosome (APC/C), Skp2, p21, and aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus on combinatorial therapies, next-generation inhibitors, and biomarkers for patient selection. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti-cancer strategy across diverse malignancies.

Hedgehog signaling mastery: R51211's promise in augmenting the therapeutic efficacy of sorafenib.

Sorafenib is a multikinase inhibitor employed for managing hepatocellular carcinoma (HCC). The emergence of sorafenib resistance presents an obstacle to its therapeutic efficacy. One notable approach to overcoming sorafenib resistance is the exploration of combination therapies. The role of hedgehog signaling in sorafenib resistance has been also examined in HCC. R51211, known as itraconazole, has been safely employed in clinical practice. Through in vitro and in vivo investigations, we assessed the potential of R51211 to enhance the therapeutic efficacy of sorafenib by inhibiting the hedgehog signaling. The zero-interaction potency synergy model demonstrated a synergistic interaction between R51211 and sorafenib, a phenomenon reversed by the action of a smoothened receptor agonist. This dual therapy exhibited an increased capacity to induce apoptosis, as evidenced by alterations in the Bax/BCL-2 ratio and caspase-3, along with a propensity to promote autophagy, as indicated by changes in BECN1, p62, and the LC3I/LC3II ratio. Furthermore, the combination therapy resulted in significant reductions in biomarkers associated with liver preneoplastic alterations, improved liver microstructure, and mitigated changes in liver function enzymes. The substantial decrease in hedgehog components (Shh, SMO, GLI1, and GLI2) following R51211 treatment appears to be a key factor contributing to the increased efficacy of sorafenib. In conclusion, our study highlights the potential of R51211 as an adjunct to sorafenib, introducing a new dimension to this combination therapy through the modulation of the hedgehog signaling pathway. Further investigations are essential to validate the therapeutic efficacy of this combined approach in inhibiting the development of liver cancer.

Phytoactive Molecules and Nanodelivery Approaches for Breast Cancer Treatment: Current and Future Perspectives.

One of the most common malignancies in women, breast cancer accounts for nearly 25% of all cancer cases. Breast cancer is a diverse cancer form that exhibits variability in both morphology and molecular characteristics, and is linked to numerous risk factors. Although various approaches and research are ongoing in the treatment and prevention of breast cancer, medication resistance in the current breast cancer treatment contributes to the disease's relapse and recurrence. Phytoactive molecules are the subject of growing research in both breast cancer prevention and treatment but currently used conventional medicines and techniques limit their application. Recent years have seen significant advancements in the field of nanotechnology, which has proven to be essential in the fight against drug resistance. The transport of synthetic and natural anticancer molecules via nanocarriers has recently been added to breast cancer therapy, greatly alleviating the constraints of the current approach. In light of these developments, interest in nano-delivery studies of phytoactive molecules has also increased. In this review, research of phytoactive molecules for breast cancers along with their clinical studies and nanoformulations, was presented from current and future perspectives.

Orexins in apoptosis: a dual regulatory role.

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis.

Comparing Metabolic Preconditioning and Diabetes As Risk Factors in Knee Arthroplasty Complications.

BACKGROUND AND OBJECTIVES: Advanced osteoarthritis of the knee joint severely affects the patient's mobility, compounded by pre-existing comorbidities such as metabolic preconditioning (such as obesity, dyslipidemia, hyperuricemia, and insulin resistance syndrome) and both type I and type II diabetes. The success of total knee arthroplasty is influenced by knowledge and management of risk factors. The present study aims to evaluate differences in the evolution of risk factors such as obesity, injuries, and sedentary lifestyle, distinguishing those with metabolic preconditions and diabetes. The objectives of our study include (1) investigating the prevalence of obesity among patients, highlighting their proportion in the five categories of body weight; (2) analyzing statistically significant differences between research groups in terms of weight status and physical activity; (3) evaluating postoperative evolution based on the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and without NSAIDs (N-NSAIDs), with an emphasis on overweight patients and those with diabetes; and (4) examining changes in metabolic preconditioning and the incidence of postoperative injury depending on the administration of anti-inflammatory drugs. MATERIALS AND METHODS:  A cohort involving 730 patients diagnosed with gonarthrosis was divided into two groups according to the administration of anti-inflammatory drugs in the first seven postoperative days: N-NSAIDs group (394 patients, 55.3%) and respectively NSAIDs group (319 patients, 44.7%). The prospective, observational study was conducted in terms of risk factors and complications that occurred upon treatment administration in relation to each type of intervention and implant used. The outcomes were assessed in terms of the influence on quality of life, the data being collected and interpreted for the entire cohort, and for each study year individually. RESULTS: The results indicate that almost 69% of them were overweight, while only 31% had a normal weight. Significant differences in weight status were observed between research groups, highlighting the association between obesity and metabolic preconditions or diabetes. Physical activity was absent in a significant proportion, having a notable impact on postoperative evolution, especially in the group without metabolic precondition. Administration of anti-inflammatory drugs influenced postoperative outcomes, with significant differences in overweight and diabetic patients. CONCLUSIONS: The findings suggest the need to manage body weight, promote physical activity, and personalize postoperative treatments, given the complex interactions between obesity, metabolic preconditions, and the administration of NSAIDs.

Nanodelivery Approaches of Phytoactives for Skin Cancers: Current and Future Perspectives.

In recent years, there has been an increase in skin cancers due to external factors, especially environmental factors, and studies on treatment alternatives have gained importance. Nanomaterials are common, from sunscreen formulas to formulations designed to treat skin cancers at various stages. Using bioactives has multiple effects in treating skin cancers, which provides many advantages. In this regard, many phytochemicals gain importance with their antioxidant, anti-proliferative, anti-inflammatory, antiangiogenic, and analgesic effects. Their delivery with nanocarriers is on the agenda for phytochemicals to gain the targeted stability, effectiveness, and toxicity/safety properties. This review presents types of skin cancers, phytochemicals effective in skin cancers, and their nanocarrier-loaded studies from an up-to-date perspective.

Histopathology Features of H. pylori Gastritis Associated With Altered Lipid Profile: An Observational Study from a Tertiary Healthcare Center in North West Romania.

BACKGROUND/AIM: H. pylori infection can promote a systemic inflammatory syndrome, eventually leading to intestinal metaplasia and gastric cancer. The aim of our study was to investigate the possible association between dyslipidemia and histopathological features of H. pylori gastritis. PATIENTS AND METHODS: An observational, retrospective study was conducted over the period 2017-2022 on symptomatic patients with a positive rapid urease test. A total of 121 patients who underwent upper gastrointestinal endoscopy with stomach biopsy were enrolled in this study. Based on the updated Sydney System, we investigated the association between neutrophils, mononuclear cells, intestinal metaplasia, or gastric atrophy and altered lipid profiles. RESULTS: A high prevalence of H. pylori infection was noticed in the studied group upon the application of the rapid urease test, being associated with dyslipidemia regardless of patient sex. All the endoscopic diagnoses (acute, chronic, or atrophic chronic gastritis, metaplasia) correlated with the histopathological features. Mononuclear cells and metaplasia were more likely to be found in H. pylori-positive patients with dyslipidemia, which is consistent with acute and chronic inflammation caused by H. pylori in the gastric mucosa. CONCLUSION: Although our study was conducted on a small scale, it offers new insights and details regarding H. pylori infection and histopathological features. Mononuclear cells and metaplasia were associated with an altered lipid profile in H. pylori-positive patients. These findings warrant future investigation, such as the evolution of gastric biopsies and lipid profiles before and after eradication.

Revolutionizing Treatment Strategies for Autoimmune and Inflammatory Disorders: The Impact of Dipeptidyl-Peptidase 4 Inhibitors.

DPP4 (Dipeptidyl-peptidase 4) a versatile protease, emerges as a prominent player in soluble and membrane-bound forms. Its heightened expression has been intimately linked to the initiation and severity of diverse autoimmune diseases, spanning rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (SSc), inflammatory bowel disease, autoimmune diabetes, and even SARS-CoV-2 infection. Operating as a co-stimulator of T cell activity, DPP4 propels T cell proliferation by binding adenosine deaminase (ADA), thereby augmenting the breakdown of adenosine-an influential inhibitor of T cell proliferation. However, the discovery of a wide range of DPP4 inhibitors has shown promise in alleviating these diseases' signs, symptoms, and severity. The available DPP4 inhibitors have demonstrated significant effectiveness in blocking DPP4 activity. Based on the characterization of their binding mechanisms, three distinct groups of DPP4 inhibitors have been identified: saxagliptin, alogliptin, and sitagliptin, each representing a different class. Elevated levels of angiotensin-converting enzyme 2 (ACE2) expression are associated with producing various coronavirus peptidases. With its anti-inflammatory properties, Sitagliptin may assist COVID-19 patients in preventing and managing cytokine storms. This comprehensive review delves into the burgeoning realm of DPP4 inhibitors as therapeutic interventions for diverse autoimmune diseases. With a discerning focus on their efficacy, the investigation sheds light on their remarkable capacity to alleviate the burdensome signs and symptoms intricately linked to these conditions.

Mapping the Spatial Evolution of Proximal Femur Osteoporosis: A Retrospective Cross-Sectional Study Based on CT Scans.

Purpose: The purpose of this study was to quantify the modifications occurring in osteoporosis at the level of the human proximal femur throughout the trabecular structure, along with the identification of certain anatomic regions preferentially affected by osteoporosis. Another goal was to map the evolution of the radiodensity of the trabecular bone as osteoporosis progresses to an advanced stage. Methods: The study included CT scans (right femur) from 51 patients, out of which 40 had various degrees of osteoporosis, but no other local pathology. Ten regions of interest in two orthogonal slices have been identified and the differences in radiodensity as well as their evolution have been statistically analyzed in terms of relative and absolute changes. Results: A detailed spatial map showing the evolution of osteoporosis was obtained. As osteoporosis evolved, the relative decrease in radiodensity was inversely correlated to the radiodensity of the healthy bone. In particular, the region covering the Ward triangle decreased the most, by an average 61-62% in osteopenia and 101-106% in advanced osteoporosis, while the principal compressive group was affected the least, showing a decrease by an average 14-15% in osteopenia and 29-32% in advanced osteoporosis. The absolute decrease in radiodensity was not correlated to the radiodensity of the healthy bone and was shifted to the inferior-posterior edge of the femur. Inside the femoral head, the upper region was affected the most in absolute terms, while the greater trochanter was less affected than the femoral neck. The maximum metaphyseal cortical bone density was unaffected by the progression of osteoporosis. Conclusion: Significant differences were noticed in terms of the absolute and relative osteoporotic changes in radiodensity related to different anatomical regions of the human femoral bone. These differences become more pronounced as the disease progresses.

Relevant Predictors in the Association Between Patients' Functional Status and Scar Outcomes After Total Hip Arthroplasty.

BACKGROUND: We aimed to investigate the relevant predictors in the association between the functional status and the consequences of the persistence of scars in patients with traumatic versus non-traumatic coxarthrosis after total hip arthroplasty (THA). METHODS: A total of 203 patients undergoing THA after traumatic or non-traumatic coxarthrosis were asked to complete the Mekeres' Psychosocial Internalization Scale (MPIS), in which they self-evaluated on a Likert scale (between one and five) by selecting the rating that corresponded to their personal opinion and the activities of daily living (ADL) form at six months postoperative. The statistical data were processed using the IBM SPSS Statistics software version 22.0 (IBM Corp., Armonk, NY). A combined assessment of the internalization of scars using MPIS and ADL forms after THA allowed for the identification of relevant predictors of the quality of life six months post-surgery in patients with traumatic or non-traumatic coxarthrosis. RESULTS: Depending on the coxarthrosis etiology (traumatic or non-traumatic), the results were further processed by a univariate ANOVA, considering the independent variables represented by symptoms, the number of surgical procedures, and the postoperative evolution, which are acting on the outcomes of physical functioning (the dependent variable) in the postoperative phase. In the case of the traumatic group, our results suggest that the number of surgical interventions, the ability to internalize scars, and autonomy in terms of body care are predictors of the quality of life. In patients with non-traumatic coxarthrosis, an important role in predicting quality of life is played by the administered treatment and the ability to maintain their autonomy regarding self-hygiene six months post-surgery. CONCLUSIONS: The predictive regression equation suggests that the quality of life in patients with traumatic coxarthrosis can be predicted by the number of surgical interventions, the administered treatment, the ability to internalize scars, and the autonomy regarding body care activities. On the other hand, for patients with non-traumatic coxarthrosis, an important role in predicting the quality of life is played by the treatment and the ability to maintain autonomy in terms of body hygiene activities.

Regulatory and pathogenic mechanisms in response to iron deficiency and excess in fungi.

Iron is an essential element for all eukaryote organisms because of its redox properties, which are important for many biological processes such as DNA synthesis, mitochondrial respiration, oxygen transport, lipid, and carbon metabolism. For this reason, living organisms have developed different strategies and mechanisms to optimally regulate iron acquisition, transport, storage, and uptake in different environmental responses. Moreover, iron plays an essential role during microbial infections. Saccharomyces cerevisiae has been of key importance for decrypting iron homeostasis and regulation mechanisms in eukaryotes. Specifically, the transcription factors Aft1/Aft2 and Yap5 regulate the expression of genes to control iron metabolism in response to its deficiency or excess, adapting to the cell's iron requirements and its availability in the environment. We also review which iron-related virulence factors have the most common fungal human pathogens (Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicans). These factors are essential for adaptation in different host niches during pathogenesis, including different fungal-specific iron-uptake mechanisms. While being necessary for virulence, they provide hope for developing novel antifungal treatments, which are currently scarce and usually toxic for patients. In this review, we provide a compilation of the current knowledge about the metabolic response to iron deficiency and excess in fungi.

Designing New Sport Supplements Based on Aronia melanocarpa and Bee Pollen to Enhance Antioxidant Capacity and Nutritional Value.

With a high number of athletes using sport supplements targeting different results, the need for complex, natural and effective formulations represents an actual reality, while nutrition dosing regimens aiming to sustain the health and performance of athletes are always challenging. In this context, the main goal of this study was to elaborate a novel and complex nutraceutical supplement based on multiple bioactive compounds extracted from Aronia melanocarpa and bee pollen, aiming to support physiological adaptations and to minimize the stress generated by intense physical activity in the case of professional or amateur athletes. Our proposed formulations are based on different combinations of Aronia and bee pollen (A1:P1, A1:P2 and A2:P1), offering personalized supplements designed to fulfill the individual requirements of different categories of athletes. The approximate composition, fatty acid profile, identification and quantification of individual polyphenols, along with the antioxidant capacity of raw biological materials and different formulations, was performed using spectrophotometric methods, GS-MS and HPLC-DAD-MS-ESI+. In terms of antioxidant capacity, our formulations based on different ratios of bee pollen and Aronia were able to act as complex and powerful antioxidant products, highlighted by the synergic or additional effect of the combinations. Overall, the most powerful synergism was obtained for the A1:P2 formulation.

Diabetes Mellitus Secondary to Endocrine Diseases: An Update of Diagnostic and Treatment Particularities.

Secondary diabetes mellitus is frequently ignored in specialized literature. In this narrative review, the main endocrinopathies accompanied by increased glycemic values are identified, as well as the mechanisms by which the excess or deficiency of certain hormones impact beta cell function or insulin resistance. The main endocrinopathies (acromegaly, Cushing's syndrome, Basedow-Graves' disease, pheochromocytoma, somatostatinoma and glucagonoma) and their characteristics are described along with the impact of hormone changes on blood sugar, body mass index and other parameters associated with diabetes. The overall information regarding the complex molecular mechanisms that cause the risk of secondary diabetes and metabolic syndrome is of crucial importance in order to prevent the development of the disease and its complications and particularly to reduce the cardiovascular risk of these patients. The purpose of this study is to highlight the particular features of endocrine pathologies accompanied by an increased risk of developing diabetes, in the context of personalized therapeutic decision making. The epidemiological, physiopathological, clinical and therapeutic approaches are presented along with the importance of screening for diabetes in endocrine diseases.

Highlighting the Advantages and Benefits of Non-NSAID Treatment After Total Knee Arthroplasty: A Cross-sectional Study.

BACKGROUND/AIM: Osteoarthritis is one of the most common degenerative conditions that causes pain, stiffness, and decreased functionality. The management of knee osteoarthritis necessitates collaboration among specialists from different disciplines, considering the primary clinical manifestations and functional level of the disease. The aim of this study was to highlight the disparities in postoperative outcomes between knee arthroplasty procedures with and without non-steroidal anti-inflammatory drugs (NSAIDs). The study specifically focuses on the immediate advantages and outcomes observed at the 6-month milestone. PATIENTS AND METHODS: This study followed 713 patients who were randomly divided into two groups: a group that did not receive non-steroidal anti-inflammatory drugs (N-NSAIDs) consisting of 394 patients, and a group that received non-steroidal anti-inflammatory drugs (NSAIDs) comprising 319 patients. The study spanned a duration of 5 years (2018-2022), with patients being followed and evaluated for up to 6 months after the surgery. RESULTS: It was observed that, from a therapeutic standpoint, the use of injectable treatments decreased. Significantly better differences were recorded in the N-NSAIDs group regarding return to pre-osteoarthritis activities at 6 months and reduced or absent night pain at 3 months (p<0.05). CONCLUSION: Statistically significant improvements were observed in the N-NSAIDs group concerning the ability to resume pre-osteoarthritis activities within 6 months, as well as a reduction or absence of nighttime pain within 3 months.

Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials.

Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.

An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors.

The world's health system is plagued by cancer and a worldwide effort is underway to find new drugs to treat cancer. There has been a significant improvement in understanding the pathogenesis of cancer, but it remains one of the leading causes of death. The imperative 1,3,4-oxadiazole scaffold possesses a wide variety of biological activities, particularly for cancer treatment. In the development of novel 1,3,4-oxadiazole-based drugs, structural modifications are important to ensure high cytotoxicity towards malignant cells. These structural modification strategies have shown promising results when combined with outstanding oxadiazole scaffolds, which selectively interact with nucleic acids, enzymes, and globular proteins. A variety of mechanisms, such as the inhibition of growth factors, enzymes, and kinases, contribute to their antiproliferative effects. The activity of different 1,3,4-oxadiazole conjugates were tested on the different cell lines of different types of cancer. It is demonstrated that 1,3,4-oxadiazole hybridization with other anticancer pharmacophores have different mechanisms of action by targeting various enzymes (thymidylate synthase, HDAC, topoisomerase II, telomerase, thymidine phosphorylase) and many of the proteins that contribute to cancer cell proliferation. The focus of this review is to highlight the anticancer potential, molecular docking, and SAR studies of 1,3,4-oxadiazole derivatives by inhibiting specific cancer biological targets, such as inhibiting telomerase activity, HDAC, thymidylate synthase, and the thymidine phosphorylase enzyme. The purpose of this review is to summarize recent developments and discoveries in the field of anticancer drugs using 1,3,4-oxadiazoles.

Interleukins (Cytokines) as Biomarkers in Colorectal Cancer: Progression, Detection, and Monitoring.

Cancer is the primary cause of death in economically developed countries and the second leading cause in developing countries. Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Risk factors for CRC include obesity, a diet low in fruits and vegetables, physical inactivity, and smoking. CRC has a poor prognosis, and there is a critical need for new diagnostic and prognostic biomarkers to reduce related deaths. Recently, studies have focused more on molecular testing to guide targeted treatments for CRC patients. The most crucial feature of activated immune cells is the production and release of growth factors and cytokines that modulate the inflammatory conditions in tumor tissues. The cytokine network is valuable for the prognosis and pathogenesis of colorectal cancer as they can aid in the cost-effective and non-invasive detection of cancer. A large number of interleukins (IL) released by the immune system at various stages of CRC can act as "biomarkers". They play diverse functions in colorectal cancer, and include IL-4, IL-6, IL-8, IL-11, IL-17A, IL-22, IL-23, IL-33, TNF, TGF-ß, and vascular endothelial growth factor (VEGF), which are pro-tumorigenic genes. However, there are an inadequate number of studies in this area considering its correlation with cytokine profiles that are clinically useful in diagnosing cancer. A better understanding of cytokine levels to establish diagnostic pathways entails an understanding of cytokine interactions and the regulation of their various biochemical signaling pathways in healthy individuals. This review provides a comprehensive summary of some interleukins as immunological biomarkers of CRC.

Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach.

Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its long-term effectiveness is limited by the emergence of resistance mechanisms. One such mechanism is the reduction of microvessel density and intratumoral hypoxia caused by prolonged sorafenib treatment. Our research has demonstrated that HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic conditions and N-Nitrosodiethylamine-exposed mice as well. This occurs through the inhibition of necroptosis on the one hand and the stabilization of HIF-1α on the other hand. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We found that ganetespib activated necroptosis and destabilized HIF-1α under hypoxia, thus enhancing the effectiveness of sorafenib. Additionally, we discovered that LAMP2 aids in the degradation of MLKL, which is the mediator of necroptosis, through the chaperone-mediated autophagy pathway. Interestingly, we observed a significant negative correlation between LAMP2 and MLKL. These effects resulted in a reduction in the number of surface nodules and liver index, indicating a regression in tumor production rates in mice with HCC. Furthermore, AFP levels decreased. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. These findings suggest that the combined therapy of ganetespib and sorafenib may offer a promising approach for the treatment of hepatocellular carcinoma by activating necroptosis, inhibiting macroautophagy, and exhibiting a potential antiangiogenic effect. Overall, continued research is critical to establish the full therapeutic potential of this combination therapy.

Molecular Understanding of ACE-2 and HLA-Conferred Differential Susceptibility to COVID-19: Host-Directed Insights Opening New Windows in COVID-19 Therapeutics.

The genetic variants of HLAs (human leukocyte antigens) play a crucial role in the virus-host interaction and pathology of COVID-19. The genetic variants of HLAs not only influence T cell immune responses but also B cell immune responses by presenting a variety of peptide fragments of invading pathogens. Peptide cocktail vaccines produced by using various conserved HLA-A2 epitopes provoke substantial specific CD8+ T cell responses in experimental animals. The HLA profiles vary among individuals and trigger different T cell-mediated immune responses in COVID-19 infections. Those with HLA-C*01 and HLA-B*44 are highly susceptible to the disease. However, HLA-A*02:01, HLA-DR*03:01, and HLA-Cw*15:02 alleles show resistance to SARS infection. Understanding the genetic association of HLA with COVID-19 susceptibility and severity is important because it can help in studying the transmission of COVID-19 and its physiopathogenesis. The HLA-C*01 and B*44 allele pathways can be studied to gain insight into disease transmission and physiopathogenesis. Therefore, integrating HLA testing is suggested in the ongoing pandemic, which will help in the rapid identification of highly susceptible populations worldwide and possibly acclimate vaccine development. Therefore, understanding the correlation between HLA and SARS-CoV-2 is critical in opening new insights into COVID-19 therapeutics, based on previous studies conducted.

Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control.

The number of diabetic patients has risen dramatically in recent decades, owing mostly to the rising incidence of type 2 diabetes mellitus (T2DM). Several oral antidiabetic medications are used for the treatment of T2DM including, α-glucosidases inhibitors, biguanides, sulfonylureas, meglitinides, GLP-1 receptor agonists, PPAR-γ agonists, DDP4 inhibitors, and SGLT2 inhibitors. In this review we focus on the possible effects of SGLT2 inhibitors on different body systems. Beyond the diabetic state, SGLT2 inhibitors have revealed a demonstrable ability to ameliorate cardiac remodeling, enhance myocardial function, and lower heart failure mortality. Additionally, SGLT2 inhibitors can modify adipocytes and their production of cytokines, such as adipokines and adiponectin, which enhances insulin sensitivity and delays diabetes onset. On the other hand, SGLT2 inhibitors have been linked to decreased total hip bone mineral deposition and increased hip bone resorption in T2DM patients. More data are needed to evaluate the role of SGLT2 inhibitors on cancer. Finally, the effects of SGLT2 inhibitors on neuroprotection appear to be both direct and indirect, according to scientific investigations utilizing various experimental models. SGLT2 inhibitors improve vascular tone, elasticity, and contractility by reducing oxidative stress, inflammation, insulin signaling pathways, and endothelial cell proliferation. They also improve brain function, synaptic plasticity, acetylcholinesterase activity, and reduce amyloid plaque formation, as well as regulation of the mTOR pathway in the brain, which reduces brain damage and cognitive decline.