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Pharmaceuticals (Basel, Switzerland) Jun 2024Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt...
Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt strategies to survive a drop in extracellular pH (pHe). In the present manuscript, we investigated the contribution of mitochondrial sirtuin 3 (SIRT3) to the adaptation and survival of cancer cells to a low pHe. SIRT3-overexpressing and silenced breast cancer cells MDA-MB-231 and human embryonic kidney HEK293 cells were grown in buffered and unbuffered media at pH 7.4 and 6.8 for different times. mRNA expression of SIRT3 and CAVB, was measured by RT-PCR. Protein expression of SIRT3, CAVB and autophagy proteins was estimated by western blot. SIRT3-CAVB interaction was determined by immunoprecipitation and proximity ligation assays (PLA). Induction of autophagy was studied by western blot and TEM. SIRT3 overexpression increases the survival of both cell lines. Moreover, we demonstrated that SIRT3 controls intracellular pH (pHi) through the regulation of mitochondrial carbonic anhydrase VB (CAVB). Interestingly, we obtained similar results by using MC2791, a new SIRT3 activator. Our results point to the possibility of modulating SIRT3 to decrease the response and resistance of tumor cells to the acidic microenvironment and ameliorate the effectiveness of anticancer therapy.
PubMed: 38931477
DOI: 10.3390/ph17060810 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Due to its rapid resistance development and ability to form biofilms, treatment of infections is becoming more complicated by the day. Drug combinations may help reduce...
BACKGROUND
Due to its rapid resistance development and ability to form biofilms, treatment of infections is becoming more complicated by the day. Drug combinations may help reduce both resistance and biofilm formation.
METHODS
Using the microtiter plate assay, we investigated the in vitro inhibition of biofilm formation and the disruption of preformed biofilms in multidrug-resistant and extensively drug-resistant clinical isolates of in the presence of peak plasma levels of eight antipseudomonal antibiotics alone and in combination with fosfomycin: ceftazidime, piperacillin/tazobactam, cefepime, imipenem, gentamicin, amikacin, ciprofloxacin and colistin.
RESULTS
Combination therapy was significantly superior to monotherapy in its inhibition of biofilm formation. The highest inhibition rates were observed for combinations with colistin, cefepime and ceftazidime.
CONCLUSION
Our results support fosfomycin combination therapy as an enhanced prophylactic option. Moreover, combinations with β-lactam antibiotics and colistin demonstrated a more potent inhibition effect on biofilm formation than protein synthesis inhibitors.
PubMed: 38931436
DOI: 10.3390/ph17060769 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Antimicrobial resistance (AMR) is an increasingly concerning phenomenon that requires urgent attention because it poses a threat to human and animal health. Bacteria... (Review)
Review
Antimicrobial resistance (AMR) is an increasingly concerning phenomenon that requires urgent attention because it poses a threat to human and animal health. Bacteria undergo continuous evolution, acquiring novel resistance mechanisms in addition to their intrinsic ones. Multidrug-resistant and extensively drug-resistant bacterial strains are rapidly emerging, and it is expected that bacterial AMR will claim the lives of 10 million people annually by 2050. Consequently, the urgent need for the development of new therapeutic agents with new modes of action is evident. The antibacterial prodrug approach, a strategy that includes drug repurposing and derivatization, integration of nanotechnology, and exploration of natural products, is highlighted in this review. Thus, this publication aims at compiling the most pertinent research in the field, spanning from 2021 to 2023, offering the reader a comprehensive insight into the AMR phenomenon and new strategies to overcome it.
PubMed: 38931385
DOI: 10.3390/ph17060718 -
Pharmaceuticals (Basel, Switzerland) May 2024The aim of this review is to present the potential application of camphor-a bicyclic monoterpene ketone-in the prevention of skin infections. Skin diseases represent a... (Review)
Review
The aim of this review is to present the potential application of camphor-a bicyclic monoterpene ketone-in the prevention of skin infections. Skin diseases represent a heterogeneous group of disorders characterized by prolonged symptoms that significantly diminish the quality of life. They affect the dermis, the epidermis, and even subcutaneous tissue. They very often have a bacterial or fungal background. Therapy for dermatological skin disorders is difficult and long-term. Therefore, it is important to find a compound, preferably of natural origin, that (i) prevents the initiation of this infection and (ii) supports the skin's repair process. Based on its documented anti-inflammatory, antibacterial, antifungal, anti-acne, anesthetic, strengthening, and warming properties, camphor can be used as a preventative measure in dermatological infectious diseases and as a component in medical and cosmetic products. This work discusses the structure and physicochemical properties of camphor, its occurrence, and methods of obtaining it from natural sources as well as through chemical synthesis. The use of camphor in industrial preparations is also presented. Additionally, after a detailed review of the literature, the metabolism of camphor, its interactions with other medicinal substances, and its antimicrobial properties against bacteria and fungi involved in skin diseases are discussed with regard to their resistance.
PubMed: 38931382
DOI: 10.3390/ph17060715 -
Pharmaceuticals (Basel, Switzerland) May 2024Diabetes mellitus is a heterogeneous metabolic disorder that poses significant health and economic challenges across the globe. Polysaccharides, found abundantly in...
Diabetes mellitus is a heterogeneous metabolic disorder that poses significant health and economic challenges across the globe. Polysaccharides, found abundantly in edible plants, hold promise for managing diabetes by reducing blood glucose levels (BGL) and insulin resistance. However, most of these polysaccharides cannot be digested or absorbed directly by the human body. Here we report the production of antidiabetic oligosaccharides from cress seed mucilage polysaccharides using yeast fermentation. The water-soluble polysaccharides extracted from cress seed mucilage were precipitated using 75% ethanol and fermented with for different time intervals. The digested saccharides were fractionated through gel permeation chromatography using a Bio Gel P-10 column. Structural analysis of the oligosaccharide fractions revealed the presence of galacturonic acid, rhamnose, glucuronic acid, glucose and arabinose. Oligosaccharide fractions exhibited the potential to inhibit α-amylase and α-glucosidase enzymes in a dose-dependent manner in vitro. The fraction DF73 exhibited strong inhibitory activity against α-amylase with IC values of 38.2 ± 1.12 µg/mL, compared to the positive control, acarbose, having an IC value of 29.18 ± 1.76 µg/mL. Similarly, DF72 and DF73 showed the highest inhibition of α-glucosidase, with IC values of 9.26 ± 2.68 and 50.47 ± 5.18 µg/mL, respectively. In in vivo assays in streptozotocin (STZ)-induced diabetic mice, these oligosaccharides significantly reduced BGL and improved lipid profiles compared to the reference drug metformin. Histopathological observations of mouse livers indicated the cytoprotective effects of these sugars. Taken together, our results suggest that oligosaccharides produced through microbial digestion of polysaccharides extracted from cress seed mucilage have the potential to reduce blood glucose levels, possibly through inhibition of carbohydrate-digesting enzymes and regulation of the various signaling pathways.
PubMed: 38931372
DOI: 10.3390/ph17060704 -
Pharmaceuticals (Basel, Switzerland) May 2024Carbapenem antibiotic resistance is an emerging medical concern. Bacteria that possess the carbapenemase (KPC) protein, an enzyme that catalyzes the degradation of...
Carbapenem antibiotic resistance is an emerging medical concern. Bacteria that possess the carbapenemase (KPC) protein, an enzyme that catalyzes the degradation of carbapenem antibiotics, have exhibited remarkable resistance to traditional and even modern therapeutic approaches. This study aimed to identify potential natural drug candidates sourced from the leaves of (). The phytoconstituents present in dried leaves were extracted using ethanol 80%. A reasonable amount of the extract was used to identify these phytochemicals via gas chromatography/mass spectrometry (GC/MS). One hundred twenty-two bioactive compounds from were identified and subjected to docking analysis against the target bacterial protein. Four compounds (PubChem CID: 6917974, 159099, 628694, and 482788) were selected based on favorable docking scores (-9, -7.8, -7.7, and -7.5 kcal/mol). This computational investigation highlights the potential of these four compounds as promising antibacterial candidates against the specific PC protein. Additionally, in vitro antibacterial assays using extracts were conducted. The minimum inhibitory concentration (MIC) against the bacterium was 125 μg/mL. Well-disk diffusion tests exhibited inhibition zones ranging from 10.3 ± 0.5 mm to 17 ± 0.5 mm at different concentrations, and time-kill kinetics at 12 h indicated effective inhibition of bacterial growth by leaf extracts. Our findings have revealed the pharmaceutical potential of as a natural source for drug candidates against carbapenem-resistant pathogens.
PubMed: 38931335
DOI: 10.3390/ph17060667 -
Nutrients Jun 2024Branched-chain amino acids (BCAAs), comprising leucine (Leu), isoleucine (Ile), and valine (Val), are essential nutrients vital for protein synthesis and metabolic... (Review)
Review
Branched-chain amino acids (BCAAs), comprising leucine (Leu), isoleucine (Ile), and valine (Val), are essential nutrients vital for protein synthesis and metabolic regulation via specialized signaling networks. Their association with cardiovascular diseases (CVDs) has become a focal point of scientific debate, with emerging evidence suggesting both beneficial and detrimental roles. This review aims to dissect the multifaceted relationship between BCAAs and cardiovascular health, exploring the molecular mechanisms and clinical implications. Elevated BCAA levels have also been linked to insulin resistance (IR), type 2 diabetes mellitus (T2DM), inflammation, and dyslipidemia, which are well-established risk factors for CVD. Central to these processes are key pathways such as mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-light-chain-enhancer of activate B cells (NF-κB)-mediated inflammation, and oxidative stress. Additionally, the interplay between BCAA metabolism and gut microbiota, particularly the production of metabolites like trimethylamine-N-oxide (TMAO), adds another layer of complexity. Contrarily, some studies propose that BCAAs may have cardioprotective effects under certain conditions, contributing to muscle maintenance and metabolic health. This review critically evaluates the evidence, addressing the biological basis and signal transduction mechanism, and also discusses the potential for BCAAs to act as biomarkers versus active mediators of cardiovascular pathology. By presenting a balanced analysis, this review seeks to clarify the contentious roles of BCAAs in CVD, providing a foundation for future research and therapeutic strategies required because of the rising prevalence, incidence, and total burden of CVDs.
Topics: Humans; Amino Acids, Branched-Chain; Cardiovascular Diseases; Biomarkers; Gastrointestinal Microbiome; Insulin Resistance; Signal Transduction; Diabetes Mellitus, Type 2; Chronic Disease; Inflammation; Oxidative Stress; TOR Serine-Threonine Kinases; Methylamines
PubMed: 38931325
DOI: 10.3390/nu16121972 -
Nutrients Jun 2024Obesity is increasingly prevalent worldwide and is linked to metabolic diseases, such as insulin resistance (IR) and type 2 diabetes mellitus (T2DM), due to excessive...
Obesity is increasingly prevalent worldwide and is linked to metabolic diseases, such as insulin resistance (IR) and type 2 diabetes mellitus (T2DM), due to excessive free fatty acids (FFAs). Although lifestyle changes are effective, they often prove to be insufficient as initial treatments for obesity. Additionally, while surgical and pharmacological interventions are available, they are not entirely safe or effective. Recently, interest has grown in utilizing food waste and plant-derived phenolic compounds for their health benefits, presenting a promising avenue for managing obesity and its related disorders. Indeed, many studies have examined the potential inhibitory effects of the natural extract on adipocyte differentiation and lipid accumulation. This study focused on the evaluation of the effects of standardized extracts obtained from red oranges and olive leaf waste on 3T3-L1 murine pre-adipocyte and adipocyte functionality. Red orange extract (ROE) and olive leaf extract (OLE), alone and in combination, were tested to assess their anti-obesity and anti-inflammatory effects, as well as their potential therapeutic benefits. Three in vitro models were established to investigate the effects of the extracts on (I) adipocyte differentiation; (II) mature and hypertrophic adipocytes challenged with palmitic acid (PA) and erastin (ER), respectively; and (III) erastin-induced cytotoxicity on pre-adipocytes.
Topics: Animals; Olea; Adipocytes; Plant Extracts; Mice; 3T3-L1 Cells; Plant Leaves; Cell Differentiation; Anti-Obesity Agents; Adipogenesis; Obesity
PubMed: 38931313
DOI: 10.3390/nu16121959 -
Nutrients Jun 2024Sarcopenia is an age-related condition characterized by progressive loss of muscle mass, strength, and function. The occurrence of sarcopenia has a huge impact on...
BACKGROUND
Sarcopenia is an age-related condition characterized by progressive loss of muscle mass, strength, and function. The occurrence of sarcopenia has a huge impact on physical, psychological, and social health. Therefore, the prevention and treatment of sarcopenia is becoming an important public health issue.
METHOD
35 six-week-old male C57BL/6 mice were randomly divided into five groups, one of which served as a control group, while the rest of the groups were constructed as a model of sarcopenia by intraperitoneal injection of D-galactose. The intervention with lactoferrin, creatine, and their mixtures, respectively, was carried out through gavage for 8 weeks. Muscle function was assessed based on their endurance, hanging time, and grip strength. The muscle tissues were weighed to assess the changes in mass, and the muscle RNA was extracted for myogenic factor expression and transcriptome sequencing to speculate on the potential mechanism of action by GO and KEGG enrichment analysis.
RESULT
The muscle mass (lean mass, GAS index), and muscle function (endurance, hanging time, and grip strength) decreased, and the size and structure of myofiber was smaller in the model group compared to the control group. The intervention with lactoferrin and creatine, either alone or combination, improved muscle mass and function, restored muscle tissue, and increased the expression of myogenic regulators. The combined group demonstrated the most significant improvement in these indexes. The RNA-seq results revealed enrichment in the longevity-regulated pathway, MAPK pathway, focal adhesion, and ECM-receptor interaction pathway in the intervention group. The intervention group may influence muscle function by affecting the proliferation, differentiation, senescence of skeletal muscle cell, and contraction of muscle fiber. The combined group also enriched the mTOR-S6K/4E-BPs signaling pathway, PI3K-Akt signaling pathway, and energy metabolism-related pathways, including Apelin signaling, insulin resistance pathway, and adipocytokine signaling pathway, which affect energy metabolism in muscle.
CONCLUSIONS
Lactoferrin and creatine, either alone or in combination, were found to inhibit the progression of sarcopenia by influencing the number and cross-sectional area of muscle fibers and muscle protein synthesis. The combined intervention appears to exert a more significant effect on energy metabolism.
Topics: Animals; Lactoferrin; Male; Sarcopenia; Mice, Inbred C57BL; Creatine; Disease Models, Animal; Muscle, Skeletal; Mice; Muscle Strength; Signal Transduction
PubMed: 38931310
DOI: 10.3390/nu16121958 -
Nutrients Jun 2024Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet...
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age. Many women with PCOS have been found to have an unbalanced diet and deficiencies in essential nutrients. This study aimed to assess the levels of folate and vitamin B12 (B12) and their relationship with metabolic factors in women with PCOS. Anthropometric, clinical, and genetic analyses were conducted to evaluate markers related to one-carbon metabolism in women with PCOS and in a control group. The PCOS group had a higher BMI and HOMA-IR (1.7 vs. 3.1; < 0.0001). HDL cholesterol levels were 23% lower and triglyceride levels were 74% higher in women with PCOS. Although there were no significant differences in folate and B12 levels between the PCOS and control groups, over 60% of women with PCOS had low B12 levels (<300 pg/mL) and high homocysteine levels. In addition, the MTHFR A1298C and C677T polymorphisms were not associated with PCOS. Moreover, erythrocyte folate levels were positively correlated with fasting glucose, triglycerides, and free androgen index, and negatively correlated with SHBG and LH levels. These results suggest that B vitamins may be associated with the metabolic phenotype in PCOS. This study emphasizes the potential link between folate, vitamin B12, and metabolic and hormonal outcomes in women with PCOS.
Topics: Humans; Female; Polycystic Ovary Syndrome; Vitamin B 12; Folic Acid; Adult; Chile; Young Adult; Triglycerides; Homocysteine; Body Mass Index; Blood Glucose; Methylenetetrahydrofolate Reductase (NADPH2); Insulin Resistance; Cholesterol, HDL; Case-Control Studies; Biomarkers
PubMed: 38931291
DOI: 10.3390/nu16121937