Renal protective potential of pentoxifylline, chlorpromazine, and lovastatin in ischemia-reperfusion injury: An experimental study.

This study aimed to evaluate the ability of pentoxifylline when compared to lovastatin and chlorpromazine as nephroprotective substances in cases of renal ischemia and reperfusion syndrome (IRI). A total of 36 adult male animals were randomly allocated into four groups (untreated control group, pentoxifylline group, lovastatin group, and chlorpromazine group), each consisting of nine animals. All groups were submitted to experimental ischemia and reperfusion procedures. The animals were evaluated 24, 72 and 120 hours after IRI, including physical examinations, serum urea and creatinine measurements, as well as histopathological, morphometric, and stereological analyses of the renal tissue. Results indicated that 24 hours after IRI, only chlorpromazine was effective in controlling azotemia. At the 72-hour mark, both chlorpromazine and pentoxifylline exhibited efficacy. After 120 hours, all three substances demonstrated renal protective qualities. Pentoxifylline was the most effective in preserving the structural integrity of kidney tissue, followed by chlorpromazine. In conclusion, all three treatments (pentoxifylline, chlorpromazine, and lovastatin) were effective. Pentoxifylline proved to be promising in the response against acute tubular necrosis, although chlorpromazine presented earlier renoprotective effects in terms of maintaining renal function.

Malignant Transformation in Porokeratosis Ptychotropica: A Systematic Review.

Porokeratosis ptychotropica (PP) is a rare and unusual variant of porokeratosis. There is a dearth of information on the natural history, epidemiology, and optimal treatment options. This study aimed to characterize the worldwide distribution, epidemiology, clinical features, and treatments attempted for all reported cases of porokeratosis ptychotropica. A total of 59 cases of porokeratosis ptychotropica have been reported, with most cases originating from the United States. The median age of patients affected with porokeratosis ptychotropica was 49 years. The most involved body locations are the buttocks and gluteal cleft. The risk of malignant transformation in porokeratosis ptychotropica is approximately 1.7% but there is significant bias in estimating rare occurrences in rare diseases. In conclusion, PP is an important but under-recognized variant of porokeratosis, with a likely low risk of malignant transformation. The best available treatment modality remains uncertain; however, the use of topical lovastatin/cholesterol cream appears promising. Long-term surveillance appears prudent for porokeratosis ptychotropica due to a risk of cancerization.

Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the LOVAMIX randomized clinical trial.

Fragile X syndrome (FXS) is the primary hereditary cause of intellectual disability and autism spectrum disorder. It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease-modifying drugs, lovastatin (40 mg) and minocycline (100 mg), administered alone for 8 weeks and in combination for 12 weeks, in 19 patients (mean age of 23.58 ± 1.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8 weeks of monotherapy (visit 2 of the clinical trial) and after 12 weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20 weeks. This was reflected by a significant increase in the resting-motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short-intracortical inhibition, a marker of GABAa-mediated inhibition after 8 weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at clinicaltrials.gov (NCT02680379).

Efficacy of Food Supplement Based on Monacolins, γ-Oryzanol, and γ-Aminobutyric Acid in Mild Dyslipidemia: A Randomized, Double-Blind, Parallel-Armed, Placebo-Controlled Clinical Trial.

The risk of cardiovascular disease (CVD) is approximately doubled in subjects with hypercholesterolemia compared to those with normal blood cholesterol levels. Monacolin K (MK), the main active substance in rice fermented by the Monascus purpureus, acts on cholesterol metabolism. Rice also contains other bioactive compounds such as γ-oryzanol (OZ) and γ-aminobutyric acid (GABA). In a randomized, placebo-controlled, double-blind trial, the efficacy and tolerability of a food supplement (FS) based on an ingredient standardized to contain monacolins (4.5%), OZ, and GABA were evaluated in subjects with mild dyslipidemia. For the duration of the trial, enrolled subjects (n = 44, each group) received the FS or placebo and were instructed to use an isocaloric diet. Compared to the placebo group, after a 3 months of the FS, the mean low-density lipoprotein cholesterol and mean TC values were reduced by 19.3 and 8.3%, respectively, while the mean high-density lipoprotein cholesterol value increased by 29.3%. On average, the subjects shifted from very high to moderate CVD risk. Glucose metabolism and hepatic and renal parameters did not change after the treatment and no adverse events were reported. Guidelines to handle hypercholesterolemia with food supplements in specific clinical settings are needed to better manage mild dyslipidemia.

Dysregulated Ribosome Biogenesis Is a Targetable Vulnerability in Triple-Negative Breast Cancer: MRPS27 as a Key Mediator of the Stemness-inhibitory Effect of Lovastatin.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited effective therapeutic options readily available. We have previously demonstrated that lovastatin, an FDA-approved lipid-lowering drug, selectively inhibits the stemness properties of TNBC. However, the intracellular targets of lovastatin in TNBC remain largely unknown. Here, we unexpectedly uncovered ribosome biogenesis as the predominant pathway targeted by lovastatin in TNBC. Lovastatin induced the translocation of ribosome biogenesis-related proteins including nucleophosmin (NPM), nucleolar and coiled-body phosphoprotein 1 (NOLC1), and the ribosomal protein RPL3. Lovastatin also suppressed the transcript levels of rRNAs and increased the nuclear protein level and transcriptional activity of p53, a master mediator of nucleolar stress. A prognostic model generated from 10 ribosome biogenesis-related genes showed outstanding performance in predicting the survival of TNBC patients. Mitochondrial ribosomal protein S27 (MRPS27), the top-ranked risky model gene, was highly expressed and correlated with tumor stage and lymph node involvement in TNBC. Mechanistically, MRPS27 knockdown inhibited the stemness properties and the malignant phenotypes of TNBC. Overexpression of MRPS27 attenuated the stemness-inhibitory effect of lovastatin in TNBC cells. Our findings reveal that dysregulated ribosome biogenesis is a targetable vulnerability and targeting MRPS27 could be a novel therapeutic strategy for TNBC patients.

Pathogenesis-directed treatment of linear porokeratosis with topical cholesterol-lovastatin.

A 2-year-old boy presented with an extensive, asymptomatic, photosensitive eruption refractory to topical steroids and tretinoin; examination and biopsies were consistent with generalized linear porokeratosis involving the face, limbs, and trunk. Treatment with topical cholesterol-lovastatin was initiated, and it successfully improved early erythematous lesions. Whole exome sequencing that targeted mevalonate pathway genes crucial in cholesterol synthesis later revealed a pathogenic, paternally inherited, porokeratosis-associated MVD, c.70+5 G>A, mutation. Topical cholesterol-lovastatin is a safe and effective empiric treatment for porokeratosis when used in the early, erythematous phase, and its success is likely mediated through its role in targeting mevalonate pathway mutations.

Efficacy of Topical Cholesterol and Statin Combination Therapy in the Treatment of Porokeratosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Porokeratosis is a group of disorders characterized by aberrant skin keratinization secondary to genetic alterations in the mevalonate pathway, which participates in cholesterol synthesis. While a rare disorder, malignant transformation to squamous cell carcinoma is seen in up to 11% of cases. Recently, topical cholesterol and topical statin therapy have been suggested as a pathogenesis-directed treatment for porokeratosis. METHODS: A PubMed/MEDLINE and Embase literature search was performed using the search terms: "porokeratosis" AND "cholesterol" OR "lovastatin" OR "simvastatin" OR "atorvastatin" OR "fluvastatin" OR "pitavastatin" OR "pravastatin" OR "rosuvastatin" OR "statin." Peer-reviewed clinical trials, case series, and case reports of all porokeratosis subtypes were included. RESULTS: Eleven articles were included in the systematic review and 9 articles in the meta-analysis. The systematic review consisted of an aggregate of 33 patients, most of whom (n=31, 93.9%) applied the treatment twice daily for an average of 9.4 weeks (median=8 weeks), with 93.9% (n=31) experiencing improvement or resolution of porokeratosis. Sixteen patients (48.5%) used lovastatin and 16 (48.5%) used simvastatin with concurrent cholesterol therapy. Mild adverse events including erythema and contact dermatitis were experienced by 12.1% of patients. Our meta-analysis yielded a random effects model supporting a robust reduction in porokeratosis severity (OR = .076, 95% CI [0.022, 0.262]). CONCLUSION: This underpowered meta-analysis provides limited, preliminary evidence supporting the efficacy of topical cholesterol/statin therapy. Overall, quality studies and aggregated sample size are limited; future large clinical trials are needed to further elucidate the role of topical cholesterol/statin therapy in the treatment of porokeratosis. J Drugs Dermatol. 2023;22(12):1160-1165. doi:10.36849/JDD.7775.

Computer-aided, resistance gene-guided genome mining for proteasome and HMG-CoA reductase inhibitors.

Secondary metabolites (SMs) are biologically active small molecules, many of which are medically valuable. Fungal genomes contain vast numbers of SM biosynthetic gene clusters (BGCs) with unknown products, suggesting that huge numbers of valuable SMs remain to be discovered. It is challenging, however, to identify SM BGCs, among the millions present in fungi, that produce useful compounds. One solution is resistance gene-guided genome mining, which takes advantage of the fact that some BGCs contain a gene encoding a resistant version of the protein targeted by the compound produced by the BGC. The bioinformatic signature of such BGCs is that they contain an allele of an essential gene with no SM biosynthetic function, and there is a second allele elsewhere in the genome. We have developed a computer-assisted approach to resistance gene-guided genome mining that allows users to query large databases for BGCs that putatively make compounds that have targets of therapeutic interest. Working with the MycoCosm genome database, we have applied this approach to look for SM BGCs that target the proteasome ß6 subunit, the target of the proteasome inhibitor fellutamide B, or HMG-CoA reductase, the target of cholesterol reducing therapeutics such as lovastatin. Our approach proved effective, finding known fellutamide and lovastatin BGCs as well as fellutamide- and lovastatin-related BGCs with variations in the SM genes that suggest they may produce structural variants of fellutamides and lovastatin. Gratifyingly, we also found BGCs that are not closely related to lovastatin BGCs but putatively produce novel HMG-CoA reductase inhibitors. ONE-SENTENCE SUMMARY: A new computer-assisted approach to resistance gene-directed genome mining is reported along with its use to identify fungal biosynthetic gene clusters that putatively produce proteasome and HMG-CoA reductase inhibitors.

Interplay of Cholesterol and Actin in Neurotransmitter GPCR Signaling: Insights from Chronic Cholesterol Depletion Using Statin.

Serotonin1A receptors are important neurotransmitter receptors in the G protein-coupled receptor (GPCR) family and modulate a variety of neurological, behavioral, and cognitive functions. We recently showed that chronic cholesterol depletion by statins, potent inhibitors of HMG-CoA reductase (the rate-limiting enzyme in cholesterol biosynthesis), leads to polymerization of the actin cytoskeleton that alters lateral diffusion of serotonin1A receptors. However, cellular signaling by the serotonin1A receptor under chronic cholesterol depletion remains unexplored. In this work, we explored signaling by the serotonin1A receptor under statin-treated condition. We show that cAMP signaling by the receptor is reduced upon lovastatin treatment due to reduction in cholesterol as well as polymerization of the actin cytoskeleton. To the best of our knowledge, these results constitute the first report describing the effect of chronic cholesterol depletion on the signaling of a G protein-coupled neuronal receptor. An important message arising from these results is that it is prudent to include the contribution of actin polymerization while analyzing changes in membrane protein function due to chronic cholesterol depletion by statins. Notably, our results show that whereas actin polymerization acts as a negative regulator of cAMP signaling, cholesterol could act as a positive modulator. These results assume significance in view of reports highlighting symptoms of anxiety and depression in humans upon statin administration and the role of serotonin1A receptors in anxiety and depression. Overall, these results reveal a novel role of actin polymerization induced by chronic cholesterol depletion in modulating GPCR signaling, which could act as a potential therapeutic target.

Pitavastatin and Lovastatin Exhibit Calcium Channel Blocking Activity Which Potentiate Vasorelaxant Effects of Amlodipine: A New Futuristic Dimension in Statin's Pleiotropy.

Background and Objectives: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits' intestinal preparations. The current study is focused on the effects of Pitavastatin and Lovastatin for possible inhibition of vascular L-Type calcium channels, which may have vasorelaxant effect(s). Combined effects of Pitavastatin and Lovastatin in the presence of Amlodipine were also tested for vasorelaxation. Materials and Methods: Possible relaxing effects of Pitavastatin and Lovastatin on 80 mM Potassium chloride (KCL)-induced contractions and on 1 µM norepinephrine (N.E)-induced contractions were studied in isolated rabbit's aortic strips preparations. Relaxing effects on 80 mM KCL-induced vascular contractions were further verified by constructing Calcium Concentration Response Curves (CCRCs), in the absence and presence of three different concentrations of Pitavastatin and Lovastatin using CCRCs as negative control. Verapamil was used as a standard drug that has L-Type calcium channel binding activity. In other series of experiments, we studied drug interaction(s) among Pitavastatin, Lovastatin, and amlodipine. Results: The results of this study imply that Lovastatin is more potent than Pitavastatin for having comparatively lower EC50 (7.44 × 10-5 ± 0.16 M) in intact and (4.55 × 10-5 ± 0.10 M) in denuded aortae for KCL-induced contractions. Lovastatin amplitudes in intact and denuded aortae for KCL-induced contractions were, respectively, 24% and 35.5%; whereas amplitudes for Pitavastatin in intact and denuded aortae for KCL-induced contractions were 34% and 40%, respectively. A left shift in the EC50 values for the statins was seen when we added amlodipine in EC50 (Log Ca++ M). Right shift for CCRCs state that Pitavastatin and Lovastatin have calcium channel antagonistic effects. Lovastatin in test concentration (6.74 × 10-7 M) produced a right shift in relatively lower EC50 (-2.5 ± 0.10) Log Ca++ M as compared to Pitavastatin, which further confirms that lovastatin is relatively more potent. The right shift in EC50 resembles the right shift of Verapamil. Additive effect of Pitavastatin and Lovastatin was noted in presence of amlodipine (p < 0.05). Conclusions: KCL (80 mM)-induced vascular contractions were relaxed by Pitavastatin and Lovastatin via inhibitory effects on L-Type voltage-gated calcium channels. Lovastatin and Pitavastatin also relaxed Norepinephrine (1 µM)-induced contractions giving an insight for involvement of dual mode of action of Pitavastatin and Lovastatin.

Pretreatment with Lovastatin Improves Depression-Like Behavior After Traumatic Brain Injury Through Activation of the AMPK Pathway.

BACKGROUND: The beneficial effect of pretreatment with statins on traumatic brain injury (TBI)-induced depression and anxiety and its mechanism of action remain unclear. In this study, we combined epidemiological and experimental animal data to clarify this issue. METHODS: We used the Taiwan National Health Insurance database to identify patients who were diagnosed with TBI from 2000 to 2013 and compared patients with and without statin treatment matched by age, sex, and underlying comorbidities in a 1:1 ratio. The risk of developing depression and/or anxiety was compared between patients with and without a statin using Cox proportional hazards regression. We also used a rat model to assess the effect of lovastatin pretreatment on neurobehavioral and neuropathological changes following TBI. RESULTS: The risk of developing depression was lower in the 41,803 patients in the statin cohort than nonstatin cohort (adjusted hazard ratio, 0.91 [95% confidence interval, 0.83-0.99]). In animal models, the lovastatin group had significantly reduced infarct volume, decreased immobility time and latency to eat, a reduced number of Fluoro- Jade-positive cells and levels of glial fibrillary acidic protein and tumor necrosis factor-alpha, and increased adenosine monophosphate -activated protein kinase (AMPK) and its upstream kinase liver kinase B1 in the hippocampal dentate gyrus. These effects were blocked in AMPK inhibitor-pretreated TBI rats. CONCLUSIONS: Our epidemiological data showed that a decreased risk of depression was associated with statin pretreatment, which was supported by an animal study. The underlying mechanism for this appears to involve AMPK activation in the statin pretreatment-induced alleviation of TBI.

Evaluating The Protective Effects Of Lovastatin Against Doxorubicin Induced Cardiotoxicity In Balb-C Mice.

BACKGROUND: Doxorubicin is one of the most commonly used anti-cancer drugs that treat a large number of haematological and solid malignancies. Its usage in dose and duration is nevertheless restricted by dose related organ damage, particularly cardiotoxicity. Lovastatin is a commonly prescribed drug for hypercholesterolemia and possesses remarkable antioxidant potential. Our study was aimed at evaluating and comparing its cardioprotective effect in two pre-treatment schedules against doxorubicin-induced cardiac damage. METHODS: In this lab-based randomized controlled experiment, 40 BALB/c mice were randomly grouped into five groups (n=8). Group 1 served as control whereas Group 2 was given doxorubicin intraperitoneally at a dose of 10mg/kg. Group 3 received 10mg/kg of oral lovastatin for five days. Groups 4 and 5 were administered lovastatin for five and ten consecutive days correspondingly and doxorubicin was given on 3rd and 8th experimental days of these groups. RESULTS: Doxorubicin caused a significant rise in cardiac enzymes; Creatine kinase MB (CK-MB) and Lactate Dehydrogenase (LDH) (p value ≤0.0001) whereas cardiac histological alterations were ranked as moderate. The damage was significantly attenuated by lovastatin in the ten-day study design with a p-value of ≤0.001 for both LDH and CK-MB whereas a slightly less efficient restoration was observed in the five-day design with a p value of ≤0.001 for LDH and 0.012 for CK-MB. Histological preservation in both pre-treatment schedules was in accordance with the biological markers. CONCLUSIONS: In doxorubicin-based regimens, pretreatment for at least seven days with an easily available and safe statin can effectively prevent its potentially life threatening cardiotoxicity.

Immuno-PET Detects Antibody-Drug Potency on Coadministration with Statins.

The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. Methods: In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the 89Zr-labeled or 64Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. Results: T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Conclusion: Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.

Improvement of synaptic plasticity and cognitive function in RASopathies-a monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (SynCoRAS).

BACKGROUND: Cognitive impairment is a common medical issue in rat sarcoma (RAS) pathway disorders, so-called RASopathies, like Neurofibromatosis type 1 (NF1) or Noonan syndrome (NS). It is presumed to be caused by impaired synaptic plasticity. In animal studies, pathway-specific pharmacological interventions with lovastatin (LOV) and lamotrigine (LTG) have been shown to improve synaptic plasticity as well as cognitive function. The aim of this clinical trial is to translate the findings of animal studies to humans and to probe the effect of lovastatin (NS) and lamotrigine (NS and NF1) on synaptic plasticity and cognitive function/alertness in RASopathies. METHODS: Within this phase IIa, monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (syn. SynCoRAS), three approaches (approaches I-III) will be carried out. In patients with NS, the effect of LTG (approach I) and of LOV (approach II) is investigated on synaptic plasticity and alertness. LTG is tested in patients with NF1 (approach III). Trial participants receive a single dose of 300 mg LTG or placebo (I and III) and 200 mg LOV or placebo (II) daily for 4 days with a cross-over after at least 7 days. Synaptic plasticity is investigated using a repetitive high-frequency transcranial magnetic stimulation (TMS) protocol called quadri-pulse theta burst stimulation (qTBS). Attention is examined by using the test of attentional performance (TAP). Twenty-eight patients are randomized in groups NS and NF1 with n = 24 intended to reach the primary endpoint (change in synaptic plasticity). Secondary endpoints are attention (TAP) and differences in short interval cortical inhibition (SICI) between placebo and trial medication (LTG and LOV). DISCUSSION: The study is targeting impairments in synaptic plasticity and cognitive impairment, one of the main health problems of patients with RASopathies. Recent first results with LOV in patients with NF1 have shown an improvement in synaptic plasticity and cognition. Within this clinical trial, it is investigated if these findings can be transferred to patients with NS. LTG is most likely a more effective and promising substance improving synaptic plasticity and, consecutively, cognitive function. It is expected that both substances are improving synaptic plasticity as well as alertness. Changes in alertness may be a precondition for improvement of cognition. TRIAL REGISTRATION: The clinical trial is registered in ClinicalTrials.gov (NCT03504501; https://www. CLINICALTRIALS: gov ; date of registration: 04/11/2018) and in EudraCT (number 2016-005022-10).

Red Yeast Rice for the Improvement of Lipid Profiles in Mild-to-Moderate Hypercholesterolemia: A Narrative Review.

Reducing low-density lipoprotein cholesterol (LDL-C) levels is a key target for lowering cardiovascular risk and preventing atherosclerotic cardiovascular disease (ASCVD). Red yeast rice (RYR) is a nutraceutical widely used as a lipid-lowering dietary supplement. The main cholesterol-lowering components of RYR are monacolins, particularly monacolin K, which is structurally identical to lovastatin and targets the same key enzyme of cholesterol biosynthesis. RYR supplementation reduces LDL-C levels by approximately 15-34% versus placebo, with a similar effect to low-dose, first-generation statins in subjects with mild-to-moderate dyslipidemia. RYR has also demonstrated beneficial reductions of up to 45% versus placebo in the risk of ASCVD events in secondary prevention studies. RYR at a dose that provides about 3 mg/d of monacolin K is well tolerated, with an adverse event profile similar to that of low-dose statins. RYR is therefore a treatment option for lowering LDL-C levels and ASCVD risk for people with mild-to-moderate hypercholesterolemia who are ineligible for statin therapy, particularly those who are unable to implement lifestyle modifications, and also for people who are eligible for statin therapy but who are unwilling to take a pharmacologic therapy.

Long-term outcomes of statin dose, class, and use intensity on primary prevention of cardiovascular mortality: a national T2DM cohort study.

PURPOSE: To investigate how statins reduce cardiovascular mortality in patients with type 2 diabetes (T2DM) in a dose-, class-, and use intensity-dependent manner. METHODS: We used an inverse probability of treatment-weighted Cox hazards model, with statin use status as a time-dependent variable, to estimate the effects of statin use on cardiovascular mortality. RESULTS: Adjusted hazard ratio [aHR; 95% confidence interval (CI)] for cardiovascular mortality was 0.41 (0.39-0.42). Compared with nonusers, pitavastatin, pravastatin, simvastatin, rosuvastatin, atorvastatin, fluvastatin, and lovastatin users demonstrated significant reductions in cardiovascular mortality [aHRs (95% CIs) = 0.11 (0.06, 0.22), 0.35 (0.32, 0.39), 0.36 (0.34, 0.38), 0.39 (0.36, 0.41), 0.42 (0.40, 0.44), 0.46 (0.43, 0.49), and 0.52 (0.48, 0.56), respectively]. In Q1, Q2, Q3, and Q4 of cDDD-year, our multivariate analysis demonstrated significant reductions in cardiovascular mortality [aHRs (95% CIs) = 0.63 (0.6, 0.65), 0.44 (0.42, 0.46), 0.33 (0.31, 0.35), and 0.17 (0.16, 0.19), respectively; P for trend < 0.0001]. The optimal statin dose daily was 0.86 DDD, with the lowest aHR for cardiovascular mortality of 0.43. CONCLUSIONS: Persistent statin use can reduce cardiovascular mortality in patients with T2DM; in particular, the higher is the cDDD-year of statin, the lower is the cardiovascular mortality. The optimal statin dose daily was 0.86 DDD. The priority of protective effects on mortality are pitavastatin, rosuvastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, and lovastatin for the statin users compared with non-statin users.

Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [177Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [177Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [177Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [177Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.

Research Progress on Gene Synthesis and Anticancer and Lipid-lowering Mechanism of Monacolin K.

Monacolin K (MK), also known as lovastatin (LOV), is a secondary metabolite synthesized by Monascus in the later stage of fermentation and is the main component of functional red yeast rice (RYR). The structure of MK is similar to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), and it can competitively bind to 3-hydroxy-3- methylglutaryl coenzyme A reductase (HMGCR), thus reducing the level of blood lipids. MK can affect the expression of MAPK, PI3K/AKT, and NF-κB pathway, prepare conjugates with other compounds, and enhance the sensitivity of cancer cells to chemotherapeutic drugs so as to induce apoptosis of acute myeloid leukemia, prostate cancer, breast cancer, lung cancer, gastric cancer, and liver cancer. Combined with the synthetic route of MK, this paper summarizes the latest lipid-lowering and anticancer mechanism of MK, and provides a reference for the application of MK in medicine.

Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models.

BACKGROUND: Anti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with superior survival in several cancer types, including HNSCC. Emerging data suggest that manipulation of cholesterol may enhance some aspects of antitumor immunity. METHODS: We used syngeneic murine models (mouse oral cancer, MOC1 and TC-1) to investigate our hypothesis that a subset of statin drugs would enhance antitumor immunity and delay tumor growth. RESULTS: Using an ex vivo coculture assay of murine cancer cells and tumor infiltrating lymphocytes, we discovered that all seven statin drugs inhibited tumor cell proliferation. Simvastatin and lovastatin also enhanced T-cell killing of tumor cells. In mice, daily oral simvastatin or lovastatin enhanced tumor control and extended survival when combined with PD-1 blockade, with rejection of MOC1 tumors in 30% of mice treated with lovastatin plus anti-PD-1. Results from flow cytometry of tumors and tumor-draining lymph nodes suggested T cell activation and shifts from M2 to M1 macrophage predominance as potential mechanisms of combination therapy. CONCLUSIONS: These results suggest that statins deserve further study as well-tolerated, inexpensive drugs that may enhance responses to PD-1 checkpoint blockade and other immunotherapies for HNSCC.

Bioconversion of lovastatin to simvastatin by Streptomyces carpaticus toward the inhibition of HMG-CoA activity.

The aim of this study was the modification of lovastatin by microbes to improve its potential. Actinobacteria exhibit staggering diversity in terms of their biosynthetic capability for specialized metabolites which has been traced back to the presence of specialized gene clusters. The objective of the study is to exploit the potential of Actinobacteria strain(s), which can biotransform lovastatin to simvastatin, which might be a more potent therapeutic agent than lovastatin. We have screened 40 Actinobacteria strains and assessed their biotransformation potential primarily through thin layer chromatography (TLC) analysis, followed by high performance thin layer chromatography and high performance liquid chromatography analysis. One strain C7 (CTL S12) has been identified as a potential Actinobacteria that favored the simvastatin biotransformation. The morphological and biochemical analysis together with 16S rRNA sequencing coupled with phylogenetic analysis confirmed the ideal strain (C7) as Streptomyces carpaticus. Successively, the purified simvastatin from S. carpaticus was characterized by liquid chromatography-mass spectrometry (LC-MS), infrared spectrometry, nuclear magnetic resonance, and HMG-CoA assay. In the LC-MS analysis, a peak at 419.24 m/z confirmed the elemental composition of simvastatin (C25 H39 O5 ). In HMG-CoA assay, the IC50 of simvastatin was 50 µg/ml, and the inhibitory potential was 1.36 times higher compared to that of lovastatin. Thus, the biotransformation of simvastatin from lovastatin by S. carpaticus is reported for the first time.